i

Schottenfeld and Fraumeni

Cancer Epidemiology and Prevention
ii
 iii

Schottenfeld and Fraumeni

Cancer Epidemiology and
Prevention
Fourth Edition

Lead Editor CHRISTOPHER HAIMAN, SCD

Department of Preventive Medicine
MICHAEL J. THUN, MD, MS Keck School of Medicine, University
Epidemiology and Surveillance Research (Retired) of Southern California
American Cancer Society Los Angeles, California
Atlanta, Georgia

Co-​Editors DAVID SCHOTTENFELD, MD, MSC

Department of Epidemiology (Retired)
MARTHA S. LINET, MD, MPH University of Michigan School of Public Health
Division of Cancer Epidemiology and Genetics Ann Arbor, Michigan
National Cancer Institute
Bethesda, Maryland Project Manager

ANNELIE M. LANDGREN, MPH, PMP

JAMES R. CERHAN, MD, PHD
Department of Health Sciences Research
Mayo Clinic
Rochester, Minnesota

1
iv

1
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the University’s objective of excellence in research, scholarship, and education
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Press in the UK and certain other countries.

Published in the United States of America by Oxford University Press

198 Madison Avenue, New York, NY 10016, United States of America.

© Oxford University Press 2018

Third Edition published 2006

Second edition published 1996
First edition published 1982

All rights reserved. No part of this publication may be reproduced, stored in

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Library of Congress Cataloging-in-Publication Data

Names: Thun, Michael J., editor. | Linet, Martha S., editor. |
Cerhan, James R., editor. | Haiman, Christopher, editor. | Schottenfeld, David, editor.
Title: Schottenfeld and Fraumeni Cancer Epidemiology and Prevention / lead editor,
Michael J. Thun ; co-editors, Martha S. Linet, James R. Cerhan,
Christopher Haiman, David Schottenfeld ; project manager, Annelie M. Landgren.
Other titles: Cancer epidemiology and prevention
Description: Fourth edition. | New York, NY : Oxford University Press, [2018] |
Preceded by Cancer epidemiology and prevention / edited by David Schottenfeld,
Joseph F. Fraumeni Jr. 3rd ed. 2006. | Includes bibliographical references and index.
Identifiers: LCCN 2017038170 | ISBN 9780190238667 (hardcover : alk. paper)
Subjects: | MESH: Neoplasms—epidemiology | Neoplasms—prevention & control
Classification: LCC RA645.C3 | NLM QZ 220.1 |
DDC 614.5/999—dc23
LC record available at https://lccn.loc.gov/2017038170

9 8 7 6 5 4 3 2 1
Printed by Sheridan Books, Inc., United States of America
 v

Contents

Acknowledgments  ix
Contributors  xi
Preface  xix

1. Introduction  1
Michael J. Thun, Martha S. Linet, James R. Cerhan, Christopher A. Haiman,
and David Schottenfeld

I  BASIC CONCEPTS
2. Biology of Neoplasia  9
Michael Dean and Karobi Moitra
3. Morphological and Molecular Classification of Human Cancer  19
Mark E. Sherman, Melissa A. Troester, Katherine A. Hoadley,
and William F. Anderson
4. Genomic Landscape of Cancer: Insights for Epidemiologists  43
Christopher J. Maher and Elaine R. Mardis
5. Genetic Epidemiology of Cancer  53
Kathryn L. Penney, Kyriaki Michailidou, Deanna Alexis Carere, Chenan Zhang,
Brandon Pierce, Sara Lindström, and Peter Kraft
6. Application of Biomarkers in Cancer Epidemiology  77
Roel Vermeulen, Douglas A. Bell, Dean P. Jones, Montserrat Garcia-​Closas,
Avrum Spira, Teresa W. Wang, Martyn T. Smith, Qing Lan, and Nathaniel Rothman
7. Causal Inference in Cancer Epidemiology  97
Steven N. Goodman and Jonathan M. Samet

II  THE MAGNITUDE OF CANCER

8. Patterns of Cancer Incidence, Mortality, and Survival  107
Ahmedin Jemal, D. Maxwell Parkin, and Freddie Bray
9. Socioeconomic Disparities in Cancer Incidence and Mortality  141
Candyce Kroenke and Ichiro Kawachi
10. The Economic Burden of Cancer in the United States  169
K. Robin Yabroff, Gery P. Guy Jr., Matthew P. Banegas, and Donatus U. Ekwueme
vi

vi Contents

III  THE CAUSES OF CANCER

11. Tobacco  185
Michael J. Thun and Neal D. Freedman
12. Alcohol and Cancer Risk  213
Susan M. Gapstur and Philip John Brooks
13. Ionizing Radiation  227
Amy Berrington de González, André Bouville, Preetha Rajaraman,
and Mary Schubauer-​Berigan
14. Ultraviolet Radiation  249
Adèle C. Green and David C. Whiteman
15. Electromagnetic Fields  259
Maria Feychting and Joachim Schüz
16. Occupational Cancer  275
Kyle Steenland, Shelia Hoar Zahm, and A. Blair
17. Air Pollution  291
Jonathan M. Samet and Aaron J. Cohen
18. Water Contaminants  305
Kenneth P. Cantor, Craig M. Steinmaus, Mary H. Ward,
and Laura E. Beane Freeman
19. Diet and Nutrition  329
Marjorie L. McCullough and Walter C. Willett
20. Obesity and Body Composition  351
NaNa Keum, Mingyang Song, Edward L. Giovannucci, and A. Heather Eliassen
21. Physical Activity, Sedentary Behaviors, and Risk of Cancer  377
Steven C. Moore, Charles E. Matthews, Sarah Keadle, Alpa V. Patel,
and I-​Min Lee
22. Hormones and Cancer  395
Robert N. Hoover, Amanda Black, and Rebecca Troisi
23. Pharmaceutical Drugs Other Than Hormones  411
Marie C. Bradley, Michael A. O’Rorke, Janine A. Cooper, Søren Friis,
and Laurel A. Habel
24. Infectious Agents  433
Silvia Franceschi, Hashem B. El-​Serag, David Forman, Robert Newton,
and Martyn Plummer
25. Immunologic Factors  461
Eric A. Engels and Allan Hildesheim

IV  CANCERS BY TISSUE OF ORIGIN

26. Nasopharyngeal Cancer  489
Ellen T. Chang and Allan Hildesheim
27. Cancer of the Larynx  505
Andrew F. Olshan and Mia Hashibe
28. Lung Cancer  519
Michael J. Thun, S. Jane Henley, and William D. Travis
29. Oral Cavity, Oropharynx, Lip, and Salivary Glands  543
Mia Hashibe, Erich M. Sturgis, Jacques Ferlay, and Deborah M. Winn
30. Esophageal Cancer  579
William J. Blot and Robert E. Tarone
 vi

Contents vii
31. Stomach Cancer  593
Catherine de Martel and Julie Parsonnet
32. Cancer of the Pancreas  611
Samuel O. Antwi, Rick J. Jansen, and Gloria M. Petersen
33. Liver Cancer  635
W. Thomas London, Jessica L. Petrick, and Katherine A. McGlynn
34. Biliary Tract Cancer  661
Jill Koshiol, Catterina Ferreccio, Susan S. Devesa, Juan Carlos Roa,
and Joseph F. Fraumeni, Jr.
35. Small Intestine Cancer  671
Jennifer L. Beebe-​Dimmer, Fawn D. Vigneau, and David Schottenfeld
36. Cancers of the Colon and Rectum  681
Kana Wu, NaNa Keum, Reiko Nishihara, and Edward L.Giovannucci
37. Anal Cancer  707
Andrew E. Grulich, Fengyi Jin, and I. Mary Poynten
38. Leukemias  715
Martha S. Linet, Lindsay M. Morton, Susan S. Devesa, and Graça M. Dores
39. Hodgkin Lymphoma  745
Henrik Hjalgrim, Ellen T. Chang, and Sally L. Glaser
40. The Non-​Hodgkin Lymphomas  767
James R. Cerhan, Claire M. Vajdic, and John J. Spinelli
41. Multiple Myeloma  797
Mark P. Purdue, Jonathan N. Hofmann, Elizabeth E. Brown, and Celine M. Vachon
42. Bone Cancers  815
Lisa Mirabello, Rochelle E. Curtis, and Sharon A. Savage
43. Soft Tissue Sarcoma  829
Marianne Berwick and Charles Wiggins
44. Thyroid Cancer  839
Cari M. Kitahara, Arthur B. Schneider, and Alina V. Brenner
45. Breast Cancer  861
Louise A. Brinton, Mia M. Gaudet, and Gretchen L. Gierach
46. Ovarian Cancer  889
Shelley S. Tworoger, Amy L. Shafrir, and Susan E. Hankinson
47. Endometrial Cancer  909
Linda S. Cook, Angela L. W. Meisner, and Noel S. Weiss
48. Cervical Cancer  925
Rolando Herrero and Raul Murillo
49. Vulvar and Vaginal Cancers  947
Margaret M. Madeleine and Lisa G. Johnson
50. Choriocarcinoma  953
Julie R. Palmer
51. Renal Cancer  961
Wong-​Ho Chow, Ghislaine Scelo, and Robert E. Tarone
52. Bladder Cancer  977
Debra T. Silverman, Stella Koutros, Jonine D. Figueroa, Ludmila Prokunina-​Olsson,
and Nathaniel Rothman
53. Prostate Cancer  997
Catherine M. Tangen, Marian L. Neuhouser, and Janet L. Stanford
vi

viii Contents
54. Testicular Cancer  1019
Katherine A. McGlynn, Ewa Rajpert-​De Meyts, and Andreas Stang
55. Penile Cancer  1029
Morten Frisch
56. Nervous System  1039
E. Susan Amirian, Quinn T. Ostrom, Yanhong Liu, Jill Barnholtz-​Sloan,
and Melissa L. Bondy
57. Melanoma  1061
Bruce K. Armstrong, Claire M. Vajdic, and Anne E. Cust
58. Keratinocyte Cancers  1089
Anala Gossai, Dorothea T. Barton, Judy R. Rees, Heather H. Nelson,
and Margaret R. Karagas
59. Childhood Cancers  1119
Eve Roman, Tracy Lightfoot, Susan Picton, and Sally Kinsey
60. Multiple Primary Cancers  1155
Lindsay M. Morton, Sharon A. Savage, and Smita Bhatia

V  CANCER PREVENTION AND CONTROL

61. Framework for Understanding Cancer Prevention  1193
Michael J. Thun, Christopher P. Wild, and Graham Colditz
62. Primary Prevention of Cancer  1205
62.1. Tobacco Control  1207
Jeffrey Drope, Clifford E. Douglas, and Brian D. Carter
62.2. Prevention of Obesity and Physical Inactivity  1211
Ambika Satija and Frank B. Hu
62.3. Prevention of Infection-​Related Cancers  1217
Marc Bulterys, Julia Brotherton, and Ding-​Shinn Chen
62.4. Protection from Ultraviolet Radiation  1221
Robyn M. Lucas, Rachel E. Neale, Peter Gies, and Terry Slevin
62.5. Preventive Therapy  1229
Jack Cuzick
62.6. Regulation  1239
Jonathan M. Samet and Lynn Goldman
63. Cancer Screening  1255
Jennifer M. Croswell, Russell P. Harris, and Barnett S. Kramer

Index 1271
 ix

Acknowledgments

We are indebted to the more than 190 chapter authors who generously contributed their time,
labor, and expertise to produce this comprehensively updated fourth edition. The multi-​authored
text reflects the increasingly interdisciplinary and collaborative nature of the field; it provides a
resource for researchers seeking to harness the unprecedented advances in genetic and molecu-
lar research into large-​scale population studies of cancer etiology, and ultimately into effective
preventive interventions. We owe special thanks to Ms. Annelie Landgren, whose energy, enthu-
siasm, and organizational expertise as project manager have been invaluable in bringing this
text to completion. We also thank Dr. Stephen Chanock for his early and unfailing encourage-
ment and for supporting the critical infrastructure necessary for such a collaborative enterprise.
This book would not have been possible without the generous forbearance of our spouses and
families. Finally, Michael Thun thanks Dr. Lynne Moody for her insights as a sounding board
throughout this process.

ix
x
 xi

Contributors

E. Susan Amirian, PhD Jennifer L. Beebe-​Dimmer, PhD, MPH

Dan L Duncan Cancer Center Wayne State University School of Medicine
Baylor College of Medicine Karmanos Cancer Institute
Houston, Texas Detroit, Michigan
William F. Anderson, MD, MPH Douglas A. Bell, PhD
Division of Cancer Epidemiology and Genetics Environmental Epigenomics, Immunity, Inflammation and
National Cancer Institute Disease Laboratory
Bethesda, Maryland National Institute of Environmental Health Sciences
Research Triangle Park, North Carolina
Samuel O. Antwi, PhD
Department of Health Sciences Research Amy Berrington de González, DPhil
Mayo Clinic College of Medicine Division of Cancer Epidemiology and Genetics
Rochester, Minnesota National Cancer Institute
Bethesda, Maryland
Bruce K. Armstrong, MD, PhD*
School of Public Health Marianne Berwick, PhD
The University of Sydney Department of Internal Medicine
Sydney, New South Wales, Australia University of New Mexico
Albuquerque, New Mexico
Matthew P. Banegas, PhD, MPH
Center for Health Research Smita Bhatia, MD, MPH
Kaiser Permanente Institute of Cancer Outcomes and Survivorship
Portland, Oregon University of Alabama at Birmingham, School of Medicine
Birmingham, Alabama
Jill Barnholtz-​Sloan, PhD
Case Comprehensive Cancer Center Amanda Black, PhD, MPH
Case Western Reserve University School of Medicine Division of Cancer Epidemiology and Genetics
Cleveland, Ohio National Cancer Institute
Bethesda, Maryland
Dorothea T. Barton, MD
Department of Surgery A. Blair, PhD
Dartmouth-​Hitchcock Medical Center Division of Cancer Epidemiology and Genetics
Lebanon, New Hampshire National Cancer Institute
Bethesda, Maryland
Laura E. Beane Freeman, PhD
Division of Cancer Epidemiology and Genetics William J. Blot, PhD
National Cancer Institute Vanderbilt-​Ingram Cancer Center
Bethesda, Maryland Nashville, Tennessee

* Retired

xi
xi

xii Contributors
Melissa L. Bondy, PhD James R. Cerhan, MD, PhD, (Editor)
Department of Medicine, Section of Epidemiology and Population Sciences Department of Health Sciences Research
Baylor College of Medicine Mayo Clinic
Houston, Texas Rochester, Minnesota
AndrÉ Bouville, PhD* Ellen T. Chang, ScD
Division of Cancer Epidemiology and Genetics Center for Health Sciences Exponent Inc.
National Cancer Institute Menlo Park, California
Bethesda, Maryland
Ding-​Shinn Chen, MD
Marie C. Bradley, PhD, MScPH Hepatitis Research Center
Division of Cancer Control and Population Sciences National Taiwan University Hospital
National Cancer Institute Taipei, Taiwan
Bethesda, Maryland
Wong-​Ho Chow, PhD
Freddie Bray, PhD Department of Epidemiology
Section of Cancer Surveillance The University of Texas
International Agency for Research on Cancer MD Anderson Cancer Center
Lyon, France Houston, Texas
Alina V. Brenner, MD, PhD Aaron J. Cohen, MPH, DSc‡
Division of Cancer Epidemiology and Genetics Health Effects Institute
National Cancer Institute Boston, Massachusetts
Bethesda, Maryland
Graham Colditz, MD, DrPH
Louise A. Brinton, PhD Division of Public Health Services
Division of Cancer Epidemiology and Genetics Washington University
National Cancer Institute St. Louis, Missouri
Bethesda, Maryland
Linda S. Cook, PhD
Philip John Brooks, PhD Department of Internal Medicine
Laboratory of Neurogenetics University of New Mexico
National Institute on Alcohol Abuse and Alcoholism, NIH Albuquerque, New Mexico
Bethesda, Maryland
Janine A. Cooper, PhD
Julia Brotherton, MD, PhD School of Pharmacy
National HPV Vaccination Program Register Queen’s University Belfast
Victorian Cytology Service Belfast, Northern Ireland
East Melbourne, Victoria, Australia
Jennifer M. Croswell, MD, MPH
Elizabeth E. Brown, PhD, MPH Patient-​Centered Outcomes Research Institute
Department of Pathology Washington, DC
University of Alabama at Birmingham
Rochelle E. Curtis, MA
Birmingham, Alabama
Division of Cancer Epidemiology and Genetics
Marc Bulterys, MD, PhD National Cancer Institute
HIV/​Hepatitis Department Bethesda, Maryland
World Health Organization
Anne E. Cust, PhD
Geneva, Switzerland
School of Public Health and Melanoma Institute Australia
Kenneth P. Cantor, PhD, MPH* The University of Sydney
Division of Cancer Epidemiology and Genetics Sydney, New South Wales, Australia
National Cancer Institute
Jack Cuzick, PhD
Bethesda, Maryland
Wolfson Institute of Preventive Medicine
Deanna Alexis Carere, ScD, CGC Queen Mary University of London
Department of Pathology and Molecular Medicine London, United Kingdom
McMaster University
Catherine de Martel, MD, PhD
Hamilton, Ontario, Canada
Infections and Cancer Epidemiology Group
Brian D. Carter, MPH International Agency for Research on Cancer
Epidemiology Research Program Lyon, France
American Cancer Society
Atlanta, Georgia

* Retired
‡
Consultant/​Contractor
 xi

Contributors xiii
Michael Dean, PhD David Forman, PhD
Division of Cancer Epidemiology and Genetics International Agency for Research on Cancer
National Cancer Institute Lyon, France
Bethesda, Maryland
Silvia Franceschi, MD
Susan S. Devesa, PhD* International Agency for Research on Cancer
Division of Cancer Epidemiology and Genetics Lyon, France
National Cancer Institute
Joseph F. Fraumeni, Jr., MD
Bethesda, Maryland
Division of Cancer Epidemiology and Genetics
Graça M. Dores, MD§ National Cancer Institute
Division of Cancer Epidemiology and Genetics Bethesda, Maryland
National Cancer Institute
Neal D. Freedman, PhD
Bethesda, Maryland
Division of Cancer Epidemiology and Genetics
Clifford E. Douglas, JD National Cancer Institute
Center for Tobacco Control Bethesda, Maryland
American Cancer Society
Søren Friis, MD
Atlanta, Georgia
Statistics and Pharmacoepidemiology
Jeffrey Drope, PhD Danish Cancer Society Research Center
Economic & Health Policy Research Copenhagen, Denmark
American Cancer Society
Morten Frisch, MD, PhD, DrSci(Med)
Atlanta, Georgia
Department of Epidemiology Research
Donatus U. Ekwueme, PhD, MS Statens Serum Institut
National Center for Chronic Disease Prevention and Health Promotion Copenhagen, Denmark
Centers for Disease Control and Prevention
Susan M. Gapstur, PhD, MPH
Atlanta, Georgia
Epidemiology Research Program
A. Heather Eliassen, ScD American Cancer Society
Brigham & Women’s Hospital and Harvard Medical School Atlanta, Georgia
Harvard TH Chan School of Public Health
Montserrat Garcia-​Closas, MD, DrPH
Boston, Massachusetts
Division of Cancer Epidemiology and Genetics
Hashem B. El-​Serag, MD, MPH National Cancer Institute
Gastroenterology and Hepatology Bethesda, Maryland
Baylor College of Medicine
Mia M. Gaudet, PhD
Houston, Texas
Epidemiology Research Program
Eric A. Engels, MD American Cancer Society
Division of Cancer Epidemiology and Genetics Atlanta, Georgia
National Cancer Institute
Gretchen L. Gierach, PhD
Bethesda, Maryland
Division of Cancer Epidemiology and Genetics
Jacques Ferlay, MSc National Cancer Institute
Section of Cancer Surveillance Bethesda, Maryland
International Agency for Research on Cancer
Peter Gies, PhD
Lyon, France
Australian Radiation Protection and Nuclear Safety Agency
Catterina Ferreccio, MD, MPH Melbourne, Victoria, Australia
Division of Public Health and Family Medicine
Edward L. Giovannucci, MD, ScD
School of Medicine, Pontificia Universidad Católica de Chile
Departments of Nutrition and Epidemiology
Santiago, Chile
Harvard TH Chan School of Public Health
Maria Feychting, PhD Boston, Massachusetts
Institute of Environmental Medicine
Sally L. Glaser, PhD
Karolinska Institutet
Cancer Prevention Institute of California
Stockholm, Sweden
Fremont, California
Jonine D. Figueroa, PhD
Lynn Goldman, MD, MS, MPH
Usher Institute of Population Health Sciences and Informatics,
Milken Institute School of Public Health
CRUK Edinburgh Centre
George Washington University
University of Edinburgh
Washington, DC
Edinburg, United Kingdom

* Retired
§
Adjunct
vxi

xiv Contributors
Steven N. Goodman, MD, PhD Henrik Hjalgrim, MD, PhD, DrSci(med)
Department of Medicine, Clinical and Translational Research Department of Epidemiology Research
Stanford University School of Medicine Statens Serum Institut
Stanford, California Copenhagen, Denmark
Anala Gossai, MPH, PhD Katherine A. Hoadley, PhD
Geisel School of Medicine Department of Genetics, Lineberger Comprehensive Cancer Center
Dartmouth College University of North Carolina at Chapel Hill
Hanover, New Hampshire Chapel Hill, North Carolina
Adèle C. Green, MD, PhD Jonathan N. Hofmann, PhD
Population Health Division Division of Cancer Epidemiology and Genetics
QIMR Berghofer Medical Research Institute National Cancer Institute
Brisbane, Queensland, Australia Bethesda, Maryland
Andrew E. Grulich, PhD Robert N. Hoover, MD, ScD
Kirby Institute Division of Cancer Epidemiology and Genetics
The University of New South Wales National Cancer Institute
Sydney, New South Wales, Australia Bethesda, Maryland
Gery P. Guy Jr, PhD, MPH Frank B. Hu, MD, PhD
National Center for Chronic Disease Prevention and Health Departments of Nutrition and Epidemiology
Promotion Harvard TH Chan School of Public Health
Centers for Disease Control and Prevention Boston, Massachusetts
Atlanta, Georgia
Rick J. Jansen, MS, PhD
Laurel A. Habel, PhD, MPH Department of Public Health
Division of Research North Dakota State University
Kaiser Permanente Northern California Fargo, North Dakota
Oakland, California
Ahmedin Jemal, DVM, PhD
Christopher A. Haiman, ScD, (Editor) Surveillance and Health Services Research Program
Department of Preventive Medicine American Cancer Society
Keck School of Medicine of University of Southern California Atlanta, Georgia
Los Angeles, California
Fengyi Jin, PhD
Susan E. Hankinson, ScD Kirby Institute
Department of Biostatistics and Epidemiology The University of New South Wales
University of Massachusetts Sydney, New South Wales, Australia
Amherst, Massachusetts
Lisa G. Johnson, PhD, MPH
Russell P. Harris, MD, MPH§ Division of Public Health Sciences
Lineberger Comprehensive Cancer Center Fred Hutchinson Cancer Research Center
University of North Carolina School of Medicine Seattle, Washington
Chapel Hill, North Carolina
Dean P. Jones, PhD
Mia Hashibe, PhD Department of Medicine
Department of Family and Preventive Medicine Emory University
Huntsman Cancer Institute, University of Utah School of Medicine Atlanta, Georgia
Salt Lake City, Utah
Margaret R. Karagas, PhD
S. Jane Henley, MSPH Department of Epidemiology
Division of Cancer Prevention and Control Geisel School of Medicine at Dartmouth
US Centers for Disease Control and Prevention Hanover, New Hampshire
Atlanta, Georgia
Ichiro Kawachi, MD, PhD
Rolando Herrero, MD, PhD Department of Social and Behavioral Sciences
Prevention and Implementation Group Harvard School of Public Health
International Agency for Research on Cancer Boston, Massachusetts
Lyon, France
Sarah Keadle, PhD, MPH
Allan Hildesheim, PhD Kinesiology Department
Division of Cancer Epidemiology and Genetics California Polytechnic State University
National Cancer Institute San Luis Obispo, California
Bethesda, Maryland

§
adjunct
 xv

Contributors xv
NaNa Keum, ScD Yanhong Liu, PhD
Department of Nutrition Department of Medicine, Section of Epidemiology
Harvard TH Chan School of Public Health and Population Sciences
Boston, Massachusetts Baylor College of Medicine
Houston, Texas
Sally Kinsey, MD, FRCP
Department of Pediatric Hematology W. Thomas London, MD*
Leeds Teaching Hospitals NHS Trust Fox Chase Cancer Center
Leeds, United Kingdom Philadelphia, Pennsylvania
Cari M. Kitahara, PhD Robyn M. Lucas, MBChB, MPH&TM, PhD
Division of Cancer Epidemiology and Genetics Radiation Health Services Branch
National Cancer Institute The Australian National University
Bethesda, Maryland Canberra, The Australian Capital Territory, Australia
Jill Koshiol, PhD Margaret M. Madeleine, PhD
Division of Cancer Epidemiology and Genetics Division of Public Health Sciences
National Cancer Institute Fred Hutchinson Cancer Research Center
Bethesda, Maryland Seattle, Washington
Stella Koutros, PhD Christopher J. Maher, PhD
Division of Cancer Epidemiology and Genetics McDonnell Genome Institute
National Cancer Institute Washington University School of Medicine
Bethesda, Maryland St. Louis, Missouri
Peter Kraft, PhD Elaine R. Mardis, PhD
Departments of Epidemiology and Biostatistics McDonnell Genome Institute
Harvard TH Chan School of Public Health Washington University School of Medicine
Boston, Massachusetts St. Louis, Missouri
Barnett S. Kramer, MD, MPH Charles E. Matthews, PhD
Division of Cancer Prevention Division of Cancer Epidemiology and Genetics
National Cancer Institute National Cancer Institute
Bethesda, Maryland Bethesda, Maryland
Candyce Kroenke, ScD, MPH Marjorie L. McCullough, ScD, RD
Division of Research Epidemiology Research Program
Kaiser Permanente Northern California American Cancer Society
Oakland, California Atlanta, Georgia
Qing Lan, MD, MPH Katherine A. McGlynn, PhD
Division of Cancer Epidemiology and Genetics Division of Cancer Epidemiology and Genetics
National Cancer Institute National Cancer Institute
Bethesda, Maryland Bethesda, Maryland
I-​Min Lee, MBBS, ScD Angela L. W. Meisner, MPH
Brigham and Women’s Hospital New Mexico Tumor Registry
Harvard Medical School University of New Mexico
Boston, Massachusetts Albuquerque, New Mexico
Tracy Lightfoot, PhD Kyriaki Michailidou, PhD
Department of Health Sciences Department of Electron Microscopy/​Molecular Pathology
University of York The Cyprus Institute of Neurology and Genetics
York, United Kingdom Nicosia, Cyprus
Sara Lindström, PhD Lisa Mirabello, PhD
Department of Epidemiology Division of Cancer Epidemiology and Genetics
University of Washington National Cancer Institute
Seattle, Washington Bethesda, Maryland
Martha S. Linet, MD, MPH, (Editor) Karobi Moitra, PhD
Division of Cancer Epidemiology and Genetics Trinity Washington University
National Cancer Institute Washington, DC
Bethesda, Maryland

* Retired
xvi

xvi Contributors
Steven C. Moore, PhD Alpa V. Patel, PhD
Division of Cancer Epidemiology and Genetics Epidemiology Research Program
National Cancer Institute American Cancer Society
Bethesda, Maryland Atlanta, Georgia
Lindsay M. Morton, PhD Kathryn L. Penney, ScD
Division of Cancer Epidemiology and Genetics ScD Department of Medicine
National Cancer Institute Brigham and Women’s Hospital /​Harvard Medical School
Bethesda, Maryland Boston, Massachusetts
Raul Murillo, MD Gloria M. Petersen, PhD
Prevention and Implementation Group Department of Health Sciences Research
International Agency for Research on Cancer Mayo Clinic College of Medicine
Lyon, France Rochester, Minnesota
Rachel E. Neale, PhD Jessica L. Petrick, PhD
Population Health Division Division of Cancer Epidemiology and Genetics
QIMR Berghofer Medical Research Institute National Cancer Institute
Brisbane, Queensland, Australia Bethesda, Maryland
Heather H. Nelson, MPH, PhD Susan Picton, BMBS, FRCPCH
Division of Epidemiology, Masonic Cancer Center Department of Pediatric Oncology
University of Minnesota, Twin Cities Leeds Teaching Hospitals NHS Trust
Minneapolis, Minnesota Leeds, United Kingdom
Marian L. Neuhouser, PhD Brandon Pierce, PhD
Division of Public Health Sciences Departments of Public Health Sciences and Human Genetics
Fred Hutchinson Cancer Research Center University of Chicago
Seattle, Washington Chicago, Illinois
Robert Newton, PhD Martyn Plummer, PhD
MRC/​UVRI Uganda Research Unit International Agency for Research on Cancer
Entebbe, Uganda Lyon, France
Reiko Nishihara, PhD I. Mary Poynten, PhD Kirby Institute
Department of Pathology The University of New South Wales
Brigham and Women’s Hospital Sydney, New South Wales, Australia
Boston, Massachusetts
Ludmila Prokunina-​Olsson, PhD
Michael A. O’Rorke, PhD Division of Cancer Epidemiology and Genetics
School of Medicine Dentistry and Biomedical Sciences National Cancer Institute
Queen’s University Belfast Bethesda, Maryland
Belfast, Northern Ireland
Mark P. Purdue, PhD
Andrew F. Olshan, PhD Division of Cancer Epidemiology and Genetics
Department of Epidemiology National Cancer Institute
Gillings School of Global Public Health Bethesda, Maryland
University of North Carolina
Preetha Rajaraman, PhD
Chapel Hill, North Carolina
Division of Cancer Epidemiology and Genetics
Quinn T. Ostrom, MA, MPH National Cancer Institute
Case Comprehensive Cancer Center Bethesda, Maryland
Case Western Reserve University School of Medicine
Ewa Rajpert-​De Meyts, MD, PhD
Cleveland, Ohio
Department of Growth & Reproduction
Julie R. Palmer, ScD Copenhagen University Hospital Rigshospitalet
Slone Epidemiology Center at Boston University Copenhagen, Denmark
Boston, Massachusetts
Judy R. Rees, BM, BCh, PhD
D. Maxwell Parkin, MD, DSc Department of Epidemiology
Nuffield Department of Public Health University of Oxford Geisel School of Medicine at Dartmouth
Oxford, United Kingdom Hanover, New Hampshire
Julie Parsonnet, MD Juan Carlos Roa, MD, Msc
Department of Medicine Department of Pathology
Stanford University School of Medicine School of Medicine, Pontificia Universidad Católica de Chile
Stanford, California Santiago, Chile
 xvi

Contributors xvii
Eve Roman, PhD Martyn T. Smith, PhD
Department of Health Sciences School of Public Health
University of York University of California at Berkeley
York, United Kingdom Berkeley, California
Nathaniel Rothman, MD, MPH Mingyang Song, MD, ScD
Division of Cancer Epidemiology and Genetics Clinical and Translational Epidemiology Unit and Division
National Cancer Institute of Gastroenterology
Bethesda, Maryland Massachusetts General Hospital and Harvard Medical School
Boston, Massachusetts
Jonathan M. Samet, MD
Department of Preventive Medicine John J. Spinelli, PhD Cancer Control Research
Keck School of Medicine of University of Southern California British Columbia Cancer Agency
Los Angeles, California Vancouver, British Columbia, Canada
Ambika Satija, ScD Avrum Spira, MD, MSc
Department of Nutrition Division of Computational Biomedicine
Harvard TH Chan School of Public Health Boston University School of Medicine
Boston, Massachusetts Boston, Massachusetts
Sharon A. Savage, MD Janet L. Stanford, PhD
Division of Cancer Epidemiology and Genetics Division of Public Health Sciences
National Cancer Institute Fred Hutchinson Cancer Research Center
Bethesda, Maryland Seattle, Washington
Ghislaine Scelo, PhD Andreas Stang, MD, MPH
Genetic Epidemiology Group Institute of Medical Informatics, Biometry and Epidemiology
International Agency for Research on Cancer University Hospital Essen
Lyon, France Essen, Germany
Arthur B. Schneider, MD, PhD* Kyle Steenland, PhD
Section of Endocrinology, Diabetes and Metabolism Rollins School of Public Health Emory University
University of Illinois at Chicago College of Medicine Atlanta, Georgia
Chicago, Illinois
Craig M. Steinmaus, MD, MPH
David Schottenfeld, MD, MSc (Editor)* School of Public Health
Department of Epidemiology University of California Berkeley
University of Michigan School of Public Health Berkeley, California
Ann Arbor, Michigan
Erich M. Sturgis, MD, MPH
Mary Schubauer-​Berigan, PhD Department of Head and Neck Surgery
Division of Surveillance Hazard Evaluation and Field Studies The University of Texas MD Anderson Cancer Center
Centers for Disease Control and Prevention Houston, Texas
Atlanta, Georgia
Catherine M. Tangen, DrPH
Joachim Schüz, PhD Division of Public Health Sciences
Section of Environment and Radiation Fred Hutchinson Cancer Research Center
International Agency for Research on Cancer Seattle, Washington
Lyon, France
Robert E. Tarone, PhD*
Amy L. Shafrir, ScD International Epidemiology Institute
Division of Adolescent and Young Adult Medicine Rockville, Maryland
Boston Children’s Hospital
Michael J. Thun, MD, MS (Editor)*
Boston, Massachusetts
Epidemiology and Surveillance Research
Mark E. Sherman, MD American Cancer Society
Health Sciences Research Atlanta, Georgia
Mayo Clinic College of Medicine
William D. Travis, MD
Jacksonville, Florida
Department of Pathology
Debra T. Silverman, ScD, ScM Memorial Sloan Kettering Cancer Center
Division of Cancer Epidemiology and Genetics New York, New York
National Cancer Institute
Melissa A. Troester, PhD
Bethesda, Maryland
Department of Epidemiology
Terry Slevin, MPH Lineberger Comprehensive Cancer Center
Cancer Council Western Australia University of North Carolina at Chapel Hill
Perth, Western Australia, Australia Chapel Hill, North Carolina

* Retired
xvii

xviii Contributors
Rebecca Troisi, ScD, MA David C. Whiteman, MD, PhD
Division of Cancer Epidemiology and Genetics Population Health Division
National Cancer Institute QIMR Berghofer Medical Research Institute
Bethesda, Maryland Brisbane, Queensland, Australia
Shelley S. Tworoger, PhD Charles Wiggins, PhD, MPH
Harvard Medical School and the Brigham and Women’s Hospital Department of Internal Medicine
Harvard TH Chan School of Public Health University of New Mexico
Boston, Massachusetts Albuquerque, New Mexico
Celine M. Vachon, PhD Christopher P. Wild, PhD
Department of Health Sciences Research Director’s Office
Mayo Clinic International Agency for Research on Cancer
Rochester, Minnesota Lyon, France
Claire M. Vajdic, PhD Walter C. Willett, MD, DrPH
Centre for Big Data Research in Health Department of Nutrition
University of New South Wales Harvard TH Chan School of Public Health
Sydney, New South Wales, Australia Boston, Massachusetts
Roel Vermeulen, PhD Deborah M. Winn, PhD
Institute for Risk Assessment Sciences Division of Cancer Control and Population Sciences
Utrecht University National Cancer Institute
Utrecht, The Netherlands Bethesda, Maryland
Fawn D. Vigneau, JD, MPH Kana Wu, MD, PhD
Wayne State University School of Medicine Department of Nutrition
Karmanos Cancer Institute Harvard TH Chan School of Public Health
Detroit, Michigan Boston, Massachusetts
Teresa W. Wang, PhD K. Robin Yabroff, PhD
Division of Computational Biomedicine Division of Cancer Control and Population Sciences
Boston University School of Medicine National Cancer Institute
Boston, Massachusetts Bethesda, Maryland
Mary H. Ward, PhD Shelia Hoar Zahm, ScD‡
Division of Cancer Epidemiology and Genetics Division of Cancer Epidemiology and Genetics
National Cancer Institute National Cancer Institute
Bethesda, Maryland Bethesda, Maryland
Noel S. Weiss, MD, DrPH Chenan Zhang, PhD
Department of Epidemiology Department of Epidemiology and Biostatistics
University of Washington University of California, San Francisco
Seattle, Washington San Francisco, California

‡
Consultant/​Contractor
x i

Preface

The Schottenfeld and Fraumeni text on Cancer Epidemiology and Prevention has served as the
premier reference text for population research on the causes and prevention of cancers since the
publication of the first edition in 1982 (Schottenfeld and Fraumeni, 1982). It is written for col-
leagues pursuing careers in research in cancer epidemiology and, more broadly, in preventive
oncology. The founding editors, Dr. David Schottenfeld, now emeritus professor of epidemiol-
ogy at the University of Michigan, and Dr. Joseph Fraumeni, recently retired as the director of the
Division of Cancer Epidemiology and Genetics at the National Cancer Institute (NCI), updated
their landmark text in 1996 and 2006 (Schottenfeld and Fraumeni, 1996, 2006).
The current edition again provides a comprehensive update of research advances in cancer
epidemiology, prevention, and related fields in the past 10–​15 years, and honors the founding
editors in the title. The new editorial team is led by Dr. Michael Thun (editor-​in-​chief), formerly
with the American Cancer Society, and includes four senior co-​editors: Drs. Martha Linet from
NCI, James Cerhan from the Mayo Clinic, Christopher Haiman from the University of Southern
California, and David Schottenfeld. We are also deeply indebted to the internationally recog-
nized experts who authored the 63 chapters. Without their generous effort and commitment, this
updated synthesis would not be possible.

xix
x
 1
1 Introduction
MICHAEL J. THUN, MARTHA S. LINET, JAMES R. CERHAN,
CHRISTOPHER A. HAIMAN, AND DAVID SCHOTTENFELD
I n this introduction, we provide an overview of the text and highlight
cross-​cutting developments and new opportunities that are trans-
forming our understanding of the causes and prevention of cancer. As
in previous editions, the text is grouped into five major parts: “Basic
Concepts,” “The Magnitude of Cancer,” “The Causes of Cancer,”
“Cancers by Tissue of Origin,” and “Cancer Prevention and Control.”
Part I first describes research advances in understanding “the biol-
ogy of neoplasia,” including the progressive disruption of genetic and
epigenetic controls that regulate cell growth, division, and survival
(Chapter 2). Advances in high-​throughput technologies have greatly
expanded the ability to identify germline and somatic mutations and
to relate these to etiology, prognosis, and treatment. Tumor classifi-
cation is also changing for certain cancers, as data on the molecular
features and lineage of the neoplastic cells is combined with infor-
mation on the primary anatomic location and the morphologic, histo-
pathologic and clinical characteristics of the tumor (Chapter 3). The
“landscape” of genomic and epigenomic alterations in tumor tissue
has been cataloged for multiple human cancers (Chapter 4), revealing
both the singularity of individual cancer genomes and the commonal-
ity of genetic alterations that drive cancer in different tissues. Chapter
5 describes advances in research on inherited genomic variants that
affect cancer risk. Genome-​wide association studies (GWAS) have
identified more than 700 germline loci associated with increased or
decreased risk for various types of cancer, although the risk estimates
for almost all are small to modest. Innovations in genomics and other
“OMIC” technologies are identifying biomarkers that reflect internal
exposures, biological processes, and intermediate outcomes in large
population studies (Chapter 6). While research in many of these areas
is still in its infancy, mechanistic and molecular insights are extending
the traditional criteria for inferring causation in epidemiologic studies
of cancer (Chapter 7).
Part 2 of the book discusses the global public health impact of can-
cer and its relationship to demographic trends, changing risk factors,
socioeconomic disparities, and economic development. It considers
the direct and indirect costs of cancer in the United States to illustrate
the economic burden in a high income country. Parts 3–​5 of the book
discuss the growing list of exposures known to affect cancer risk, the
epidemiology of over 30 types of cancer by tissue of origin, and the
encouraging progress in cancer prevention and control. Major devel-
opments in these areas are discussed below, beginning with those that
affect the public health impact of cancer.
MAJOR NEW DEVELOPMENTS
Global Trends in Cancer Risk and Burden
Part II, “The Magnitude of Cancer,” provides a global public health
perspective on cancer. The human and economic costs of cancer are
increasing worldwide (http://​globocan.iarc.fr). The World Health
Organization (WHO) estimates that 14 million new cases and 8.2 mil-
lion deaths from cancer occurred in 2012. This burden is projected to
increase to 24 million cases and 13 million deaths annually by 2035
(Ferlay et al., 2013). Chapter 8 decribes the disproportionate increase
in the cancer burden in low-​and middle-​income countries (LMICs),
which can least afford additional health-​related, social and financial
costs. In 2012, these countries accounted for over half (57%) of all
incident cancers; this is projected to increase to nearly two-​thirds
(65%) by 2035. Much of the increase will result from the growth and
aging of populations, since LMICs currently comprise about 80% of
the world’s population, and large numbers of young adults are now
surviving to older ages, when cancer becomes more common. In
addition to the effect of demographic changes, cancer incidence and
mortality rates are increasing in LMICs because of the widespread
adoption of Western patterns of diet, physical inactivity, excess body
fat, delayed reproduction, and tobacco smoking, especially of manu-
factured cigarettes. As countries advance economically, the incidence
rates of cancers traditionally associated with Westernization (e.g.,
breast, colorectum, lung, and prostate) increase more rapidly than the
decrease in cancers caused partly or wholly by infectious agents (e.g.,
stomach, liver, uterine cervix). Survival after a diagnosis of cancer is
also lower in LMICs than in high-​resource countries, because of later
stage at diagnosis, a higher proportion of tumors diagnosed clinically
rather than incidentally, and limited access to standard and state-​of-​
the-​art treatment protocols.
In economically developed countries, the incidence rates of most
cancers are either stabilizing at a high level or decreasing, depend-
ing on the temporal trends of underlying risk factors and utilization of
cancer screening. Despite the decreasing rates, the disease burden, or
number of cancer cases and deaths, continues to increase. The increas-
ing burden results from the aging and growth of populations, and the
decline in competing causes of death from circulatory and infectious
diseases. Mortality rates are decreasing more rapidly than incidence
rates for many cancer sites due to a combination of prevention, early
detection, and improvements in treatment.
Part III, “The Causes of Cancer,” discusses 15 broad categories
of exposure that affect cancer risk. These include exposures that are
typically considered “environmental” by the public (chemical carcino-
gens, ionizing radiation, occupational exposures, pollutants in air and
drinking water), as well as exposures that are less widely recognized as
carcinogenic (infectious agents, metabolic factors, body composition,
reproductive and other hormones, pharmaceutical drugs, and immu-
nological conditions). All of these exposures are “environmental” in
the sense that they are acquired after conception rather than inherited.
Some are genotoxic and damage the structure of DNA or alter DNA
repair; others modify gene expression, induce oxidative stress and/​
or chronic inflammation, suppress host immunity, immortalize cells,
modulate receptors, and/​or alter cell proliferation, cell death, or nutri-
ent supply (Smith et al., 2016).
Although some exposures are conventionally perceived as “life-
style choices”, they are by no means entirely voluntary. For example,
behavioral risk factors such as tobacco smoking, energy imbal-
ance, and physical inactivity are strongly influenced by factors in
the social, economic, and cultural environment, beginning in early
childhood. Physiologic addiction is a major driver of tobacco use at
all ages.
Part IV of the book describes “Cancers by Tissue of Origin” for
33 anatomic sites, multiple primary tumors, and cancers in children.
Rapid advances in discovering the molecular events that drive certain
forms of cancer are transforming clinical diagnoses and treatment, and
affecting tumor classification. This will influence future endpoints in
etiologic studies and population-​based cancer surveillance.
1
2
2 Introduction
Part V, “Cancer Prevention and Control,” discusses the impact of
interventions that effectively reduce carcinogenic exposures or disrupt
the multistage progression of tumors. It focuses on interventions that
demonstrably reduce cancer risk in the general population, rather than
in special circumstances or high-​risk subgroups. Examples of these
are discussed in Chapters 61–​63. In all cases, the design and imple-
mentation of preventive measures require translational research to
ensure safety, optimize feasibility and impact, and critically evaluate
all stages of the process.
Cancer Prevention and Control
A growing number of population-​level preventive interventions are
proving to be highly effective, as confirmed by the decreases in inci-
dence as well as mortality rates from certain cancers (Chapters 61–​63).
Tobacco control has reduced the age-​standardized incidence rate of
lung cancer by up to 40% among men in high-​and middle-​income
countries. Increased screening for colorectal cancer and removal of
precursor lesions is credited for the 30% decrease in the incidence
rates at this site in the United States. Universal neonatal vaccination
against hepatitis B virus (HBV) has markedly decreased the preva-
lence of chronic HBV infection and liver cancer at younger ages in
high-​risk areas of East Asia and will yield maximal benefits against
cancer in the future. The development of safe and effective vaccines
against human papillomavirus (HPV) and less expensive and less oner-
ous screening tests for cervical cancer have greatly expanded opportu-
nities to prevent HPV-​related cancers among women in many LMICs.
Increased funding is becoming available for application research and
cancer preventive services in LMICs. Cancer prevention presents both
opportunities and challenges, as discussed in Part V of the text. The
best practices developed for tobacco control provide an encourag-
ing model of how health-​related policies can address the behavioral
causes of cancer. However, these must be tailored to fit the particular
social, economic, and other considerations that affect the exposure
(Chapter 61).
Advances in Genomics and other OMICs
Technological advances in high-​ throughput genotyping/​ sequenc-
ing and gene expression arrays have transformed research on both
inherited (germline) susceptibility variants and the largely acquired
(somatic) mutations in tumor tissue. Epidemiologic studies of cancer
genetics have focused mainly on germline variants associated with
cancer risk and etiology, whereas clinical and basic researchers have
characterized the landscape of somatic alterations in tumor cells that
drive the development and progression of cancer.
Germline Susceptibility Variants
The tools to identify inherited genetic susceptibility variants have
advanced enormously since publication of the previous edition of
this text in 2006. At that time, studies involved either high-​risk fami-
lies or the evaluation of a small number of pre-​specified “candidate
genes” in case-control studies of sporadic cancers in the general pop-
ulation. The candidate gene approach was largely unsuccessful in
identifying robust associations for several reasons, including small
sample size, limited statistical power, failure to account for multi-
ple testing (generating negative and false positive results, respec-
tively), and limited biologic knowledge to inform the selection of
candidate genes. Following the completion of the Human Genome
Project in 2003, genome-​wide maps of single nucleotide polymor-
phisms (SNPs) became available. Advances in high-​ throughput
genotyping technology, combined with knowledge about the struc-
ture of genetic linkage disequilibrium, created opportunities to con-
duct exploratory (hypotheis-​free or “agnostic”) surveys across the
entire genome. Over the past decade, GWAS have robustly identi-
fied more than 700 common (i.e., minor allele frequency >5%) sus-
ceptibility loci associated with cancer risk, as discussed for specific
sites in Part IV, “Cancers by Tissue of Origin.” Because GWAS test
millions of alleles across the genome, they require stringent criteria
(“genome-​wide significance”), large sample size, and replication
in more than one study to exclude chance associations. Most of the
associations identified through GWAS are modest (per allele ORs:
1.5–​2.0) or weak (ORs <1.5), but in aggregate these loci can distin-
guish a wide range of risk in the population, thus providing oppor-
tunities for targeted screening and prevention. While our current
knowledge regarding germline risk comes from studies in popula-
tions of European ancestry, the identification of population-​specific
risk loci highlights the importance of conducting GWAS in diverse
racial and ethnic populations.
Statistical modeling suggests that, for many cancers, additional
variants remain to be identified, yet the search for variants with smaller
effect sizes, as well as less common variants, drives the need for
even larger studies. With the recent development of next-​generation
sequence technology, it is now practical to sequence whole exomes
(coding regions plus regulatory regions) and whole genomes in
population-​and family-​based studies in the search for heritability not
identified through common variation in GWAS.
An important limitation of GWAS is biological interpretation,
as the vast majority of risk variants revealed through GWAS are in
non-​coding genetic sequences. Functional analyses are underway to
address this issue. The process is time-​consuming, however, since
it incorporates new bioinformatics tools and a comparison of gene
expression in tumor and normal tissue to localize the functional SNP
and ultimately the affected gene.
There has as yet been little progress in identifying interactions
between inherited germline loci identified through GWAS and acquired
“environmental” risk factors. Candidate gene studies have docu-
mented gene–​environment interactions between tobacco smoking and
the slow NAT-​2 acetylation phenotype for bladder cancer (Chapter 52)
and between alcohol consumption and slow ADH1B metabolizers for
esophageal cancer (Chapter  30). However, much larger GWAS with
more precise measures of exposure and risk will be needed to assess
other, subtler gene–​environment interactions.
Somatic Genomic Alterations
Most of the somatic genomic alterations, including mutations,
indels, copy number alterations, and chromosomal rearrangements,
that drive neoplastic progression in tumor tissue are acquired rather
than inherited. As mentioned, the Human Cancer Genome Project
and other international laboratory and clinical collaborations have
characterized so-​called driver mutations (i.e., those which confer
growth advantage to a mutated cell line) for multiple types of human
cancer (Chapter 4). These mutations represent the events involved in
the multistage development of particular forms of cancer (Armitage
and Doll, 2004; Hornsby et al., 2007; Wu et al., 2016). It is notewor-
thy that discoveries in somatic mutations over the past three decades
provide strong support for the theory of multistage carcinogenesis
that was proposed by Armitage and Doll, 10 years before elucidation
of the structure of DNA, and over 30 years before the identification
of the first proto-​oncogenes and tumor suppression genes (Armitage
and Doll, 1954). Sequencing studies have also implicated epigenetic
modification as a major source of alterations in cancer (Chapters 2
and 4).
Variable combinations of genetic and epigenetic abnormalities
account for the phenotypic heterogeneity within and among cancers.
Molecular characterization of tumors is increasingly used to predict
prognosis and to guide the use of targeted therapies for individual can-
cer patients. These markers are only beginning to be evaluated and
integrated into large-​scale epidemiologic studies, yet they are already
changing the taxonomy of some types of cancers and are likely to pro-
foundly affect future etiologic studies (Chapter  3). There has been
some progress in efforts to link specific classes of somatic muta-
tions, such as the mutational signatures of ultraviolet (UV) radiation,
tobacco smoke, and oncogenic viruses, to established carcinogenic
exposures (Chapters  2 and 4). These molecular signatures may, in
the future, identify the causal exposure(s) for cancer in individuals as
well as populations. Hopefully this goal will motivate interdisciplinary
collaborations between epidemiologists, cancer prevention scientists,
geneticists, cancer biologists, and clinicians.
 3
Introduction 3
Other OMICs
While genomic research is the poster child for the value of agnos-
tic, comprehensive explorations of germline variants associated with
cancer, other areas of OMIC research are moving toward this goal
(Chapter  6). The development of technologies to screen many thou-
sands of analytes related to gene expression (e.g., RNAseq), epi-
genetics (methylation; ChIP-​Seq), metabolomics, and the microbiome
will open new opportunities to identify the connections between expo-
sures and the biologic effects that mediate carcinogenesis. Various
OMIC technologies are at different stages of development. One of the
more advanced efforts along these lines is the identification of hor-
mone metabolites that influence breast cancer risk, illustrating the
potential of these new technologies (Chapter 22).
OUTCOMES AND EXPOSURES
Changing Taxonomy of Cancer
Accurate and reproducible classification of neoplastic diseases is
essential for advances in diagnosis and treatment, for quantifying
geographic, temporal, and demographic variations in incidence, and
for identifying etiologic relationships and mechanisms. Tumor clas-
sification has historically been based on the primary anatomic site and
morphology for most solid tumors and on histologic characteristics for
leukemias. Classification systems have evolved to incorporate infor-
mation on morphology, genetics, cell lineage, developmental char-
acteristics, and an array of molecular, clinical, and etiologic factors
(ICD-​O-​3, 2013) (Fritz et al., 2000).
While the refinement of cancer endpoints based on molecular or
other characteristics will potentially increase the ability of etiologic
studies to detect associations with specific tumor subtypes, it also
poses serious challenges. Very large studies will be needed for both
discovery and replication. Even well-​established tumor markers are
not measured uniformly in all patients. Newer classification systems
based on molecular features have generally been evaluated in only a
few hundred sporadic cancers, with little consideration of patient or
population characteristics. Clonal heterogeneity within tumors and
changes in tumor pathology during treatment further complicate clas-
sification (Norum et al., 2014). While the use of automated algorithms
and computer-​based image analysis is increasing among pathologists,
these methods and the assessment of reproducibility and validity may
not be reported to clinicians, epidemiologists, and others using the data.
Population-​based cancer registries are already challenged by efforts to
keep abreast of changing tumor classifications, especially when the
new criteria are not uniformly applied in a standardized manner.
Exposures and Exposure Measurement
More than 100 different agents and exposures are now designated as
causally related to cancer in humans (Group I) by the International
Agency for Research on Cancer (IARC). Variations in the prevalence
and intensity of these exposures account for the striking geographic
and temporal variations in the occurrence of many types of cancer.
While many exposures such as tobacco, alcohol, and numerous indus-
trial chemicals have long been classified as human carcinogens, expo-
sure patterns change, new agents are introduced, the ability to measure
exposures or outcomes progresses, and the quality, quantity, and/​or
specificity of evidence improves. For example, the contining global
increase in obesity, metabolic syndrome, and type II diabetes, com-
bined with improvements in laboratory assays to measure hormones
in large population studies, has created new opportunities to study
metabolic and hormonal effects on cancer. Thus, the discussion of
“Hormones and Cancer” (Chapter 22) has been expanded to consider
endogenous as well as exogenous exposures and peptide hormones
(insulin, insulin-​like growth factors, growth hormone, leptin, adipo-
nectin, resistin, ghrelin, etc.) in addition to steroidal sex hormones.
Several agents recently classified as Group  1 human carcinogens
affect massive numbers of people. These include outdoor air pollution
(Chapter 17), the combustion of coal as household fuel (Chapters 16,
17, and 28), diesel engine exhaust (Chapter  17), the consumption
of red and processed meat (Chapter 19), and to a lesser extent, UV-​
emitting tanning beds (Chapter 14). The search for other modifiable
causes of cancer continues. New associations have been reported with
shift work, sedentary behavior (as distinct from physical inactivity),
computed tomography scans during childhood, sun-​sensitizing phar-
maceutical drugs, and others. While the studies may be methodologi-
cally strong, the evidence for causality is not yet considered definitive.
There is a continuing need to monitor both the immediate and long-​
term effects of more recently implemented medical technologies
and newly developed drugs, products such as cellular phones and e-​
cigarettes, nuclear accidents, exposures occurring in war zones, and
other exposures potentially related to cancer.
Technological advancements in biomarker studies will allow more
comprehensive examination of an individual’s metabolome, microbi-
ome, genome, epigenome, and exposome. The use of specific biomark-
ers to assess internal exposures and identify children, adolescents, and
other subsets of individuals who may be particularly susceptible to the
factor being investigated (for example, dietary exposure, pesticide act-
ing as a hormonal disruptor, or medication) could increase our ability
to detect complex exposure–​disease relationships.
ESTIMATES OF ATTRIBUTABLE FRACTION
Epidemiologists have long debated the fraction of cancer cases or
deaths that could be avoided by preventive interventions (Chapter 61).
Estimates of the percent of cancer deaths that could theoretically be
avoided, if the exposures were eliminated, range from 50% to 80%,
although the potential for primary prevention differs for incidence and
mortality, by geographic region, gender, and attained age (Whiteman
and Wilson, 2016). About half of the deaths that could be avoided in
principle relate to 11 potentially avoidable risk factors, including the
behavioral risk factors discussed above. The attributable fraction esti-
mates are predicated on the idea that cancer risk is largely acquired,
rather than inherited. Inherited factors do contribute to the variation in
risk among individuals, but they cannot account for the large tempo-
ral changes in risk within countries, or the differences in risk among
migrants who move from one country to another.
Chapter 19, “Diet and Nutrition,” provides the first estimates of the
fraction of all cancers attributable to diet, in combination with or sepa-
rate from overweight and physical inactivity. The authors estimated
the total as about 20% overall, which is weaker than previously esti-
mated. The proportion contributed by dietary composition indepen-
dent of adiposity is less clear because some dietary factors have yet to
be identified or established with sufficient certainty, and associations
are likely underestimated because of measurement error or misspecifi-
cation of temporal relationships. The authors estimate an etiologic
contribution of 5%–​12% for dietary composition alone, but suggest
that this could be appreciably higher when considering nutrient and
genetic interactions.
ONGOING CHALLENGES
Tumor Diagnosis and Classification
In LMICs, the completeness and specificity of tumor diagnosis var-
ies depending on economic resources and medical infrastructure.
Less than 10% of people in Africa and South America are covered
by population-​ based tumor registries (Chapter  8). In high-​ income
countries, tumor classification is more advanced because of earlier
application of diagnostic innovations and revised classification sys-
tems. Classification systems evolve with the introduction of new histo-
chemical and molecular markers and advances in understanding tumor
biology. Even in high-​income countries, there is wide variability in
the proportion of tumors incompletely or inadequately characterized.
Molecular profiling at major cancer centers may include a range of
established tumor markers, exome or whole genome sequencing, copy
4
4 Introduction
number, messenger and micro RNA sequencing, DNA methylation,
and proteomics analysis (Hoadley et al., 2014). While this information
may be useful clinically, it is not yet available for most cancer patients,
nor are the data routinely incorporated into cancer surveillance sys-
tems (Chapter 8). Even cancers that have undergone intensive multi-
disciplinary review to improve classification, such as hematopoietic
and lymphoproliferative malignancies, include subtypes characterized
as “not otherwise specified” or provisionally classified (Swerdlow
et al., 2016). Thus epidemiologic studies of cancer must collect and
archive tumor tissue in order to ensure a uniform, more complete, and
contemporary approach to molecular testing.
Over-​diagnosis
“Over-​diagnosis” refers to the incidental detection of small and/​or
indolent cancers that otherwise might not cause clinical problems
during the patient’s lifetime (Chapter  8). Extreme examples of this
have been the sudden increase in prostate cancer diagnoses follow-
ing the introduction of PSA screening (Chapter 53), and the increase
in thyroid cancer diagnoses due to screening programs using ultra-
sound (Chapter 44). Overdiagnosis is most problematic if it leads to
unnecessary treatment and serious adverse effects. The introduction
of new screening tests can also distort temporal trends in incidence
and bias observational studies of the impact of screening (Chapter 63).
The likelihood of over-​diagnosis varies by cancer site and depends
on the baseline incidence and risk characteristics of a population.
An estimated 10–​30% of newly diagnosed breast cancers identified
with screening mammography may reflect over-​diagnosis (Bleyer &
Welch, 2012; Loeb et al., 2014; Vickers et al., 2014). In the absence of
molecular markers that reliably distinguish indolent from aggressive
tumors, clinicians must grapple with the potential for “over-​treatment”
(Chapter 3). Over-​diagnosis poses a greater clinical dilemma for early
stage cancers in internal organs than for premalignant lesions detected
by colorectal or cervical screening, because the treatment is more
invasive.
Exposure Measurement Issues
Regardless of the epidemiologic study design used, it is challenging
to characterize accurately many types of acquired exposures due to
a lack of comprehensive measurements during the relevant exposure
window. This presents a greater problem for some exposures than oth-
ers. For example, as described in Chapters 19–​21, misclassification of
exposure is of great concern in characterizing patterns of nutrition and
physical activity, especially at earlier stages of life. It presents less of a
problem in studying cigarette smoking, menopausal hormonal therapy,
or exposure to microbial agents, since these exposures can be reason-
ably well defined qualitatively, and biomarkers exist to supplement
questionnaire data. Certain exposures are experienced in multiple
settings, including workplace, residential, recreational, medical, war
zone, and other settings. Chemical exposures often occur as mixtures
in air or water. Surrogate measures, such as job titles for occupational
exposures and administrative databases for residential exposures, do
not capture variations among individuals or over time.
The timing of exposure is an area of special interest and challenge.
Exposures that occur during a particular time window or a susceptible
stage of development may have adverse effects that are not evident
when exposure occurs later in life. A classic example of this involved
in utero exposure to high doses of the hormone di-​ethyl stilbesterol
(DES) in the daughters of mothers treated to prevent pregnancy com-
plications, who subsequently developed vaginal carcinoma in adoles-
cence (Chapter 49). For breast cancer, it is hypothesized that hormonal
exposures received in utero or immediately postnatally may affect
early stages in tumor development, or that breast tissue may be more
susceptible to certain exposures (e.g., ionizing radiation, cigarette
smoking, or alcohol consumption) during the period between men-
arche and first full-​term pregnancy, when cells are proliferating but not
fully differentiated (Chapter  45). Similar hypotheses have been pro-
posed for nasopharyngeal cancer and Hodgkin lymphoma in relation
to early childhood infection with Epstein-​Barr virus (Chapters 26 and
39). Although these hypotheses are important, they are difficult to test
without biomarkers or experiments of nature that demarcate the timing
of exposure. Serial acquisition of biological samples over many years
of follow-​up would be informative, although this approach must be
tempered by feasibility and cost considerations.
FUTURE RESEARCH DIRECTIONS
While individual chapters outline future research directions for spe-
cific exposures or cancers, we highlight here selected cross-​cutting
issues that apply broadly to many cancers.
Team Science
One of the benefits of GWAS and pooled risk factor studies has been
the formation of multi-​institutional international consortia to share
biospecimens and primary data in order to maximize statistical power
for discovery and robust replication (Boffetta et al., 2007). These con-
sortia have been instrumental in creating new models of funding, lead-
ership, and authorship, and in sharing and harmonizing primary data
across studies. The formation of larger and more complex data sets has
stimulated innovations in informatics and the development and appli-
cation of novel analytic methods. Further advances in high-​throughput
laboratory technology will continue to create new opportunities to
explore the complex biology of genomics, metabolomics, proteomics,
and so on, in large population studies. This will generate vast amounts
of data to be analyzed. It will also require insights from diverse disci-
plines to plan analyses and to interpret the results.
“Transdisciplinary research” signifies a level of collaboration in
which researchers from different scientific disciplines come together
to identify the most important research questions, design the optimal
approach, and collect, analyze, and publish the study results jointly
(Rosenfield, 1992). This level of team science transcends disciplinary
boundaries and benefits all parties. For example, the application of
haplotype analyses based on the structure of genetic linkage disequi-
librium, initially proposed by geneticists, greatly accelerated explor-
atory analyses across the entire genome in large population studies.
Similarly, the involvement of epidemiologists in tumor genomics has
brought a population science perspective to this field, increasing atten-
tion to population sampling, sex, and racial/​ethnic differences, and
exposures such as smoking that can affect the mutational spectrum
of various cancers. There are many opportunities for collaborations
involving laboratory scientists, analytic chemists, epidemiologists,
and others to accelerate research on etiologic issues related to can-
cer. One example would be transdisciplinary research to understand
hormonal carcinogenesis at the molecular level in human populations
(Chapter 22).
Cancer Survivorship
The number of people surviving after a diagnosis of cancer has
increased rapidly in high-​income and many middle-​income countries
due to improvements in treatment and the effects of screening on both
early diagnosis and more complete ascertainment. In the United States,
the estimated number of people alive for at least 5 years after a diagno-
sis of cancer increased from 4 million in 1978 (~1.8% of the popula-
tion) to 13.7 million in 2012 (~4% of the population), and is predicted
to approach 18 million by 2022 (de Moor et al., 2013; Harrop et al.,
2011). A substantial proportion of these are long-​term survivors. Forty
percent of individuals who survived for at least 5  years were alive
10 or more years after diagnosis, and 15% had survived 20 or more
years (Howlader et al., 2015). To address the rapidly increasing pop-
ulation of cancer survivors, the NCI Office of Cancer Survivorship
and a 2006 publication from the Institute of Medicine (Committee
on Cancer Survivorship, 2006) provided a framework for identifying
and addressing the unmet needs of this growing population. Disease
and treatment affect multiple health domains (e.g., medical, physical
 5
Introduction 5
function, psychiatric and psychosocial, cognitive, work, sexual, and
reproductive). These factors and heath-​related quality of life should
be assessed at discrete intervals following diagnosis. Studies should
examine whether quality of life and survivorship issues differ for can-
cers in children from those in later life. Research on survivorship is
largely still in its infancy (de Moor et al., 2013; Harrop et al., 2011;
Richardson et al., 2011). The occurrence of multiple primary and sec-
ondary cancers following treatment is an important area of research
(Chapter  60). Cancer epidemiologists should have a major research
role in cancer survivorship because of their expertise in observational
study designs and exposure assessment.
Risk Prediction Models
Risk prediction models estimate the absolute risk of being diagnosed
with or dying from a specific condition during a defined time period
for individuals with defined demographic characteristics and risk fac-
tors. These models are widely used to predict individual risk and to
guide treatment decisions in cardiovascular medicine. Unfortunately,
the models currently available for cancer provide reasonably accu-
rate predictions for groups of people but not for individuals (Amir
et al., 2010).
Site-​specific chapters discuss research on risk prediction models
for cancers of the lung (Chapter 28), colorectum (Chapter 36), breast
(Chapter  45), and multiple primary cancers (Chapter  60). Brinton
and colleagues in Chapter 45 review the research on factors that may
improve the discriminatory accuracy of existing models of breast can-
cer. These include endogenous hormone levels, proliferative benign
biopsy diagnoses, behavioral risk factors, mammographic density, and
genetic polymorphisms. Although the associations with genetic poly-
morphisms identified by GWAS are modest (per allele ORs: 1.5–​2.0)
or weak (ORs <1.5), as discussed earlier, it is hoped that in the aggre-
gate the addition of these loci to the model can more accurately predict
risk for individuals, thereby improving targeted approaches for screen-
ing and prophylactic treatment (Garcia-​Closas et al., 2014).
Risk prediction models of colorectal cancer have been used to esti-
mate the independent and combined effects of behavioral, medical,
familial and genetic risk factors on attributable risks. One such study
estimated that a population with the optimal distribution of established
modifiable risk factors for colorectal cancer would have a 43% percent
lower (95% CI:  0.14, 0.65) incidence of disease (Lee et  al., 2016).
Meester et al. (2015) estimated the effect of screening on deaths from
colorectal cancer and concluded that the non-​use of screening methods
among people aged ≥ 50 years in the United States accounted for more
than 50% of colorectal cancer deaths.
The Microbiome
Remarkable advances have been achieved in identifying microbial
pathogens that influence cancer risk (Chapter 24). This research has
focused historically on disease-​causing organisms, rather than on the
trillions of “commensal” organisms that live in or on the human body.
Increased interest in the human microbiome has broadened the scope
of inquiry. The greatest concentration of commensal microorgan-
isms is in the upper and lower gastrointestinal tract, although there
are well-​ characterized symbiotic communities in the skin, mouth,
sinonasal cavities, and vagina. Diverse species of bacteria, archaea,
viruses (including bacteriophages), and fungi can be identified. Some
species have coevolved with humans for millennia and maintain essen-
tial physiologic enzymatic functions, such as the synthesis of essential
vitamins and the metabolism of carbohydrates, bile acids, and xeno-
biotics. Commensal flora may have detrimental as well as beneficial
effects on cancer. The colonic microbiome is thought to account for
the approximately 40-​fold higher incidence of adenocarcinoma in the
colon than in the small intestine (Chapter 35). While the small intes-
tine is not sterile, it has comparatively few commensal organisms. The
difference in cancer risk between the two sites is remarkable, given
that both organs undergo rapid cell replication. The small intestine
comprises about 90% of the mucosal absorptive surface area of the
gastrointestinal system, yet in the United States accounts for only
3.2% of digestive system cancer cases (Howlader et al., 2015).
The tools for studying complex microbial communities are only now
becoming available. There is great interest, however, in characterizing
alterations in the microbiome caused by changes in diet, antibiotic
use, and other exposures, and in the inflammatory responses that result
from the influx of pathogenic organisms into organ-​specific microbi-
omes (Dale and Moran, 2006). Future epidemiologic and experimental
research on the human microbiome will likely continue to focus on
the carcinogenic effects of disturbed homeostasis and the disruption
of the normal diversity of the microbial flora (Bultman, 2016), and
as well as on potential role(s) of the microbiome on the pathogenesis
of obesity, diabetes (Okeke et  al., 2014), and autoimmune diseases
(Hooper et al., 2012).
Development of New Cohorts
There is an ongoing need to develop new cohorts to complement exist-
ing cohorts, with a particular focus on collecting and banking biologi-
cal samples needed for broader OMICs studies (e.g., tumor tissue,
blood, urine, stool), the inclusion of state-​of-​the-​art exposure mea-
surements and data collection strategies, data on new and emerging
exposures, and repeated assessments over time to capture important
changes in exposures, behaviors, or physiological factors. Besides
enrolling participants from more recent birth cohorts, there is also a
critical need to increase the racial/​ethnic and socioeconomic diversity
of participants. Careful consideration must be given to cost-​effective
data sources and methods of data collection to address these needs in
the long-​term follow-​up of future cohorts. Data access and data shar-
ing also need to be considered since data collected from more recent
cohorts (such as the UK Biobank, the NCI Cohort Consortium, and
the Childhood Cancer Survivor Study) are increasingly made broadly
available as a resource for qualified investigators. Finally, new models
of governance and participant engagement and interaction will need to
be developed for the next generation of cohort studies.
New and Non-​Traditional Data Sources
A variety of new data sources are enriching the opportunities for
descriptive and analytic epidemiologic studies. The expanding use of
electronic health records, along with a movement toward interoperabil-
ity and standardized content, can potentially provide individual-​level
medical data on tumor characteristics, comorbidity, and treatment.
Data linkage between population-​based cancer registries, vital status
and mortality records, hospital and other medical records, and admin-
istrative data sets provides an important resource for studies of cancer
survivorship. Personal devices such as accelerometers or smart phones
to track movement can improve the measurement of physical activity.
In parallel, many other types of digital data are increasingly avail-
able. Potentially linkable data from diverse fields of science (e.g.,
OMICs; environmental and geographic sciences) and areas outside
of science (e.g., business, finance, telecommunications, social media,
and the Internet of things) are being promoted under the umbrella of
“Big Data.” Non-​traditional data sources have been touted as a rev-
olutionary development in the future of epidemiology (Khoury and
Ioannidis, 2014; Mooney et al., 2015). It should be recognized that the
use of non-​traditional data sources involves much more than working
with large volumes of data. These sources have been characterized as
high variety (secondary use from many diverse sources), high volume
(both in numbers of observations and/​or variables per observation) and
high velocity (real time) (Douglas, 2012). It is important that epide-
miologists collaborate with informaticians and computer scientists
to explore the promise of Big Data. Expertise in observational study
design, along with efforts to assess validity and reproducibility, will
be essential to avoid “big error” driven by chance, bias (e.g., selection
bias, measurement error, confounding) and lack of external validity.
Cancer epidemiologists bring the subject matter expertise needed to
frame and interpret Big Data results for clinical and public health rel-
evance. While the long-​term impact of Big Data on cancer surveillance
6
6 Introduction
and analytical epidemiology is not yet clear, we anticipate that this
may have a major impact on the field over the next decade.
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 7

I
BASIC CONCEPTS
8
 9
2 Biology of Neoplasia
MICHAEL DEAN AND KAROBI MOITRA
OVERVIEW
The biology of tumors is being understood in unprecedented detail in
terms of the development, growth, survival, and spread of cancer cells
in the body, and their interaction with the host. Analyses of familial
cancer syndromes and in vitro and animal assays have revealed the
major tumor suppressor genes and oncogenes that regulate cell growth
and survival. More recent scans of large numbers of cancer cases and
controls with single nucleotide polymorphism (SNP) arrays, known as
genome-​wide association studies (GWAS), have identified additional
genetic loci, mostly in regulatory regions that influence cancer risk.
The genomic characterization of tumors through exome and whole
genome sequencing, transcriptome, and DNA methylation analyses
are identifying further complexity in the somatic alterations present
in tumor cells. A new field of tumor signature analysis seeks to cor-
relate exposures (tobacco, carcinogens, radiation) to specific classes
of mutations in the tumor genome. Alterations in the DNA repair pro-
cesses of the cell also can be shown to leave a signature in the point
mutations and structural alterations found in cancer. A major new class
of somatically altered genes are those encoding proteins that modify
histones and other components of chromatin and/​or alter the methyla-
tion of DNA. Such epigenetic alterations appear to be central to late
events in cancer, such as metastasis and therapy resistance, and further
understanding of these alterations will be the key to effective therapy.
Single-​cell analyses are identifying complex patterns of cancer cell
heterogeneity and evolution and have supported the concept of the
tumor cell as a multi-​cellular entity. Finally, the cancer cell arises from
the body’s normal cells, and interacts throughout the entire lifetime of
the tumor with surrounding host cells, blood supply, and the immune
system. Inflammation is both a major cause and consequence of can-
cer, and increasingly modulators of the immune system are being used
in cancer therapy.
INTRODUCTION
The Odyssey of a Tumor
In the epic poem The Odyssey, Homer details the long, adventurous
journey of Odysseus as he returns home from the Trojan Wars. Over
the course of this decade-​long, arduous journey, Odysseus must use
all his talents, physical strength, prowess as a soldier, and intelligence
to survive. At times the gods are against him, and at other times they
actually come to his aid. In the end, he is the only surviving member
of his army.
There is a similar long and difficult path of a tumor from a single
abnormal cell to a mature and often lethal growth (Figure 2–1). In the
odyssey of the tumor, though, our own cells are the villains of the epic,
and it is science and medicine (rather than the gods) that are called
upon to wage the epic battle against our own cells. The initial tumor
can arise at virtually any time of our life, from just after birth until old
age, and in fact cancer risk continues to increase at least until 80 years
of age (Harding et al., 2008; Pedersen et al., 2016).
Tumors can arise from virtually any cell type or tissue in the body.
Despite this diversity, there are certain traits in common with tumors in
different individuals and from different tissues. We have identified the
major genetic and external risk factors for most cancers, the principal
genes that are altered somatically in tumors, and many of the mecha-
nisms. While external factors, like mutagens and infectious agents, initi-
ate cancer, in the later stages of tumor development we find the tumor
cell tapping into diverse tools and pathways that are the basis of life itself.
Definition of Cancer
• “Cancer” refers to a large, heterogeneous group of diseases with
common underlying pathology characterized by uncontrolled cel-
lular growth and division.
• Cancer is inherently a genetic disease at the cellular level.
• Genetic and epigenetic changes accumulate in localized (somatic)
tissue and dysregulate genetic control over basic cellular functions.
Cancer involves all of the organ systems and cell types of the body
(although some tissues are more susceptible than others) and is there-
fore inherently more complicated than other major disease such as car-
diovascular or neurological disease.
Cancer is a genetic disease in the sense that the tumor cell has
suffered from multiple lesions in its DNA, nearly always involving
multiple gene mutations, chromosome rearrangements, and extensive
alteration of the epigenome, through changes in DNA methylation and
histone modification (Figure 2–2). Depending on the tumor type, up to
10% of cancers are caused by inherited germ-​line mutations that are
moderately to highly penetrant. Common germline variants raising or
lowering cancer risk 0.1–​4-​fold have also been described for nearly
every tumor type.
Cancers begin as localized growths or pre-​malignant lesions. In a
number of cancer types, we can see these growths in the form of colon
polyps, cervical dysplasia, enlarged moles, and ductal carcinoma in
situ, among others. Many of these early lesions will not progress or
can regress or disappear spontaneously. Early colon cancer lesions are
among the best studied of these growths. Nearly all colon polyps have
been observed to have inactivating mutations in the APC tumor sup-
pressor gene (Kinzler and Vogelstein, 1996). The APC protein func-
tions as an antagonist of WNT signaling, and was first identified in
familial adenomatous polyposis (FAP), an autosomal dominant dis-
ease characterized by a large number of colon polyps and a high risk
for colon cancer.
A very critical transition is the evolution or progression of the
pre-​malignant lesion into a local, malignant tumor. This stage
involves the accumulation of yet more genetic insults. Few local
malignant lesions can be eliminated by the body. The final transition
is to an invasive and/​or metastatic tumor that is capable of invad-
ing adjacent tissues or spreading across the body. The vast majority
of cancer morbidity and mortality is due to cancers in this third,
metastatic stage.
Inherited Cancer Syndromes
Family history has been noted as a risk factor since the early days
of medicine, but the major inherited cancer syndromes began to be
described in the 1900s. For example, the von Hippel Lindau syndrome
was independently described by von Hippel and Landau in 1904 and
1927 and involves tumors of the kidney and pheochromocytomas
inherited in an autosomal dominant fashion.
9
10

10 Part I:  Basic Concepts

(d)
(a)

Normal
Cell (b) (c)

Therapy
Resistant
Tumor
Germline
Mutant
Cell

Pre-Malignant
Lesion
Locally
Genetic Invasive
Susceptible Cell Lesion

Metastatic
Tumor

Figure 2–1.  Odyssey of a cancer cell. (a) Cancer cells derive from normal cells and form a pre-malignant lesion. Inherited mutations can predispose to
pre-malignant lesions and cancers (germline mutations), and over 500 cancer susceptibility alleles are known. (b) Pre-malignant lesion can be studied
(colon polyps, cervical lesions), and in some cases regress. (c) Or, pre-malignant lesions can progress to local invasive cancer (carcinoma in situ). (d) The
final phase involves the development of the fully malignant, invasive, and metastatic tumor, with the potential to develop resistance to therapy (radiation,
chemotherapy, targeted or immune therapy).

The Role of Tumor Suppressor Genes are almost always genes that are mutated in sporadic cancers (Table 2–1).
Most of the genes causing these inherited syndromes have turned out to
A major conceptual breakthrough came in 1975 when Al Knudson pub- play critical roles in the cell cycle or growth control, and therefore their
lished an analysis of retinoblastoma and correctly predicted that indi- loss imparts a lack of control of the cell-​division process and/​or loss of
viduals inherited a defective copy of a gene (that we now call a tumor recognition of damage and checkpoints to cell cycle progression. Calling
suppressor gene) and that the tumor cells suffer a somatic loss or loss them tumor suppressor genes explains the role of these genes in cancer
of function of the normal copy (Knudson, 1971). Therefore, individuals formation, but not their role in normal growth and development.
affected by these syndromes often display multiple tumors such as bilat- Genes involved in DNA repair constitute another class of genes that
eral breast cancer or retinoblastoma, multiple kidney or colon tumors cause inherited cancer. Again, they are mutated in the germline, but
(Knudson, 2002). Although the inheritance pattern is dominant, at the the tumor has a further mutation or loss of the normal allele (the sec-
cellular level, both copies of the gene must be inactivated or disabled. ond hit). These tumors contain lesions in critical components of DNA
The same tumor suppressor gene can also suffer mutation or loss of repair and therefore can accumulate lesions that can lead to cancer.
both alleles in a person without an inherited defect (spontaneous muta- A critical conclusion made by Knudson was that the same gene that
tion). Therefore, the genes identified from inherited cancer syndromes causes an inherited cancer syndrome can suffer somatic mutation to
both copies and contribute to sporadic cancer. He demonstrated math-
ematically that this can explain the tendency for inherited retinoblasto-
(a) (b) (c) (d) (e) mas to occur bilaterally and at an earlier age of onset, whereas tumors
Genetic Point Mutation Point Insertion/ Gene Gene in patients without a family history are more likely to be unilateral and
Lesions (SNV) Deletion Translocation Deletion/Gain appear at a later age. This model has held true for many of these genes,
(indel) (CNA)
and APC (colon cancer), RB1 (retinoblastoma), VHL (renal tumors),
PTCH1 (basal cell carcinoma), and TP53 (multiple tumor types) are
GGG GGG very frequently somatically mutated (Hahn et al., 1996; Kinzler et al.,
Gly Gly
Genetic 1991; Latif et al., 1993; Murphree and Benedict, 1984; Varley, 2003).
Susceptible
Several of these genes have been termed “gatekeepers,” as they are
GAG GG often the first gene mutated in the tumor and/​or are inactivated in close
Germline
Mutant
Ser X to 100% of specific tumor types (Kinzler and Vogelstein, 1997). This
is consistent with the critical role that the gatekeeper genes play in
Figure  2–2. Genetic lesions in cancer cells. (a) Some individuals have the formation of the pre-​malignant lesion, the necessary precursor to
germline mutations (rare, highly penetrant mutations) or susceptibility the local malignancy. For example, patients with germline APC muta-
alleles. (b) Point mutations result in the replacement of a single nucleo- tions develop hundreds of colon polyps, and virtually all sporadic
tide, a single-nucleotide variant (SNV). These can cause the replacement colon polyps display somatic mutation of the APC gene (Kinzler and
of a single amino acid in a protein (non-synonymous variant), create a new Vogelstein, 1996).
stop codon (nonsense mutation) or alter a splice site or regulatory element. There are exceptions to this paradigm, mostly in the DNA repair
(c) Insertions or deletions (indels) of one or more nucleotide in the coding genes. Germline mutations in the BRCA1 and BRCA2 genes confer
region of a gene can result in a shift in the reading frame and an inactive high penetrance for breast cancer, moderate penetrance for ovar-
protein. (d) Chromosome translocations result in the formation of a fusion ian cancer, and risk for prostate, pancreas, and other tumors. In the
protein containing portions of two previously distinct genes. (e) An entire tumors of such germline-​mutated patients, there is virtually always
gene can be deleted or amplified. Copy number alterations (CNA). inactivation of the normal allele, consistent with the two-​hit model
 1

Biology of Neoplasia 11
Table 2–1. Major Inherited Cancer Genes

Type of Cancer Syndrome Gene(s)

All cancers Bloom syndrome BLM

Breast, ovarian, pancreatic, prostate Breast-​ovarian cancer syndrome BRCA1, BRCA2
Breast, thyroid, endometrial Cowden syndrome PTEN
Colorectal Familial adenomatous polyposis (FAP) APC
Colorectal Hereditary non-​polyposis colorectal MLH1, MSH2, MHS6, PMS2
cancer/​Lynch syndrome
Retinal Familial retinoblastoma RB1
Melanoma Familial atypical multiple mole-​melanoma CDKN2A
syndrome (FAMM)
Leukemia Fanconi’s anemia FACC, FACA
Pancreatic Hereditary pancreatitis/​familial pancreatitis PRSS1, SPINK1
Leukemias, breast, brain and soft Li-​Fraumeni TP53
tissues cancer
Pancreatic cancers, pituitary adenomas, Multiple endocrine neoplasia 1 MEN1
benign skin and fat tumors
Skin and brain Nevoid basal cell carcinoma syndrome PTCH1
Thyroid, pheochromocytoma Multiple endocrine neoplasia 2 RET, NTRK1
Pancreatic, liver, lung, breast, ovarian, Peutz-​Jeghers syndrome STK11/​LKB1
uterine, and testicular
Tumors of the spinal cord, cerebellum, Von Hippel-​Lindau syndrome VHL
retina, adrenals, and kidneys
Kidney Wilms tumor WT1
Skin Xeroderma pigmentosum XPD, XPB, XPA
Leukemias and lymphomas Ataxia telangiectasia ATM

Source: Adapted from: http://dceg.cancer.gov/research/what-we-study/gene-host/hereditary-cancer-syndrome and the AACR Cancer Progress

Report, 2015.

(Couch et al., 2014; Miki et al., 1994; Moran et al., 2012; Struewing
et al., 1997; Wooster et al., 1995). However, BRCA1 and BRCA2 are
not gatekeeper genes for breast and ovarian cancer, as they are rarely
somatically mutated in breast or ovarian tumors in non-​hereditary
cases (Cancer Genome Atlas Research Network, 2011, 2012).
At the molecular level, both inherited and somatic mutations of
tumor suppressor genes serve to inactivate the protein. They are fre-
quently frameshift or nonsense mutations generating a truncated pro-
tein, and are less likely to be point mutations causing the change of a
single critical amino acid.
Somatic Mutations and Oncogenes
Oncogenes are the other major class of genes that are frequently
mutated in cancer. These are genes that are activated by mutation, cre-
ating a molecule with a dominant function in the cell (Croce, 2008;
Dean, 1997). These genes are almost never found to be mutated in the
germline, and are often lethal when introduced in the activated form
in the germline of a mouse. Most oncogenes were discovered as the
cellular homologues of viral oncogenes (Stehelin et al., 1976; Watson
et al., 1982), or by cellular assays in which DNA from a tumor cell was
introduced into immortal cells in culture and a morphological change
was noted, or the cells became tumorigenic in the mouse (Der et al.,
1982; Pulciani et al., 1982).
Most oncogenes have a direct role in cell growth and can be growth
factors (PDGFA, KITL), growth factor receptors (MET, EGFR,
PDGFR), intracellular growth signaling molecules (RAS, PIK3CA,
RAF, MAPK1), or transcription factors mediating growth signals
(MYC, FOS) (Croce, 2008; Dean, 1997; Dean et al., 1985; Weinberg,
1996). The mutations in these genes tend to be either specific muta-
tions that activate the protein (G12E in RAS, H1047Y in PIK3CA)
or gene amplifications creating an overabundance of the protein. The
mutations activating oncogenes are among the most common somatic
events in multiple cancer types.
Oncogenes can also be activated by chromosomal translocations
that generate fusion proteins. In the example of the Philadelphia chro-
mosome, the t(9;21) event joins the BCR protein on chromosome 9 to
the ABL oncogene on chromosome 21 (de Klein et al., 1982; Rowley,
1973). The hybrid protein contains a portion of BCR at the N termi-
nus and the kinase portion of ABL at the C terminus. This leads to the
production of an activated ABL tyrosine kinase constitutively signal-
ing and stimulating cell division (Clark et al., 1988). Certain cancer cell
types are known to be dependent on this oncogene signal for sustained
cell growth and are known as “oncogene addicted.” In the case of the
Philadelphia translocation, ABL tyrosine kinase inhibitors can inhibit
CML cells and, barring the appearance of drug resistance, can perma-
nently keep the tumor cells suppressed (Druker et al., 2001a, 2001b).
Oncogenic Driver Genes
The advent of large-​scale exome and whole genome sequencing of
tumors has led to an explosion of information on the extent of somatic
mutations in tumors (Vogelstein et al., 2013). There is a high variation
in the number of somatic mutations per tumor, with pediatric tumors
and most hematopoietic tumors showing low mutation load, and solid
tumors higher mutation loads (Kandoth et al., 2013). Critical to this work
is the elucidation of the functional mutations in a given tumor and the
separation of these mutations (driver mutations) from random mutations
accumulating in the tumor that may have little or no effect on the tumor-
igenesis process (passenger mutations). Vogelstein et al. developed an
operational definition to define oncogenes and tumor suppressor genes
based on the frequency of certain types of mutations (Lawrence et al.,
2013; Vogelstein et al., 2013). But mathematical calculations have also
been performed to determine if a gene is significantly mutated in a given
tumor type based on the size of the gene (Lawrence et al., 2013). For
most of the well-​known oncogenes and tumor suppressor genes, there is
experimental evidence in cell culture or model systems to demonstrate
that they drive cell growth or tumor formation at the cellular level. But
genome sequencing of tumors has identified many frequently mutated
genes that have not been experimentally validated.
Chromatin Remodeling Genes
The genes most frequently mutated in cancers that were not discovered
as oncogenes or tumor suppressors are the class of genes involved in
the modification of histone molecules found in chromatin, or proteins
12

12 Part I:  Basic Concepts

directly involved in the position and remodeling of nucleosomes on Table 2–2. Continued
DNA. The role of nearly all of these genes as frequently mutated genes
was discovered during exome or whole genome sequencing of large Gene Symbol RefSeq ID Chromosome Location
numbers of specific tumors (Kishimoto et  al., 2005; Muraoka et  al., CXXC1 NM_​001101654.1 18q21.1
1996; Santos-​Rosa and Caldas, 2005). For example, the exome sequenc- DEK NM_​001134709.1 6p22.3
ing of bladder tumors led to the identification of KDM6A, a previously DMAP1 NM_​001034023.1 1p34.1
obscure enzyme functioning as a lysine methylase of histones, as one of DPF1 NM_​001135155.2 19q13.2
the most frequently mutated genes in this tumor type (Gui et al., 2011; DPF2 NM_​006268.4 11q13.1
Guo et al., 2013). In fact, four of the five mutated genes in bladder can- DPF3 NM_​001280543.1 14q24.2
cer come from this class. And for nearly every solid tumor, one or more EP400 NM_​015409.4 12q24.33
chromatin remodeling genes are commonly inactivated (Table 2–2). ERCC6 NM_​000124.3 10q11.23
GADD45A NM_​001199741.1 1p31.2
GADD45B NM_​015675.3 19p13.3
Epigenetic and Regulatory Changes in Cancer GADD45G NM_​006705.3 9q22.1-​q22.2
At the molecular level, most of these chromatin remodeling genes HCFC1 NM_​005334.2 Xq28
have the same spectrum of mutations as the tumor suppressor genes, HELLS NM_​001289067.1 10q23.33
frameshift, and nonsense mutations; and both alleles are inactivated HLTF NM_​003071.3 3q25.1-​q26.1
in the tumor cell. However, they are not found as germline mutations HMG20B NM_​006339.2 19p13.3
causing cancer, but they often cause developmental disorders (Santos-​ IKZF1 NM_​001220766.1 7p12.2
Rosa and Caldas, 2005). ING3 NM_​019071.2 7q31.31
Therefore, tumor genome sequencing has uncovered a major new INO80 NM_​017553.2 15q15.1
class of genes (epigenetic modifiers) that is commonly mutated in can- INO80B NM_​031288.3 2p13.1
cer. In fact, in nearly every tumor type, there is at least one gene from INO80C NM_​001098817.1 18q12.2
this class that is frequently mutated. While in a few cases, genes from INO80D NM_​017759.4 2q33.3
this class have been shown to accelerate cell growth, invasion, and INO80E NM_​173618.1 16p11.2
tumor growth in model systems, in the majority of these genes, we KAT5 NM_​001206833.1 11q$
do not have a molecular mechanism explaining their function in the LRWD1 NM_​152892.1 7q21.1
cancer process. One exciting idea is that the tumor cell may need to MBD5 NM_​018328.4 2q23.1
undergo a wholesale change in gene expression and regulation and that MBD6 NM_​052897.3 12q13.3
the loss of critical chromatin regulatory genes allows the tumor cell to MTA1 NM_​001203258.1 14q32.33
be more plastic and to turn on programs of gene expression that enable MTA3 NM_​004689.3 2p21
the more complex phenotypes of invasion and metastasis. MYBBP1A NM_​001105538.1 17p13.3
Except for rare embryonic mutations and certain pediatric MYO1C NM_​001080779.1 17p13.3
tumors, cancers develop over decades and involve the accumulation NASP NM_​001195193.1 1p34.1
NCOA2 NM_​006540.2 8q13.3
NFRKB NM_​001143835.1 11q24.3
Table 2–2. Chromatin Remodeling Genes PHF10 NM_​018288.3 6q27
PHF17 NM_​001287437.1 4q28.2
Gene Symbol RefSeq ID Chromosome Location PHF19 NM_​001009936.2 9q33.2
PIWIL4 NM_​152431.2 11q21
ACTB NM_​001101.3 7p22.1
PSIP1 NM_​001128217.1 9p22.3
ACTL6A NM_​004301.3 3q26.33
RAD54B NM_​001205262.2 8q22.1
ACTL6B NM_​016188.4 7q22.1
RAD54L NM_​001142548.1 1p32
ACTR3B NM_​001040135.2 7q36.1
RAD54L2 NM_​015106.2 3p21.2
ACTR5 NM_​024855.3 20q11.23
RB1 NM_​000321.2 13q14.2
ACTR6 NM_​022496.4 12q23.1
RSF1 NM_​016578.3 11q14.1
ARID1A NM_​006015.4 1p36.11
RUVBL1 NM_​003707.2 3q21.3
ARID2 NM_​152641.2 12q12
RUVBL2 NM_​006666.1 19q13.3
ATAD2 NM_​014109.3 8q24.13
SETD6 NM_​001160305.1 16q21
ATRX NM_​000489.3 Xq21.1
SMARCA1 NM_​001282874.1 Xq25
BAHD1 NM_​014952.3 15q15.1
SMARCA5 NM_​003601.3 4q31.21
BAZ2A NM_​013449.3 12q13.3
SMARCAD1 NM_​001128429.2 4q22.3
BRD4 NM_​014299 19p13.12
SMARCAL1 NM_​001127207.1 2q35
BPTF NM_​004459.6 17q24.3
SMARCC1 NM_​003074.3 3p21.31
BRMS1 NM_​001024957.1 11q13.2
SMARCC2 NM_​001130420.1 12q13.2
CHAF1A NM_​005483.2 19p13.3
SMARCD1 NM_​003076.4 12q13.12
CHAF1B NM_​005441.2 21q22.13
SMARCD2 NM_​001098426.1 17q23.3
CHD1 NM_​001270.2 5q15-​q21
SMARCD3 NM_​001003801.1 7q36.1
CHD1L NM_​001256337.1 1q21.1
SMARCE1 NM_​003079.4 17q21.2
CHD2 NM_​001042572.2 15q26.1
SRCAP NM_​006662.2 16p11.2
CHD3 NM_​001005273.2 17p13.1
TFPT NM_​013342.3 19q13
CHD4 NM_​001273.2 12p13.31
TOP2A NM_​001067.3 17q21-​q22
CHD5 NM_​015557.2 1p36.31
TOP2B NM_​001068.3 3p24.2
CHD6 NM_​032221.4 20q12
TP73 NM_​017818.3 1p36.32
CHD7 NM_​017780.3 8q12.1-​q12.2
VPS72 NM_​001271087.1 1q21.3
CHD8 NM_​020920.3 14q11.2
YY1 NM_​003403.4 14q32.2
CHD9 NM_​025134.4 16q12.2
ZHX1 NM_​001017926.2 8q24.13
CTBP1 NM_​001328.2 4p16.3
ZNHIT1 NM_​006349.2 7q22.1
CTCF NM_​001191022.1 16q22.1
ZRANB3 NM_​001286568.1 2q21.3
CTCFL NM_​001269041.1 20q13.31
 13
Biology of Neoplasia 13
of genetic and epigenetic alterations in interplay with the immune
system.
HALLMARKS OF CANCER CELLS
From the careful dissection of the properties of many tumor types,
Weinberg and Hanahan, in two review articles over a decade apart,
described the most common features, or hallmarks, of the tumor cell
(Hanahan and Weinberg, 2000, 2011) (Figures 2–3a and 2–3b). These
are common characteristics of most tumor types. At the individual
cell level, the most important hallmarks are self-​renewal, uncontrolled
growth, absence of growth regulation, loss of DNA repair, and loss of
programmed cell death in the face of these lesions. These hallmarks
are especially important at the initial stages of carcinogenesis in the
formation of the pre-​malignant and later malignant lesion.
At later stages, a tumor acts as a multicellular entity that interacts
with multiple normal cells of the immune system, stimulates the pro-
duction of new blood vessels (angiogenesis), and develops the ability
to invade other tissues and metastasize.
Cancer Stem Cell Model
The most important hallmark of cancer cells is the continual growth
of the tumor, or self-​renewal. In the body’s normal stem cells, self-​
renewal is a mechanism to generate cells identical to the stem cell and
maintain a population of pluripotent, multipotent, or oligopotent cells.
One model of cancer places a major emphasis on the ability of cancer
cells to undergo self-​renewing replication like that which occurs in
stem cells (Al-​Hajj et al., 2004; Dean et al., 2005). In certain tumor
types and tumor models, cancer stem cells or tumor initiating cells
have been isolated (Al-​Hajj et al., 2003).
One pathway to tumor development starts with a chronically rep-
licating normal stem cell. These cells naturally possess several of the
“hallmarks of cancer.” Sustained or chronic tissue damage and/​or
inflammation can lead to the activation of stem cells and their con-
tinuous replication. Such a population of replicating stem cells can
become a target for somatic mutations that cause sustained prolifera-
tive signaling and/​or evasion of growth suppression.
This leads to a pre-​malignant cancer stem cell, a target for further
mutation and uncontrolled proliferation and loss of growth control.
Early mutations can also promote defective DNA repair, and the loss
of checkpoints in the cell cycle preventing cells with damaged DNA
or aneuploid chromosomes from replicating. Genome instability and
(a) (b) (c) (d)
Self-
Renewal
Uncontrolled
Growth
Replication of Defective DNA Repair/
Damaged Cell Chromosome Integrity
Oncogene Tumor DNA Repair
Activation Suppressor Gene Mutation
Loss
Figure 2–3a.  Hallmarks of cancer cells: early stages. Tumors often show
properties common across cancer types. (a) Self-renewal is a type of cell
division that generates daughter cells identical to the original cell. Stem
cells also undergo this type of division. These cells have been termed can-
cer stem cells, or cancer-initiating cells. (b) Whereas most normal cells
will stop dividing as they come in contact with other cells (contact inhibi-
tion), many tumor cells continue to grow. (c) Reduced cell death. Cell death
is a normal process for many cells in the body, but many tumor cells are
defective in this process and continue to survive in the presence of damage.
(d) Tumor cells can be defective in DNA repair their telomeres.
(e) (f) (g)
Altered energetics/
Metabolism
Loss of
Immune Control
Angiogenesis
(h) (l)
Epigenetic
Reprogramming
Invasion and Metastasis
Figure 2–3b.  Hallmarks of cancer cells: late stages. (e) The immune system
can recognize abnormal or infected cells and destroy them. Cancer cells can
evade the immune system. One mechanism is the secretion of inhibitory
factors such as checkpoints and cytokines. (f) A growing tumor requires a
blood supply, and tumors can stimulate the production of new blood ves-
sels. (g) Many tumors switch to glycolosis as an energy source (Warburg
effect). (h) Invasion into surrounding tissues and other parts of the body
(metastasis) are common tumor properties. (i) Tumor cells mutate one or
more genes that modify the histone proteins that form chromatin (chromatin
remodeling genes) and permit epigenetic reprogramming of the genome.
defective DNA repair promote further genome instability and mutation
and tumor evolution.
However, most morbidity and mortality from cancer is the result of
tumor invasion and/​or metastasis, and tumor progression involves the
activation of invasion and metastasis, the induction of angiogenesis
to provide a blood supply to the growing tumor, the evasion of the
immune system, and altered cell energetics.
Epigenetic Reprogramming
In virtually all tumor types, a newly described class of frequently
mutated genes consists of enzymes involved in histone modification
and components of chromatin remodeling complexes. One model of
cancer involves a stage of cellular reprogramming of expression state
(epigenetic state), altering entire programs of gene expression. The
ability to turn on or off whole programs of expression allows the tumor
cell to adapt to virtually all encountered barriers
• Invasion:  The cancer cell can turn on (or the cancer stem cells
already possess) the ability to respond to homing signals, migrate
through tissue into the bloodstream, and travel to other parts of the
body. Portions of the tumor may establish a niche whereby other
cells in the tumor can proliferate and grow.
• Immune evasion: Tumor cells can express immune evasion signals
(such as PD-​L1) and inhibit immune cells that recognize the tumor
as foreign.
• Cell metabolism: Many tumor cells alter their energetics and metab-
olism. For example, initiating programs of gene expression that
allow the use of glucose, or anaerobic glycolysis.
14

14 Part I:  Basic Concepts

Tumor Differentiation and Evolution
At first glance, the tumor seems like one of the mythical beasts that
Ulysses encountered on his journey, a Hydra or a Cyclops. But in fact
the cancer cell is a human cell and therefore utilizes tools that our
normal cells employ and is subject to most of the same constraints
and restrictions. A human being goes from a single fertilized egg to an
adult with thousands of cell types and tissues with diverse function,
without changing the DNA of the cells (Figure 2–4). This development
and differentiation are all accomplished by the coordinated activation
and repression of distinct programs of gene expression, the secretion
of proteins and other factors that influence neighboring cells, and the
contact and interaction of cells with each other. The tumor likewise
evolves from a single cell, forms a network of self-​renewing and com-
mitted cells, secretes factors that stimulate other cells in the tumor,
and interacts with other tumor cells as well as normal cells.
The transition from a normal fetus to an adult human involves the
continued growth and differentiation of cells to form multiple organs
and specialized cell types. Cells migrate in the growing human, estab-
lish niches for stem cells, develop blood supplies, and in certain cases
alter metabolism and energy utilization. In a parallel fashion, the cells
of a growing and developing tumor alter gene expression profiles in
subpopulations of cells, migrate to different locations, adapt to new
environments, survive over years or decades, and adapt to therapeutic
strategies to eliminate the tumor cell.
A key finding in the connection between the developing embryo and
the tumor was the discovery of oncogenes and tumor suppressors that
are also key embryonic differentiation factors. Gorlin syndrome, or
nevoid basal cell carcinoma syndrome (NBCCS), is an inherited disor-
der characterized by hundreds to thousands of basal cell carcinoma, jaw
cysts, facial and bone abnormalities, and occasionally medulloblastomas
(Anderson et al., 1967; Gorlin and Goltz, 1960). Genetic linkage studies
localized the gene for NBCCS to chromosome 9, and the gene responsi-
ble was identified as Patched (PTCH1) (Gailani et al., 1992; Hahn et al.,
1996; Johnson et al., 1996). This gene was first discovered in drosophila
as part of a group of genes required for normal embryonic development
of the fly, and mutants cause the patchy formation of bristles. Patched is
a cell surface protein and the receptor for a class of secreted, modified
peptides, Hedgehogs (SHH) (Dean, 1996). Patched repressed the activ-
ity of a G-​protein-​coupled receptor Smoothened (SMO), and the binding
of SHH to PTCH1 releases SMO from repression and leads eventually
to changes in gene regulation in the nucleus through the GLI family of
transcription factors (van den Heuvel and Ingham, 1996).
All of the major components of this signaling pathway are conserved
in insects, vertebrates, and other organisms. The correct functioning of
these proteins is required for the development of the growing embryo
and the polarity and symmetry of cells and structures during develop-
ment. We now recognize all the components of this pathway as either
tumor suppressor genes (PTCH1) or oncogenes (SHH, SMO, GLI). In
nearly all cases of NBCCS, we find germline mutations in the PTCH1
gene, and in nearly all sporadic basal cell carcinomas and a portion of
medulloblastomas PTCH1 is mutated. This work provided a clear con-
nection to the functions of development and differentiation of embry-
onic stem cells and the formation of tumors (Bale and Yu, 2001).
Evolution and the Tumor
Our species and all other vertebrates are the product of a billion years
of evolution. Through this process we evolved unique characteristics,

Blood Cells

(a)

Neurons

Muscle Cells
Normal
Stem Cell
Embryo Stem
Fetus Kidney Cells
Cell

(b)
Angiogenic Cells

Tumor Metastatic Cells

Cell

Immune Resistant Cells

Pre-Malignant
Lesion Locally
Invasive
Lesion Tumor Therapy Resistant Cells
Stem
Cell

Figure 2–4.  Cancer development and differentiation. The progression of the tumor cell, from single cell to fully developed malignancy, displays paral-
lels to the development of the organism and differentiation. The embryo is a mix of self-renewing stem cells and cells committed to discrete pathways
of differentiation. A pre-malignant lesion also contains these two classes of cells. (a) The fetus displays an increasing array of differentiating cells types;
formation of blood vessels, altered metabolism, and energy utilization. The local malignant tumor accumulates necrotic cells, and can be angiogenic. The
development from fetus to adult organism requires a large-scale reprogramming of gene expression networks to carry out the generation of cells of multiple
organ and tissue types by epigenetic reprogramming. Epigenetic plasticity in the developing tumor can also lead to the development and differentiation
of a large number of cell types. This can allow spread of the tumor, evasion of cellular processes such as immune attack, and/or survival from therapeutic
approaches. (b) The tumor also undergoes evolutionary selection. The tumor cell progresses from a single-cell organism to a small multi-cellular organ-
ism. Just as evolution allowed diverse classes and species of organisms to evolve from largely the same sets of genes, the tumor can undergo selection for
altered, duplicated, or deleted genes. To adapt to new conditions and survive therapy, the tumor adapts resistance mechanisms. Many of the same principles
of natural selection apply to tumors as apply to populations of species.
 15
Biology of Neoplasia 15
adapted to changing environments, individuals were selectively
removed, and surviving individuals went on to reproduce and survive.
A tumor also undergoes this same selective process, only in the
context of our body and over the time scale of years, decades, or our
lifespan. Many cells in the tumor die, and necrotic areas of larger
tumors are often seen. Radiation, chemotherapy, and other treatments
can kill off large portions of the cancer, and in some cases all cells,
resulting in cures. However, those cells that survive treatment and
retain the property of self-​renewal can continue to grow, resulting in
remission. Many of the principles and concepts that were developed
and used to understand and explain evolution can also be applied to
the evolution of cancer. DNA sequencing of tumor cells at different
sites of the body and/​or stages of the disease is resulting in deeper
understanding of these processes, sometimes at the resolution of sin-
gle cells (Xu et al., 2012).
Key Points
• Cancer cells within a tumor display tremendous diversity.
• New mutations, epigenetic changes, and gene rearrangements occur
continually during the cancer process.
• Cancer cells face barriers to survival that include immune evasion,
therapy resistance, and development of invasion/​metastasis.
Tumor Microenvironment
The cancer cell is a human cell, with many properties in common with
non-​malignant human cells. In the body of the individual, the cancer
cell interacts in a complex manner with the host cells. Therefore, there
exists a microenvironment surrounding the tumor that is composed of
host cells interacting and responding to the tumor and is subject to
modification by the tumor cells. The major classes of cells in the tumor
microenvironment (TME) include the following:
Vasculature:  For tumor cells to advance beyond a size typically
greater than 2 millimeters requires the development of new blood
vessels (angiogenesis). However, the interior of many tumors is
hypoxic and may contribute to tumor cell properties including ther-
apy resistance.
Stromal cells: Fibroblasts can be recruited into the TME and their func-
tions altered to support tumor growth (Hanahan and Coussens, 2012;
Pickup et al., 2013). Myeloid-​derived suppressor cells (MDSCs) are
cells derived from the myeloid lineage’s T cell repressive properties
(Talmadge and Gabrilovich, 2013). Tumor-​infiltrating lymphocytes
are T cells with reactivity against the tumor cells. In certain cases,
these cells have been expanded and used therapeutically (Hinrichs and
Rosenberg, 2014).
Cancer cells need to evade the immune system’s constant probing
for virally infected or otherwise foreign cells. This can be accom-
plished by not expressing foreign antigens or suppressing the immune
response. Many of the new checkpoint inhibitor cancer strategists
using PD-​L1 or PD-​1 inhibitors seek to reverse the immune suppres-
sion of tumors (Sunshine and Taube, 2015).
FIELDS OF EPIDEMIOLOGY AND
THE CANCER PROCESS
Our understanding of the process of cancer development not only has
been shaped by, but also influences all areas of epidemiology, and
increasingly genetic and genomic studies of cancer are applied to sub-
divisions of the field.
Genetic Epidemiology
Classical genetic epidemiology involved the identification of rare can-
cer families, the study of genetic conditions that contain cancer as a
phenotype, and the determination of heritability. More recent genetic
epidemiology has involved the study of genome-​ wide association
studies (GWAS), identification of common but low relative risk alleles,
and more broadly the genetic architecture of genetic risk in popula-
tions in relation to cancer (Chung and Chanock, 2011). Currently there
are almost 500 loci identified in the genome that modify risk of one
or more cancers. However, in only a few cases do we understand the
molecular basis of these effects.
Occupational/​Environmental Epidemiology
The role of environment (broadly defined, including lifestyle factors)
and occupation in the development of cancer has been critical. Acute
or long-​term environmental or occupational exposures can contribute
to chronic inflammation or tissue damage (smoking, asbestos expo-
sure, benzene, etc.). Agents may cause tissue damage/​inflammation
(UV exposure, radiation, asbestos, infectious agents), or may induce
mutations (radiation, mutagenic chemicals, mutagenic viruses), or
commonly both. In some cases (tobacco, UV exposure, viral infec-
tions), we can now detect specific mutational signatures in cancer
genomes.
Radiation Epidemiology
Radiation exposure can occur through the environment, occupation,
accidents, or medical treatment, and can often be accurately measured
and modeled in many organisms. While in acute or concentrated doses
radiation can cause tissue damage, the majority of the carcinogenesis
of radiation is due to DNA damage and mutation.
Hormonal Epidemiology
Many major cancers involve reproductive organs or organs exclu-
sive or largely to one gender (cervix, prostate, breast, ovary). These
tumor types involve major hormonal effects. For example, many breast
tumors are dependent on estrogens and/​ or progesterone, and this
knowledge has aided both prevention and therapy.
However, there is also a large gender discordance for many other
types:  male bias in bladder cancer, any pediatric cancers, and liver
cancer; female bias in chronic lymphocytic leukemia and thyroid can-
cer. In most cases we do not understand these effects. As hormone
production and exposure change dramatically over time for males and
females, this is a critical area of cancer epidemiology.
Infectious Disease Epidemiology
Many of the world’s most common cancers and the cancers that dis-
play the greatest disparities due to income involve infectious agents
(cervical and HPV, liver and HBV and HCV, and gastric and H. pylori)
(Klein, 2002; Schiffman and Castle, 2005; Torre et al., 2015; Uemura
et al., 2001; zur Hausen and de Villiers, 1994). The list of direct causes
of cancer by infectious agents and pathogens is impressive. And the
role of other chronic infections remains to be fully explored.
Nutritional Epidemiology
The nutritional state of the individual, diet, body mass index (BMI),
and related conditions such as diabetes and obesity are increasingly
recognized as major risk factors for cancers. Studies show that virtu-
ally all cancer types increase with increasing BMI. Furthermore, the
increase in BMI and obesity in world populations has led to projec-
tions that this will be a more significant risk factor than tobacco in the
future (Calle et al., 2003).
The mechanisms by which increased body mass contributes to can-
cer are poorly studied. However, some of the hormones regulated by
energy consumption, such as insulin and insulin-​like growth factors,
are tied to cellular pathways for growth and division. Many tumor
suppressor and oncogene networks connect to metabolic pathways,
and some enzymes of the tricarboxylic acid (TCA) cycle are tumor
suppressor genes. In addition, fat deposition and obesity can cause an
inflammatory state and may therefore be analogous to other inflamma-
tory states such as viral and bacterial infections.
16
16 Part I:  Basic Concepts
AGING AND CANCER
Just as cancer is a genetic disease, it is also a disease of aging. Age is
the most important risk factor for most adult cancers, and many of the
processes that we understand are operative in cancer development can
be thought of in light of aging.
DNA Damage
With time, the cells of our body accumulate DNA damage. Much
of this occurs through natural processes, such as the deamination of
5-​methyl-​cytosine found in many DNA regions; 5-​methyl-​cytosine
spontaneously deaminates to uracil, and the body has an enzyme/​DNA
repair system to recognize this damage and repair it. However, this
process is error prone, and DNA lesions accumulate over time, leading
in cases to the accumulation of sufficient mutations in a single cell to
start the cancer process.
One of the new areas of cancer genome study is the ability to exam-
ine the whole genomes of cancer cells and discern the signatures of
mutational processes (Alexandrov et al., 2013). By tabulating all muta-
tions in the tumor genome, and noting the nature of the base changes
and the local context of the mutation, signatures can be identified.
The most common cancer signature is indeed one in which a CpG is
mutated (Shiraishi et al., 2015).
Chronic Infection
Especially for cervical, gastric, and liver cancer, chronic infections
by HPV, H. pylori, and hepatitis viruses (HBV, HCV) are the prin-
cipal cause. None of these infections causes cancer shortly after
infection; all require a long latency period in which the infectious
agent stimulated tissue damage, inflammation, local repair, and
activation of tissue stem cells before pre-​malignant and malignant
lesions arise.
It is recently appreciated that activation of innate anti-​viral infection
mechanisms, such as the ABOBEC family of anti-​viral proteins, over
long periods of time can lead to somatic mutations in tumor cells. The
second most common signature is one consistent with APOBEC activa-
tion (Lawrence et al., 2013; Shiraishi et al., 2015). It is indeed commonly
found in cervical cancer and head and neck cancers associated with HPV
infection, but also with acute lymphocytic leukemia (ALL), bladder,
breast, kidney, pancreas, and some forms of lung cancer. Whether there
are unappreciated viral infections influencing these cancers, or alternate
pathways to activate APOBECs, remains to be determined.
Chronic Inflammation
A large number of cancers are caused by chronic inflammation caused
by radiation, irritants, toxins, or immune inflammatory processes. For
example, a person with ulcerative colitis or Crohn’s disease has an
elevated risk to develop colorectal cancer (Jess et al., 2012). The role
of asbestos in lung cancer, UV radiation and sunburn in skin cancer,
and irritants in tobacco products in lung and oral cancers are well doc-
umented. As with viral infections, these cancers develop over many
decades, and the aspects of aging on the development of cancer due to
inflammation are poorly understood.
Cell Senescence and Telomere Regulation
Telomeres are the protective elements at the chromosome ends that
aid in preventing unscheduled DNA repair and degradation. They are
composed of repetitive DNA sequences (TTAGGG repeats) bound to
an array of proteins with specialized functions (Donate and Blasco,
2011). The protection afforded to the chromosome depends on the
length of telomeric repeats and the integrity of the telomere-​binding
proteins. The length and integrity of telomeres are regulated by specific
epigenetic modifications, indicating that a higher order control of telo-
mere function exists. After each round of cell division is completed,
the telomeres are shortened because the conventional DNA polymer-
ases are unable to replicate the ends of chromosomes. This is known as
the “end replication problem” (Donate and Blasco, 2011). This is why
a cellular enzyme called telomerase may be recruited in certain situa-
tions to add TTAGGG repeats to the chromosome ends. The enzyme
telomerase consists of a subunit Tert that possesses reverse transcrip-
tase activity, an RNA element called Terc that is the template on which
DNA is synthesized, and a protein called dyskerin (DKc1) that has the
ability to bind and stabilize Terc. Upregulated telomerase expression
is a feature of pluripotent stem cells and also of early stage embryonic
development; however, telomerase activity can also be present in adult
stem cell compartments (Blasco, 2005).
Telomere length and Tert are critical factors determining the mobili-
zation of stem cells. However, it was also found that shelterin, a major
protein complex bound to mammalian telomeres, may play a role in the
initiation of neoplasia (Donate and Blasco, 2011). Mice conditionally
deleted for the shelterin proteins TRF1, TPP1, and Rap1 were gener-
ated, and this demonstrated that telomere dysfunction is sufficient to
produce premature tissue degeneration, acquisition of chromosomal
aberrations, and the initiation of neoplastic lesions (Blasco, 2005).
Based on further experiments, a stem-​cell-​based model for the role
of telomeres related to cancer and aging was proposed (Donate and
Blasco, 2011). It was proposed that in young or adult organisms, stem
cells have the ability to repopulate certain tissues as needed. During
this process, the stem cells undergo telomere shortening, which is
only partially counterbalanced by the action of telomerase. However,
in older organisms, the stem cell telomeres are actually too short.
Critically short telomeres are recognized by the body as DNA damage.
This recognition of potential DNA damage activates a p53-​mediated
DNA damage signaling response that can impair stem cell mobiliza-
tion, leading to suboptimal tissue regeneration, which may ultimately
lead to organ failure. This phenomenon of decreased stem cell mobi-
lization reduces the probability that abnormal cells will accumulate in
tissues and thus provides a mechanism for cancer protection. On the
other hand, if stem cells express aberrantly high levels of the enzyme
telomerase (by the acquisition of tumorigenic, telomerase-​reactivating
mutations), stem cell mobilization is more efficient and tissue fitness
is maintained for a longer time. This would increase life span, but
would also increase the probability of initiating a tumor (Donate and
Blasco, 2011).
The Aging Immune System and Cancer
It has been found that the incidence of most common cancers increases
with age and may possibly be caused by a decline in immune func-
tion. This phenomenon is called “immune senescence” (Foster et al.,
2011). The causal determinant for this phenomenon, although highly
controversial, may be deleterious changes to T-​cell subsets that over
time may impair immunity. In one murine study, tumors were able to
limit the function of CD8 + T cells, including specific responses to
tumor antigens specific for prostate tumors (Anderson et  al., 2007).
Another study showed that microvesicles isolated from human tumor
cells were able to induce the generation and expansion of Treg (T regu-
latory cells) that are capable of suppressing T-​cell responses (Szajnik
et al., 2010). In relation to this, the immunoregulatory effects of the
tumor (and its environment) on T cells, along with the decreasing abil-
ity of the body to replace naïve T-​cell populations, may allow cancers
to progress because T cells seem to have a fixed immune repertoire
associated with age-​related immunosenescence. The intricate mecha-
nisms that lead to declining cellular immunity are very unclear, but
the progressive decline in thymic output of T cells may be the primary
event leading to immune senescence in old age. With age, the produc-
tion of new naïve T cells reduces, resulting in the peripheral T cells
having to undergo repeated rounds of cell division in order to main-
tain the status quo so that the overall size of the T-​cell compartment
remains relatively stable. This prolonged survival of the peripheral
T cells results in defects in all types of activation states of T cells, from
the naïve to the terminally differentiated. This reduction in functional
immunity can be permissive to tumor formation and might promote
 17
Biology of Neoplasia 17
tumor formation by contributing to low-​level inflammation. In order
to circumvent this pro-​inflammatory environment, specific cytokine
blockers may be beneficial to both neoplasia and other inflammatory
disease states, but have the drawback of compromising the immune
system (Zidi et al., 2010). Thus, more research needs to be carried out
to determine the specific mechanisms of action of cytokine blockers to
allow for the development of targeted therapies.
Another strategy would be to delay replicative senescence in T cells,
utilizing strategies that sustain telomerase activity (Effros, 2011).
While we have learned a lot about the role of age-​related declining
immunity as it relates to cancer incidence, the precise cellular mecha-
nisms through which this occurs still remain elusive. As research pro-
gresses, from animal models to human clinical trials, new therapeutic
strategies to enhance immune function may become powerful tools to
reduce cancer incidence (Foster et al., 2011).
CONCLUSIONS
Many of the genetic and biological processes that occur in cancer cells are
now well documented. Through the study of animal models, cell culture
systems and human tumors we have detailed catalogs of the following:
• The genes in which germline mutations cause highly penetrant can-
cer syndromes;
• Genetic loci from GWAS studies that influence cancer risk;
• Genes frequently altered somatically in cancer.
There is considerable work still in progress to identify rare alleles
involved in cancer risk, to understand the function of cancer GWAS
loci, and to understand complex copy number changes and gene rear-
rangements in cancer cells.
Most of the major environmental and occupational risk factors associ-
ated with cancer have been identified and can now be at least partially
understood at the molecular level from current data. The exciting new
area of mutation signatures promises to further reveal the effect of spe-
cific exposures on somatic alterations in tumors. However, even the well-​
known cancer-​causing infections, such as human papillomavirus (HPV),
hepatitis B virus (HBV), and hepatitis C virus (HCV), are only partially
understood, and there is much left to be learned regarding agents such
as asbestos, tobacco smoke, and chemical carcinogens. The long latency
of cancer and the complexity of the human immune system and tumor
microenvironment leave enormous areas for future investigation.
Epigenetic modification has emerged as a major factor in the devel-
opment of cancer, largely in the later stages of the disease. Nearly
all cancers have mutations in one or more histone-​modifying enzyme
affecting chromatin structure, and/​or enzyme-​regulating DNA methyl-
ation (Figure 2–5). An intriguing outcome of these findings is that the
deregulation of the epigenome, and/​or “return to an embryonic state,”
may be a newly appreciated hallmark of cancer. This model would
(a) Naked DNA
(b) DNA covered in histones
and other chromatin proteins
(c) Histones modified by adding or
removing methyl or acyl groups
(d) Remodeling of histones to
create “open” chromatin or
closed, inaccessible regions
Figure  2–5.  Chromatin alteration and remodeling (a) DNA is a charged
molecule. (b) DNA is covered by histones and other proteins to form
nucleosomes and chromatin. (c) Histones undergo extensive modification.
(d) Other protein complexes (chromatin remodelers) can alter the location
of nucleosomes, make DNA open to transcription factors turning genes on,
or, covering regulatory regions, turning genes off.
suggest that cancer cells can acquire a plastic state that would allow
the generation of cells in the tumor capable of diverse functions and
evolution. A therapeutic attraction to this model is that this may be a
reversible process that could be manipulated.
Single cell genomic analyses of tumors are revealing an enormous
level of complexity and heterogeneity. These studies can be used to
follow the evolution of cancer cells over both time and location in the
cancer patient.
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 19
3 Morphological and Molecular Classification of Human Cancer
MARK E. SHERMAN, MELISSA A. TROESTER, KATHERINE A. HOADLEY,
AND WILLIAM F. ANDERSON
OVERVIEW
Defining etiological, biological, and clinical heterogeneity are impor-
tant goals in epidemiologic research. To achieve these aims, epide-
miologists conduct trans-​ disciplinary studies to relate both newly
identified and established cancer risk factors to specific cancer sub-
types defined by histopathological and molecular features. Thus, the
traditional model of identifying cancer risk factors by organ site alone
has been supplemented, and largely supplanted.
Relating specific cancer risk factors to groups of tumors that share
a common molecular pathogenesis offers opportunities to strengthen
risk associations and provides a strong basis for translational research
on early detection or prevention based on underlying biology. The
promise of this strategy has been revealed through efforts to offer
carriers of deleterious mutations in high-​penetrance genes, such as
BRCA1/​2, comprehensive strategies to prevent breast and ovarian
cancers, and the administration of prophylactic human papillomavi-
rus (HPV) vaccines to dramatically reduce risks of cervical cancer
and HPV-​induced cancers arising at other anogenital sites and in the
head and neck.
This chapter provides a primer on approaches that use pathology
and molecular biology to subclassify cancers in epidemiologic studies.
Given the breadth of this topic and its rapid evolution with changing
technologies, the goal is to emphasize important principles and pro-
vide illustrative examples, rather than to comprehensively review this
subject. Readers are encouraged to consult specific chapters through-
out the text that demonstrate the application of the principles presented
to cancers of specific organs or exposures.
INTRODUCTION
Cancer is a biologically and clinically heterogeneous class of dis-
eases. Much of epidemiological research is concerned with under-
standing the causal and mechanistic sources of this diversity
because identification of etiologically “refined” cancer subtypes
may increase the specificity of risk associations and predictions,
enabling more effective screening, prevention, and population
surveillance.
Cancers arising from different organs are associated with distinct
clinical presentations and behaviors, and therefore primary ana-
tomic site of origin is a critical determinant of clinical management.
However, expanding knowledge of the epidemiology, pathology, and
molecular profiles of cancer, and the intersection of these factors, has
led to development of novel tumor classifications, which categorize
tumors within and across organ sites and disciplines. This new per-
spective has had a major influence on therapeutic research, and has
led to development of “basket trials,” in which participant eligibility
is based on molecular characteristics of tumors, rather than primary
sites. In treatment trials, such as the MATCH Trial (McNeil, 2015),
individuals with cancers that demonstrate particular candidate driver
mutations are selected to receive targeted therapies, irrespective of site
of origin. Basket trials are innovative, but their promise is tempered
by data suggesting that primary site remains an indicator of response,
even among cancers that share a common mutation in a putative driver
gene, such as BRAF (Hyman et al., 2015).
The “basket trial” concept has received less attention in the context
of etiological and prevention research than in the realm of treatment
trials, but recognition that cancers of different sites may share com-
mon etiologic exposures and molecular mechanisms of carcinogene-
sis suggest that this concept may have similar potential. For cancers
that are causally linked to an infectious agent, such as carcinogenic
human papillomavirus (HPV) genotypes (Jemal et al., 2013), highly
effective prophylactic HPV vaccines may lower risks of HPV-​related
cancers of the cervix, vagina, vulva, anus, penis, and head and neck
(Herrero et al., 2015). For cancers driven by common molecular
mechanisms, such as specific DNA repair defects (e.g., Lynch syn-
drome and BRCA1/​2 mutations), hormonal imbalances or metabolic
disturbances (e.g., breast and gynecologic cancers), the possibility of
identifying individuals at risk for a set of cancers that are related to
common etiological and/​or mechanistic factors offers the prospect of
lowering incidence rates of several cancers with a single intervention.
Achieving this aim will require epidemiologists to extend their efforts
from accurate assessment of exposures to detailed characterization of
endpoints.
Evolving methods of tumor classification integrate data across mul-
tiple scales, encompassing populations, patient-​level factors, primary
anatomical site, histopathological typing, and molecular characteriza-
tion. Research at each of these scales, as well as synthesis of informa-
tion across them, is needed to gain the comprehensive understanding
of cancer etiology and pathogenesis that will be required to develop
improved strategies for cancer prevention and lower cancer mortality.
The aims of this chapter are to introduce the breadth of approaches
for tumor classification, comment on their strengths and weaknesses,
and illustrate their applications in epidemiological research. Given the
immensity of this subject, and its rapid evolution, this chapter empha-
sizes histopathologic and molecular classifications of cancer and their
relationships with complementary approaches (Hoadley et al., 2014).
Specific examples are provided to demonstrate principles. Detailed
discussions of individual organ sites are presented throughout this
volume.
CHARACTERISTICS AND DEFINITIONS
OF NEOPLASMS (NEW GROWTHS), CANCERS,
AND CANCER PRECURSORS
The synonymous terms “neoplasm” and “tumor” refer to new growths
that do not respond physiologically to growth signals and disrupt nor-
mal anatomy. Tumors are further categorized as benign or malignant.
Benign neoplasms (and tumor-​like lesions, such as hamartomas) are
circumscribed, remain confined to the primary site of origin, and
are usually curable with surgical removal. In contrast, lesions desig-
nated with the synonymous terms “malignant neoplasm” or “cancer”
are defined by the potential to invade and destroy benign tissues and
metastasize (spread) to other sites.
Metastatic lesions cause death by damaging normal tissues, leading
to organ dysfunction, and by producing deleterious systemic effects,
such as coagulation abnormalities or metabolic disturbances that dis-
rupt homeostasis. Even small metastases may prove lethal, if deposits
impair critical physiological functions, such as occurs with metasta-
ses to cardiorespiratory centers in the brainstem. In some instances,
19
20
20 Part I:  Basic Concepts
cancers result in poorly understood metabolic defects leading to
multiple organ failures, arrhythmias, cardiorespiratory arrest, hem-
orrhage, or thrombosis. Other cancers behave indolently initially and
may remain asymptomatic for long periods of time, even if untreated.
Asymptomatic cancers may be detected through targeted screening
or incidentally via routine clinical practices such as blood tests or
radiologic imaging. The behavior of certain cancers, particularly a
subset of breast and prostate cancers, is characterized by variable
periods of dormancy at metastatic sites, which may become clinically
symptomatic years following initial diagnosis and treatment (Yeh
and Ramaswamy, 2015). Thus, defining the mechanisms and mark-
ers associated with asymptomatic cancers and late recurrences is an
important challenge.
The definition of metastasis is sometimes complex. For example,
endometriosis is a benign disease that is hypothesized to develop
from sloughed benign menstrual endometrium (uterine lining) that
passes through the fallopian tube, implants, and grows outside of the
uterus, especially in the ovaries (Vercellini, 2015). Epidemiologic and
molecular data suggest that in rare instances, endometriotic lesions
may undergo malignant change, thereby giving rise to ovarian endo-
metrioid or clear cell carcinomas (Pearce et al., 2012). Further, tubal
ligation is protective for ovarian cancer, particularly the endometrioid
subtype, which could reflect a reduction in endometriotic lesions from
which these tumors arise, among other postulated mechanisms (Rice
et al., 2012). Other non-​metastatic processes may also “transport”
benign or malignant cells to distant sites, either naturally or secondary
to instrumentation, but if such lesions do not cause harm, they may not
constitute metastases.
PATHOLOGY IN CANCER DIAGNOSIS AND RESEARCH
In diagnostic pathology, macroscopic, microscopic, and molecu-
lar features in conjunction with clinical data are used to distinguish
non-​neoplastic from neoplastic lesions, and to divide the latter into
benign or malignant tumors. Although pathologic criteria are gener-
ally useful in predicting the average behavior of groups of tumors, the
performance of histopathology alone in estimating the prognosis and
treatment response of individual cancers is more variable. The power
of morphology derives from the concept that it reflects the integrated
interaction of tumor and host characteristics over time (i.e., form fol-
lows function). However, the force of this advantage is limited by the
inability to accurately measure specific features, which reflects the
subjectivity of visual assessment, the enormous morphologic vari-
ability of malignant and benign tissues under varying physiologic and
pathophysiologic states, and the effects of technical artifacts. In addi-
tion, different molecular alterations may yield similar morphologic
features.
Benign neoplasms show greater cellular organization than malig-
nant tumors and are composed of cells that more closely resemble
normal cells of the organ site of origin (Table 3–​1). Microscopically,
benign tumor cells are generally smaller than cancers cells and con-
tain smaller nuclei with modest variability in size and shape, mini-
mal hyperchromasia, fine chromatin detail, a lower ratio of nuclear
to cytoplasmic area, and a low mitotic index. Malignant tumors are
composed of cells in disordered arrangements, which are character-
ized by a higher ratio of nuclear to cytoplasmic area and nuclei that
Table 3–​1. Distinctive Features of Benign Versus Malignant Tumors
(Cancers)
Feature Benign Malignant
Differentiation High—​resembles normal Variable—​basis for grading
Pleomorphism Generally low Variable—​generally high
Mitoses Variable Variable—​may be abnormal
Organization High Disorganized
Growth Circumscribed or Invasive, metastatic potential
encapsulated
have irregular shapes and uneven chromatin distribution, and appear
hyperchromatic (dark) on hematoxylin and eosin-​stained sections (a
correlate of aneuploidy or polyploidy).
Histopathology aims to predict biological behavior by analyzing tis-
sues, whereas cytopathology relies on the microscopic appearance of
individual cells and small cell clusters. Newer morphologic computer-​
based methods are demonstrating the possibility of predicting cellular
behavior based on characteristics beyond unaided human visualization
(Beck et al., 2011). Further, improved methods for identifying and/​or
isolating rare circulating tumor cells based on physical properties and
molecular markers may eventually enable detailed characterization of
such cells to predict prognosis or guide treatment, especially in the
setting of therapy-​resistant or recurrent cancer. With respect to isolat-
ing circulating tumor cells, developing methods to improve recovery,
purity, viability, relative enrichment, and throughput remain as chal-
lenges (Esmaeilsabzali et al., 2013). Analysis of cell free macromol-
ecules (DNA, RNA, etc.) derived from cancers represent an alternate
approach.
A goal of quantitative pathology techniques is to convert sub-
jective semi-​quantitative and qualitative observations (i.e., ana-
log data) to measured quantities (digital data) that are amenable
to statistical analysis and interpretation. While this process brings
the power of analytical methods to bear, unrecognized subjective
clues that experienced pathologists use may be lost. Conversely,
identification of quantitative features with image analysis may help
pathologists refine microscopic diagnostic criteria. Nonetheless,
under certain states, benign cells may demonstrate morphologic
and non-​morphologic features that overlap with cancer, including
mutations in cancer-​associated genes, such as p53 in the fallopian
tube, PTEN in endometrium, and mutations in sun-​exposed eyelid
skin (Lee et  al., 2007; Martincorena and Campbell, 2015; Mutter
et al., 2001).
Proliferation is among the best-​recognized features of cancer cells,
but like many other cancer hallmarks (Hanahan and Weinberg, 2011),
it is not a pathognomonic or specific diagnostic feature. Benign cells
located at the base of epithelia and immature cells in benign bone
marrow may also be highly proliferative. However, in contrast to can-
cer cells, mitotically active benign cells help preserve homeostasis
by responding appropriately to the balance of multiple signals (e.g.,
growth factors, hormones), reflect the intrinsic state of cells (e.g.,
senescence, dormancy), and interact physiologically with the systemic
milieu and the microenvironment, rather than dividing autonomously.
Cancer treatments, such as chemotherapy and radiation, that non-​
specifically damage dividing cells may also injure benign dividing
cells, accounting for some adverse effects of these treatments (e.g.,
bone marrow toxicity or mucositis). In response to injury (e.g., radia-
tion or chemotherapy) or hormone exposures, benign cells may show
nuclear pleomorphism (variable appearances) that mimics cancer
cells (Arias-​Stella, 2002; Oliva et  al., 2013). The broad overlapping
range of morphologic appearances of benign and malignant cells may
pose challenges for classifying lesions using morphologic and non-​
morphologic methods.
CLASSIFICATION/​TERMINOLOGY OF MALIGNANT
TUMORS (CANCERS)
Overview
Cancers are divided according to states or stages of progression
(American Joint Committee on Cancer [AJCC], 2011), such as in situ
versus invasive, and the latter are grouped according to patterns of
differentiation as carcinomas (epithelial) versus sarcomas (mesenchy-
mal or connective tissue). Lymphoid/​hematologic tumors (technically
sarcomas), germ cell tumors, and melanomas (technically carcinomas)
are typically considered separately because of their distinctive biologi-
cal and clinical features (Figure 3–​1). The basic morphologic classi-
fication of cancers is important because it is a fundamental indicator
of tumor biology and is related to etiology, pathogenesis, molecular
alterations, and clinical management.
 21
Morphological and Molecular Classification of Human Cancer 21
Tumor = Neoplasm
Benign Malignant Tumor
• “omas” Malignant Neoplasm
• Adenoma (glands) Cancer
• Fibroma, Chondroma,
etc. (Any Stromal
Component)
• Tumor-like
Carcinoma Sarcoma Other
• Lymphoma
• Papillomas • Epithelial • Stroma
• Melanoma
• Polyps
• Germ Cell
Adenocarcinoma Squamous Cell Carcinoma Other
Undifferentiated
Neuroendocrine
Carcinosarcoma
Figure 3–​1.  Terminology of neoplasms.
Carcinomas Are Malignant Tumors That Demonstrate
Epithelial Differentiation
Carcinomas arise predominantly from the surface linings of hollow
viscera, including the respiratory, gastrointestinal, gynecological, and
genitourinary tracts, or solid organs, such as breast, prostate liver, pan-
creas and kidney, and skin. Given that the lumens of hollow viscera
are connected, at least indirectly, to the environment outside the body,
these surfaces are exposed to potential carcinogens derived from both
the external (exogenous) environment (e.g., inhaled, ingested, ascend-
ing genital and genitourinary pathogens) and those generated within
the body (endogenous). The thickness, cellular composition, and
organization of visceral epithelium are highly variable, but a major
distinction is whether the lining is composed of squamous cells or
glandular cells.
Maintenance of epithelia requires continuous regeneration to replace
cells that have died, have been shed, or have undergone senescence.
Epithelium is characterized by a more highly proliferative basal com-
partment (away from lumen) and a non-​dividing compartment charac-
terized by cellular maturation or differentiation (specialized function).
Current knowledge about number, distribution, and plasticity of stem
cells, factors that may influence expansion, contraction, or elimination
in the context of mutations, and their tissue context-​dependent func-
tions (i.e., stem cell niches) continues to evolve (Frede et al., 2014).
The number of divisions in normal stem cells required for epithelial
maintenance in specific organs is hypothesized to correlate with can-
cer risk (Tomasetti and Vogelstein, 2015). Thus, the predominance of
carcinomas as opposed to other types of cancer among humans may
reflect the total number of cells comprising epithelia, the requirement
for cells to proliferate to maintain these epithelia (perhaps increasing
the risk of replication errors and clonal expansion of such cells), expo-
sure to carcinogens, and human longevity, with its attendant decline in
functions, such as immunity, DNA repair, telomere maintenance, epig-
enomic markers, and other mechanisms that promote genetic stability
(Franzke et al., 2015).
Visceral epithelium is typically multilayered and coated with vari-
ous acellular substances, such as keratin or mucins that protect under-
lying parenchyma from injurious agents (i.e., mucosae). In addition,
the epithelia are in contact with a microbiome film, which is receiving
increasing attention with respect to its role in cancer and other dis-
eases. Metaplasia, the process by which one type of benign epithelium
is replaced by another, occurs at multiple organ sites. Anatomic sites of
metaplasia are often sites of cell turnover and cancer formation.
Metaplastic transitions between squamous and glandular epithe-
lium occur normally at the junctions of the ectocervix and endocervix,
rectum and anus, larynx and trachea, and esophagus and stomach. In
general, squamous cell carcinomas arise from squamous epithelium
and adenocarcinomas from glandular epithelium. However, the devel-
opment of metaplasia at aberrant sites, often in response to epithe-
lial injury, may result in carcinomas with differentiation that does not
match that of the native epithelium. For example, the esophagus is
lined by squamous epithelium, but glandular metaplasia in the form
of Barrett’s mucosa, often occurring in the context of chronic gastric
reflux, may undergo dysplasia and progress to adenocarcinoma (gland
forming cancer) (Runge et al., 2015). Analogous to many other organ
sites, more meticulous evaluation (endoscopy and biopsy) has led to
increased detection of Barrett’s mucosa with dysplasia (i.e., putative
cancer precursor), but lowered risks of progression to cancer (Runge
et al., 2015). Similarly, the development of squamous metaplasia and
dysplasia in large bronchi of smokers may contribute to the high fre-
quency of squamous cell carcinomas centrally in the lung (Ishizumi
et al., 2010). It is notable that the inter-​observer reproducibility of dys-
plasia diagnoses in Barrett’s mucosa, bronchial epithelium, and other
sites is often imperfect, if not suboptimal.
Definition and Significance of Carcinoma in Situ (CIS)
Carcinomas arise from alterations in benign epithelium, denoted by
terms such as “dysplasia,” “atypia,” or “atypical hyperplasia.” The
most proximate antecedent of invasive carcinoma is referred to as “in
situ carcinoma” (carcinoma in situ [CIS]). In CIS, “malignant appear-
ing” cells are confined within a preexisting epithelial lining or struc-
ture, whereas in invasive carcinoma, malignant cells invade adjacent
tissue compartments (Figure 3–​2). The boundaries between epithelia
(e.g., linings of visceral lumens) and underlying tissues (walls of vis-
cera or dermis) are demarcated by basement membranes, which are
complex acellular structures composed mainly of collagens and pro-
teins (Halfter et al., 2015). These acellular structures contribute impor-
tantly to tissue compartmentalization, organization, and biophysical
properties, and change with aging and pathologic states.
Clinically, the term “cancer” generally refers to invasive carcinoma,
a lesion that has metastatic potential by virtue of breaching the base-
ment membrane and gaining access to blood vessels and lymphatic
channels. Considering CIS as “cancer” is arguably a misnomer because
CIS lacks these features, and generally does not pose risks of lethal-
ity. The majority of CIS lesions are asymptomatic and are detected
by screening with methods such as Papanicolaou (Pap) smear, mam-
mography, colonoscopy, and so on. The term “CIS” has engendered
substantial controversy because of its somewhat arbitrary distinction
from less-​developed precursor lesions of invasive carcinomas and its
threatening connotation.
Cancer registries maintain variable practices with respect to record-
ing CIS lesions at different organ sites. Monitoring incidence rates of
CIS is important in organ systems that are subjected to cancer screen-
ing because the diagnosis of these lesions typically prompts treat-
ment to prevent progression. However, progression of CIS to invasive
Figure 3–​2.  Left: Colon polyp forming exophytic mass projecting from
colonic mucosa. Note well-​formed glands invading stalk of polyp (arrow).
Right: High power view showing invasive adenocarcinoma (malignant
glands) associated with inflammation and stromal changes. From website:
Juan Rosai’s Collection of Surgical Pathology Seminars (http://​rosaicol-
lection.org/​)
2
22 Part I:  Basic Concepts
carcinoma is neither certain nor necessarily rapid, and some CIS
lesions may regress. However, methods to accurately predict which
CIS lesions will become invasive and possibly metastasize during a
patient’s lifetime are lacking. If detecting and treating CIS is beneficial,
then these interventions should lead over time to reduced population-​
based incidence rates of invasive carcinomas (in the absence of other
changes in population risk) and, eventually, lower mortality.
Removal or destruction of screen-​detected cancer precursors in the
colon and cervix has led to substantial reductions in the incidence of
invasive cancers at these sites (Brenner et al., 2014; Peirson et al., 2013).
Given that only a fraction of cancer precursors is destined to progress,
screening inevitably results in “over-​diagnosis” and “over-​treatment”
of many innocuous lesions. Controversies in mammography screening
for breast cancer exemplify this issue. During 1980–​2004, diagnoses
of ductal carcinoma in situ (DCIS) increased seven-​fold, and rates of
early-​stage invasive cancer have increased, whereas incidence rates of
metastatic breast cancer have remained stable, supporting the impor-
tance of over-​diagnosis (Bleyer and Welch, 2013; Sherman et  al.,
2014; Welch et al., 2015).
Risk factor associations for CIS and invasive cancer in many organs
are similar, as might be expected for factors that are genetic, devel-
opmental, or act early in adult life. Nonetheless, risk associations for
“cases” may differ, depending on whether CIS is included, especially
in populations with screening. Most CIS lesions, even in organs that
can be palpated such as the breast, are found by screening (Claus et al.,
2001); thus, differences in screening practices across populations
could affect the consistency of risk factor associations in the epide-
miologic literature, particularly for CIS.
Issues related to the validity and utility of CIS as an endpoint are
further complicated by variability in the biology of CIS. Some CIS
lesions are composed of cells that already possess the capacity to
invade and metastasize, whereas others lack invasive potential. For
example, incidence rates of cervical intraepithelial neoplasia 3 (i.e.,
CIN 3, severe dysplasia, or CIS) among screened women in their late
twenties or thirties are comparatively high, but invasive squamous
cell carcinomas are uncommon until women reach their forties and
fifties, and the morphology, molecular alterations, and biology of
these lesions are different (den Boon et al., 2015; Hariri et al., 2015).
Accordingly, most CIN 3 lesions have neither invaded nor possess that
capacity. In contrast, observational findings suggest that some intraep-
ithelial lesions (endometrial intraepithelial carcinoma or serous tubal
intraepithelial carcinoma) may exfoliate cells that pass into the peri-
toneal cavity (either through or from the fallopian tube), implant on
the peritoneum, and grow as metastases (Rabban and Zaloudek, 2007;
Seidman et al., 2011; Wheeler et al., 2000).
Terminology of Cancer Precursors, Including
Carcinoma in Situ
Epithelial intraepithelial neoplasia (EIN) terminology is conceptu-
alized as a universal nomenclature for carcinoma precursor lesions,
ranging from least to most severe (EIN 1, 2, 3), which can be applied to
all organ sites (e.g., cervical [CIN], vaginal [VAIN], prostatic intraepi-
thelial neoplasia [PIN], etc.). The term “neoplasia” has been criticized
because it may be misconstrued as cancer. In addition, the numbering
of EIN lesions might suggest an orderly progression through levels of
increasing severity, but evidence that such progression occurs in tis-
sues is lacking for many organ systems. Further, risk of progression of
EIN to invasive carcinoma may differ by organ site, characteristics of
lesions, patient characteristics, and exposures.
Prompted by concerns related to over-​diagnosis of mammographi-
cally detected DCIS, the novel term “indolent lesions of epithelial ori-
gin” (IDLE) has been proposed for these lesions (Esserman et al., 2014).
A fundamental dilemma is that the natural history of these putative cancer
precursors is ill-​defined, in part because biopsy and resection alter their
natural history. Further, the nature of intraepithelial lesions may change
as the sensitivity of screening methods increases over time. For example,
CIN 3 lesions detected with sensitive HPV DNA testing are often so
small that they are removed by diagnostic biopsy (Sherman et al., 2003).
CARCINOMAS: MACROSCOPIC
AND HISTOPATHOLOGIC FEATURES
Most carcinomas form discrete, ill-​defined, firm masses, although
diffusely infiltrating carcinomas that merge imperceptibly with sur-
rounding tissues are characteristic of tumors such as lobular carci-
noma of the breast and signet ring cell gastric carcinoma (Figure
3–​3). Carcinomas may be associated with desmoplastic stroma that
includes abundant collagen, and imparts a firm consistency (scir-
rhous). Other carcinomas, including medullary carcinomas, are
soft secondary to high cellularity with scant stroma. Central soften-
ing is also characteristic of rapidly growing cancers that have out-
grown their blood supply and have undergone necrosis, which may
lead to metabolic changes and acquisition of aggressive features
(Cairns, 2015).
Carcinomas are characteristically composed of cohesive cells that
express specific molecular weight keratin proteins (Ordonez, 2013) and
show evidence of differentiation, such as intra-​or extra-​cellular keratin
(squamous cell carcinoma) or gland formation or secretions (adeno-
carcinoma) (Figure 3–​4). Squamous cell carcinomas form distinctive
cell-​cell attachments referred to as intercellular bridges.
Invasive carcinoma may undergo epithelial mesenchymal transi-
tion, which is characterized by reduced intercellular cohesion and loss
of polarity, increased migration, and shape change from cuboidal to
spindly, consistent with a mesenchymal phenotype (Pasquier et  al.,
2015). These changes are best appreciated in vitro and are not reli-
ably defined by microscopy in clinical specimens. Invasion results in
epithelial-​stromal interactions, which may involve fibroblasts, adipo-
cytes, immune and non-​immune inflammatory cells, and lymphatic
and blood vascular channels. Historically, stroma was viewed as a pas-
sive contributor in carcinogenesis, but this view has been supplanted
by a model that emphasizes the important role of tumor–​stromal inter-
actions in either promoting or inhibiting cancer progression. In fact,
the formation of metabolically activated cancer-​associated fibroblasts
and cancer-​associated adipocytes may contribute to tumor growth by
producing factors that stimulate proliferation (Marcucci et al., 2014).
Cancer-​associated fibroblasts often appear enlarged, express smooth
muscle proteins (e.g., actin), and are rich in organelles when examined
by electron microscopy.
The composition of stromal matrix has received limited attention in
cancer epidemiology, but factors such as hyaluronan, which interacts
with CD44 receptors, may promote epithelial mesenchymal transition,
a stem cell–​like phenotype, and features associated with aggressive-
ness and treatment resistance (Chanmee et al., 2015). In contrast, spe-
cific types of immune infiltrates may improve prognosis for several
cancer types, and efforts to expand breast cancer staging to include a
characterization of the density of such infiltrates has been proposed
(Salgado et al., 2015). Biophysical properties of tumor stroma, specifi-
cally stiffness, have emerged as important in carcinogenesis and can-
cer progression and may contribute broadly to the hallmarks of cancer
(Pickup et al., 2014). Further, the topography and alignment of colla-
gen fibers may be important in invasion. For example, data suggest that
Figure 3–​3. Left: Gastric wall expanded by diffuse infiltrate of tumor
cells. Right: High power view demonstrating signet ring cell adenocarci-
noma. Blue-​grey material is mucin. From website: Juan Rosai’s Collection
of Surgical Pathology Seminars (http://​rosaicollection.org/​)
 23
Morphological and Molecular Classification of Human Cancer 23
Figure 3–​4.  Left: Squamous cell carcinoma demonstrating abundant keratin formation and keratin pearls (arrow). Right: Well-​formed glands of adenocar-
cinoma comprised of malignant appearing cells surrounding gland lumens. From website: Juan Rosai’s Collection of Surgical Pathology Seminars (http://​
rosaicollection.org/​)
parallel fibers at the boundary between breast cancer and surrounding
tissues may create a path of “least resistance” for tumor migration and
portend a worse survival (Riching et al., 2014).
Immune infiltrates in the tumor microenvironment can be charac-
terized using immunohistochemistry, which may provide information
about prognosis and treatment responses. Immune cells can be either
pro-​tumorigenic or tumoricidal, and a major goal of certain forms of
cancer immunotherapy is to “educate” the immune system to respond
with tumoricidal mechanisms. Immune signatures are also prominent
in the molecular classification of many tumor types. Dense immune
infiltrates are characteristic of medullary carcinomas arising at vari-
ous organ sites, such as breast and pancreas. Cancers associated with
defects in DNA mismatch repair may produce abundant neoantigens
that elicit dense lymphoid infiltrates, but expression of immune check-
point ligands on the tumor cells diminishes the effectiveness of immune
surveillance. Recent data suggest that treatment of these cancers with
checkpoint inhibitors may unleash effective immune responses (Diaz
and Le, 2015). Ironically, the term “inflammatory breast carcinoma”
refers to a cancer that mimics mastitis clinically, but the erythematous
and edematous appearance of the breast on physical examination pri-
marily reflects dermal lymphatic obstruction with tumor emboli, rather
than inflammation.
Most instances of inflammation represent rapid, non-​ specific
innate immune responses (see Chapter  25 on immunologic factors).
Inflammation may disrupt basement membranes and alter tissue
organization, resulting in epithelial–​ stromal interactions that may
be pro-​carcinogenic, as reflected in the conceptualization of cancers
as “wounds that do not heal” (Dvorak, 2015). Observational epide-
miological data suggests that anti-​ inflammatory medication may
lower risks of some cancers, but estimated effect sizes are variable
and often small, and interpretations are limited in post hoc analyses,
which may misclassify the amount, frequency, and timing of drug
use in relation to potentially pro-​carcinogenic inflammatory insults.
The suggested role of inflammation in carcinogenesis underpins the
exploration of anti-​ inflammatory agents for chemoprevention (see
Chapter 23 on pharmaceutical drugs other than hormones). The role
of adaptive immunity in cancer is more complex. Antigen-​specific
immunity responses may inhibit tumor development or progression in
some instances and elevate risk in others (e.g., autoimmune disease
and lymphoma, and inflammatory bowel disease and colon cancer).
Adaptive immune responses provide the basis for the development of
vaccines and immune therapies for treatment and prevention (Finn,
2014; Mandal et al., 2014).
Predictors of Carcinoma Clinical Behavior: Grade
and Stage
Grade refers to the degree of tumor differentiation—​the extent to which
carcinomas cells show cytologic features, functional specialization,
and organization similar to that of corresponding benign cells.
Histopathologic grade, as assessed microscopically, is associated with
genomic instability, and in many cancers with proliferation. In breast
cancer, grade is related to Ki67 index, assessed by immunohistochem-
istry (proliferation marker) and molecular panels that reflect prolifera-
tion, but genomic grade, which is based on molecular analysis, may
provide refined prognostic information (Ignatiadis et al., 2016).
In some tumors, such as prostatic adenocarcinoma, the Gleason
grade is particularly important for prognosis and choosing manage-
ment. Men diagnosed on biopsy with well-​differentiated adenocarci-
nomas (low Gleason scores) may opt for observation alone, whereas
men with poorly differentiated adenocarcinomas (higher Gleason
scores) generally require aggressive management. However, increased
understanding of the molecular pathogenesis of prostate cancer and
its progression under treatment suggest the value of a new classifi-
cation with immediate treatment implications, reflecting whether a
tumor is androgen-​dependent, and the hormone stimulation is endo-
crine or paracrine, or has progressed to a more autonomous, androgen-​
independent growth phase (Logothetis et  al., 2013). Similarly,
premenopausal women with low-​ grade endometrioid endometrial
carcinomas may opt for fertility-​ preserving medical management,
whereas for other women, hysterectomy and adjuvant therapy are rec-
ommended (Colombo et al., 2016).
Stage refers to tumor size and extent of spread from local-​regional
to distant sites. Grade can be a predictor of stage, but the latter is gen-
erally the stronger prognostic predictor. Although high stage augurs a
poor prognosis, some tumors that are clinically considered low stage at
diagnosis later demonstrate metastases and result in death. For exam-
ple, a low-​stage estrogen receptor (ER)-​negative breast cancer may
have a worse prognosis than a higher stage well-​differentiated ER-​
positive cancer. The impetus for developing molecular marker panels
to predict prognosis derives from frustrations with the shortcomings
of traditional assessment of grade and stage. Thus, adjuvant systemic
treatment is often given even after surgery for early-​stage tumors, if
risk of recurrence is considered unacceptably high.
For some tumors, neoadjuvant therapy is administered prior to
resection to assess tumor response (and to facilitate surgery). However,
the biology of metastatic tumor cells or circulating tumor cells may
differ from that of the tumor at its primary site, especially after treat-
ment. Thus, the development of “liquid biopsy” methods that enable
repeated molecular analysis of circulating tumor cells during treatment
is emerging as a potential method to detect chemotherapy resistance
(Dawson et al., 2013).
Most carcinomas that metastasize spread via the lymphatic system;
accordingly, removal and examination of draining lymph nodes for
metastatic deposits is often performed to stage carcinomas. The pri-
mary purpose of staging lymphadenectomy is to guide the need for sys-
temic therapy, rather than to remove the cancer deposits, although the
latter may have debatable effects on risk of recurrence. Demonstration
that patterns of lymphatic drainage are predictable has enabled the
24
24 Part I:  Basic Concepts
development of “sentinel node” techniques in which examination of
one or a few nodes may provide required staging information with-
out full lymph node dissection (Niebling et  al., 2016). Specifically,
if sentinel nodes are negative, the entire nodal basin is considered
cancer-​free, and a complete dissection is avoided, reducing morbid-
ity and operative time. If sentinel nodes are positive, the remaining
nodes in the region are typically removed to provide complete staging.
Carcinomas may also spread hematogenously to sites such as liver,
lung, and bone, or invade through viscera, leading to spread via direct
extension or release of cancer cells into body cavities, producing fluid
collections containing malignant cells (i.e., malignant ascites or pleu-
ral effusions).
Although anatomy and lymphovascular drainage are likely impor-
tant determinants of sites of metastases, accumulating data indicate
that molecular characteristics of primary tumor cells and microen-
vironments at potential metastatic sites are also significant (Langley
and Fidler, 2011). Building on the “seed and soil” hypothesis that was
first proposed by Stephen Paget in the late nineteenth century (Paget,
1889), investigators have proposed the “cancer diaspora” concept,
which analogizes cancer spread with phases of emigration, migration,
and immigration in human populations (Pienta et al., 2013). This view
proposes continued interactions between metastatic cells and primary
tumors, including homing of circulating tumor cells back to primary
sites, and has prompted the theoretical suggestion that inducing cells
to migrate to sites unfavorable for growth and survival might represent
a therapeutic strategy.
Knowledge of usual patterns of metastases may aid in the recogni-
tion of misclassification of primary tumor sites. For example, gastro-
intestinal cancers often metastasize via the draining portal circulation
to the liver, and misclassification of metastatic adenocarcinoma as
primary hepatocellular carcinoma may affect the interpretation of
epidemiological studies, especially when the former are numerically
predominant. Metastatic lobular carcinomas of the breast may mimic
primary linitis plastica of the stomach (Cormier et al., 1980). Similarly,
data suggest that metastases to the ovary from occult gastrointestinal
carcinomas have been frequently misclassified as primary mucinous
ovarian carcinomas historically (Soslow, 2011). Use of improved
Figure 3–​5.  Sarcomas are malignant tumors displaying mesenchymal differentiation: top left: chrondrosarcoma; top right: osteogenic sarcoma; bottom
left: rhabdomyosarcoma; bottom right: leiomyosarcoma. From website: Juan Rosai’s Collection of Surgical Pathology Seminars (http://​rosaicollection.org/​)
diagnostic criteria and immunohistochemistry has improved the accu-
racy of pathology diagnosis, but misclassification persists, particularly
in studies that rely on self-​reported data to define primary site. As the
molecular profiles of different tumor types have become more com-
prehensively defined, the possibilities for distinguishing primary from
metastatic sites has increased.
Cancers Demonstrating Stromal
Differentiation: Sarcomas and Carcinosarcomas
Among adults, sarcomas are extremely rare, whereas these tumors
account for a greater percentage of non-​hematologic cancers among
children. Incidence rates of osteogenic sarcomas spike during ado-
lescence (Ward et al., 2014). Sarcomas also occur among adults fol-
lowing treatment for cancer. Sarcomas are classified based upon the
matrix products they produce or the mesenchymal differentiation they
display: cartilage (chondrosarcoma); osteoid (osteogenic sarcoma);
collagen (fibrosarcoma); smooth muscle (leiomyosarcoma), skeletal
muscle (rhabdomyosarcoma); or blood vessels (angiosarcoma) (Figure
3–​5). Grossly, these tumors present as large masses, sometimes with
focal softening if partly necrotic. However, some large benign mes-
enchymal tumors, such as leiomyomas, may also infarct. Sarcoma
cells are detached, and have been classified as round cell, epithelioid
(morphology that mimics carcinoma), or spindle cell, as opposed to
the typical cuboidal or columnar shape of carcinoma cells. Sarcomas
usually spread hematogenously; hence, lymph node staging is not per-
formed routinely for these tumors.
The molecular classification of sarcomas includes tumors with trans-
locations and relatively few alterations, tumors with complex karyo-
types, and others with point mutations or amplifications in suspected
driver oncogenic mutations (Hameed, 2014). Testing for translocations
in genes such as KMT2A/​MLL, ETV6, and EWSR1 is performed rou-
tinely in many centers. Interestingly, gene fusions do not necessarily
correspond with specific histopathologic subtypes, such that classifi-
cation requires integration of clinical, histopathological, and molecu-
lar data. Some sarcomas may form bone or involve bone and require
 25
Morphological and Molecular Classification of Human Cancer 25
special processing prior to histologic processing, which may interfere
with immunohistochemistry and other molecular testing. In contrast to
epithelia, which are bound by a well-​defined basement membrane, the
organization of benign mesenchymal tissue is less well understood.
Consequently, sarcoma precursors are largely uncharacterized.
Carcinosarcomas are tumors composed of mixed components,
including areas of carcinoma and sarcoma. Uterine carcinosarco-
mas, sometimes referred to as malignant mixed mullerian tumors
(MMMTs), are among the best studied (Berton-​Rigaud et al., 2014).
Homologous MMMTs produce malignant stroma native to the uterus
(e.g., leiomyosarcomas [smooth muscle] or fibrosarcoma [fibrous
tissue]), whereas heterologous types produce stromal tissues not
normally found in the uterus (e.g., osteogenic sarcoma [bone] or chon-
drosarcoma [cartilage]). At other sites (e.g., breast), tumors contain-
ing malignant epithelial and mesenchymal elements are referred to
as “metaplastic carcinomas.” Data suggest that many uterine carcino-
sarcomas are clonal, and the final diagnostic classification may not
indicate the subtype of cancer that was present when the tumor first
formed (D’Angelo and Prat, 2011). Diagnostic classification of can-
cer is based on the most clinically aggressive component because this
is paramount for determining prognosis and treatment; however, this
approach may not be ideal for etiologic studies.
Malignant Tumors of the Immune System
and Blood: Lymphoma and Leukemia
Overview
Historically, the hematolymphoid malignancies were divided into lym-
phomas (lymphopoietic cancers), which were defined mainly as solid
tumors arising in lymph node, spleen, or mucosal-​associated lymphoid
tissue, and leukemias (hematopoietic cancers), which were character-
ized by a predominance of tumor cells in blood and bone marrow.
However, since 2001, the World Health Organization (WHO) has clas-
sified these malignancies according to lineage: myeloid, lymphoid, and
histiocytic/​dendritic cell (Harris et al., 2000). The leukemias are now
divided into two major groupings—​myeloid and lymphoid neoplasms.
Myeloid neoplasms derive from granulocytic (neutrophil, eosinophil,
basophil), monocytic/​ macrophage, erythroid, megakaryocytic, and
mast cell lineages, and include acute myeloid leukemia (AML), myelo-
dysplastic syndromes (MDS), myeloproliferative neoplasms (MPNs),
and “overlap” disorders termed “myelodysplastic/​myeloproliferative
neoplasms” (MDS/​MPN). Lymphoid neoplasms derive from B-​cells,
T-​cells, and natural killer (NK) cells and include Hodgkin (HL) and
non-​Hodgkin lymphomas (NHL), plasma cell neoplasms (e.g., mul-
tiple myeloma), and lymphoid leukemias. B-​and T/​NK-​cell leukemias
are now classified with the lymphomas due to several of these entities
having circulating (blood) and solid (tissue) phases that represent dif-
ferent manifestations of the same disease (e.g., CLL [blood phase] and
small lymphocytic lymphoma [tissue phase]; lymphoblastic leukemia
[blood phase] and lymphoblastic lymphoma [tissue phase]).
Taxonomy of the hematolymphoid cancers demonstrates the value
of interdisciplinary, integrated approaches for tumor categorization.
Classification incorporates etiologic factors, clinical presentation, his-
topathologic features, and molecular markers that reflect cell type, cel-
lular growth patterns, and molecular characteristics related to aberrant
differentiation, incomplete maturation, and dysregulated proliferation.
A central diagnostic feature is identification of a monoclonal cell pop-
ulation with an aberrant phenotype, whereas diagnosis of most other
cancers relies more heavily on histopathologic and clinical evidence.
Rapid progress in understanding normal blood and lymphoid cell
development and maturation, combined with tools for defining clonal
proliferations, enabled the early development of the molecular hema-
tolymphoid taxonomies. As sensitive methods for detecting clonal cell
populations have developed, concerns about what constitutes a hema-
tologic cancer precursor or a cancer have arisen, analogous to concerns
about over-​diagnosis in other organ systems. The sections that follow
briefly contrast approaches for classifying lymphomas and leukemias;
more details are provided elsewhere in this volume (Chapters  38
[leukemias], 39 [Hodgkin lymphoma, 40 [non-​Hodgkin lymphoma],
and 41 [multiple myeloma]).
Categorization of Hematolymphoid Cancers
Lymphoma.  The WHO lymphoma classification was updated in
2008 to reflect evolving concepts, including multidisciplinary clas-
sification, inclusion of borderline categories, and provisional entities
requiring further study (Campo et al., 2011; Menon et al., 2012; Xie
et  al., 2015). Like other tumor classifications, questions about what
constitutes a specific “entity” and whether distinctive molecular mark-
ers alone are sufficient to justify separate classification continue to
evolve. Lymphomas are divided into HL or NHL (Figure 3–​6), and
may affect both children and adults, but the biology and behavior of
these tumors differ substantially among younger and older persons.
Although screening per se is not performed routinely for hemato-
lymphoid malignancies, routine blood testing may prompt evaluation
of abnormal cell counts (e.g., lymphocytosis) and lead to discovery of
asymptomatic (chronic lymphocytic leukemia or small lymphocytic
lymphoma [CLL]) and precursor (monoclonal B-​cell lymphocytosis)
disease. Similarly, detection of high levels of a particular immuno-
globulin or light chain in serum or urine may suggest an occult tumor
(e.g., plasma cell myeloma). These clinical results raise concerns about
over-​diagnosis, the need to treat, and the appropriateness of manage-
ment. In contrast to solid tumors, the natural history of hematolym-
phoid tumors and their putative precursors generally remains unaltered
by procedures leading to their diagnosis; therefore, these tumors are
especially well suited to natural history studies that aim to identify
markers and mechanisms associated with disease progression.
Lymphomas can be further divided into tumors of immature (lin-
eage precursor) or mature (peripheral) B-​cells or T/​NK-​cells, which
reflect differences in cell of origin, etiological factors, and clinical
behavior. Factors considered in clinical classification of B-​cell lym-
phomas include anatomic site of presentation, association with immu-
nodeficiency states (ascribed to HIV infection or aging), morphologic
features, detection of Epstein-​Barr virus or human Herpesvirus-​8,
and expression of immunohistochemical markers of differentiation.
Less progress has been made in understanding T-​cell than B-​cell lym-
phomas, perhaps reflecting the rarity of these neoplasms, incomplete
knowledge of normal T/​NK-​cell development, and the greater ten-
dency of these tumors to contain an admixture of tumor cells and reac-
tive cells (Campo et al., 2011).
In Hodgkin lymphoma, histopathologic features and systemic
symptoms are the mainstay of diagnosis (Kuppers et  al., 2012).
Hodgkin lymphoma is distinctive in that it forms masses composed of
rare monoclonal Reed Sternberg cells in a background of many reac-
tive cells (variably including lymphocytes, plasma cells, and eosin-
ophils). These features pose challenges for molecular analysis. The
nature of Reed Sternberg cells remains uncertain; these cells share
markers with germinal B-​cells, but also demonstrate dysregulation of
NF-​ĸB and JAK/​STAT signaling and commonly latent infection with
Epstein-​Barr virus.
Figure 3–​6.  Left: Non-​Hodgkin diffuse large B-​cell lymphoma (left) and
Right: Hodgkin Lymphoma with prominent Reed Sternberg cell showing
binucleation with prominent nucleoli (arrow). From website: Juan Rosai’s
Collection of Surgical Pathology Seminars (http://​rosaicollection.org/​)
26
26 Part I:  Basic Concepts
Leukemia.  Leukemia is divided into acute forms, which are more
common among children and young adults, and chronic forms, which
occur later in life. Approximately 70% of acute lymphoblastic leuke-
mia cases (ALL) occur among children, and these are further divided
into B-​cell and T-​cell types. The pathogenesis of ALL is broadly con-
ceptualized as resulting from arrested B-​cell or T-​cell development,
coupled with uncontrolled cellular proliferation. B-​cell ALL is largely
subclassified according to detection of specific translocations (Paolini
et al., 2011).
Hematologic malignancies provide well-​characterized examples in
which a chronic, low-​grade cancer evolves into high-​grade, aggressive
disease. The development of blast crisis (i.e., ALL) among individuals
with chronic myelogenous leukemia (Chereda and Melo, 2015)  and
conversion of low-​grade to high-​grade lymphomas in Richter’s syn-
drome (Jain and O’Brien, 2012)  represent two important examples.
In contrast, the progression from low-​to high-​grade carcinoma is less
well described in solid tumors, although some carcinomas with mixed
patterns of differentiation may represent tumors in transition. In con-
trast to the relative importance of gene expression patterns in develop-
ing classification of most solid tumors, cytogenetic changes have been
more important in the classification of hematologic cancers, which
in some instances has revealed strong evidence of progression of one
tumor subtype into another, such as the identification of BCR-​ABL1
fusion gene in both chronic myelogenous leukemia and blast crisis
(Chereda and Melo, 2015).
Acute myeloid leukemia is classified based on morphology, cytoge-
netics, mutations in oncogenes, and clinical features, such as identifi-
cation of leukemogenic exposures or pre-​leukemic syndromes, which
augur a poor prognosis (Hasserjian, 2013). Detection of characteristic
molecular changes in cases with prior treatment of myelodsyplastic
syndromes may provide the basis for exploring novel etiologic associ-
ations or mechanisms associated with progression. Characterization of
molecular abnormalities in non-​neoplastic background bone marrow
elements invites parallels with malignant field effects in epithelium
surrounding in situ or invasive carcinomas.
Chronic lymphocytic leukemia (CLL) is among the most com-
mon hematologic malignant tumors, accounting for an estimated
15,000 incident cases annually in the United States, with a median
age at diagnosis of 70 years (Hallek, 2013). The diagnosis is based
on detection of a monoclonal population of mature B-​cells. The
prognosis of these tumors is quite variable, and discovery of the eti-
ologic factors, markers, and mechanisms that characterize aggres-
sive versus indolent types could facilitate the development of early
detection tests and possibly improved treatments. This mirrors
themes in solid tumors, such as prostate cancer, in which identify-
ing men with indolent cancers who are candidates for conservative
treatment (including monitoring) is important. Similar to findings
for solid tumors, TP53 mutations are associated with genetic insta-
bility and a poor prognosis. The molecular findings in CLL are
identical to those of small lymphocytic lymphoma, and the two are
distinguished based on whether the predominant manifestation is in
the circulation or solid organs (lymph nodes or spleen). Given that
leukemia is by definition a systemic disease, the staging models
used for solid tumors, which mainly reflect anatomical distribution,
do not apply. Among asymptomatic patients with CLL, deferred
treatment has been considered for many years, and as such, this
approach may provide a model for limited intervention for other
indolent cancer types.
CANCER CLASSIFICATION AND STAGING
The WHO International Classification of Diseases for Oncology (ICD-​
O, 3rd edition) is a dual numerical classification system for coding
topography (tumor site) and morphology (histopathology). Topography
describes the anatomical location of the tumor. Topography codes are
prefixed by a letter “C,” followed by two numeric digits for the pri-
mary site and a single digit for the subsite. Morphology codes describe
the histopathological cell type with four digits and a single digit for
benign or malignant behavior.
Historically, stage has been the best predictor of prognosis and a
critical determinant of management, though cancer staging is actually
more of a chronological than biological characteristic (Winer et  al.,
2005). US staging efforts are led by the American Joint Committee
on Cancer (AJCC, 2011). The AJCC’s TNM (tumor, node, and metas-
tasis) staging system is based on the extent of disease in the primary
tumor (T), regional lymph nodes (N), and distant or systemic metasta-
ses (M). In brief, Stage 0 refers to carcinoma in situ (CIS), Stage I inva-
sive cancers refer to “early” lesions that are confined to the primary
organ site of origin, Stage II tumors have spread to the regional lymph
nodes, whereas “late” Stages III–​IV lesions have greater degrees of
local extension and/​or distant metastases. Missing T, N, or M is coded
as “X.”
MULTIPLE APPROACHES FOR CANCER
CLASSIFICATION: FROM THE GENERAL POPULATION
TO MOLECULAR CATALOGUING SCHEMES
Choosing fit-​for-​purpose cancer classification systems involves trade-​
offs between statistical power, assay costs, logistical constraints related
to availability of tissues, and philosophical uncertainties about “lump-
ing” versus “splitting.” Classifications optimized to achieve clinical
research aims, such as determining prognosis or predicting treatment
responses, reflect mechanisms that govern tumor behavior, whereas
the goal of etiological classifications is to group cancers according to
mechanisms that transform normal tissues into cancer precursors and
cancers (Table 3–​2).
Developing useful classifications for high-​grade cancers is com-
plex because tumors are genetically unstable and spawn sub-​clones,
which can emerge as dominant under the influence of selection pres-
sures. From an etiologic perspective, downstream tumor progression
obscures the relationships between the initial risk-​factor exposures and
the characteristics of the cancer when first formed. Clinically, high-​
grade tumors demonstrate great plasticity in response to therapy, such
that minor cell subpopulations that were present within the cancer
at diagnosis or cells bearing newly acquired mutations post-​therapy
may emerge as dominant. Cancers arising among carriers of BRCA1/​
2 mutations offer a notable example; these cancers may arise from
loss of DNA repair functions, and often respond to poly-​(ADP-​ribose)
polymerase (PARP) inhibitors, which further impair these processes,
leading to “synthetic lethality.” However, following treatment, some
of these tumors re-​express BRCA1/​2, restore DNA repair mechanisms,
and become resistant (Lord and Ashworth, 2013).
Classification systems that broadly lump tumors based on funda-
mental biological similarities leverage statistical power gained from
larger sample sizes per category, which improves precision, whereas
finer classifications gain strength from specificity of association. Inter-​
relationships between approaches for tumor classification are pre-
sented here, followed by additional comments on strategies that use
morphologic and molecular methods.
Age and Morphological and Molecular
Classification of Cancer
Age is the single most important risk factor for cancer overall and is
also reflected in the morphologic and molecular heterogeneity of spe-
cific types of cancer. Our understanding of the biology of aging, cancer
risk, and cancer heterogeneity has evolved since Armitage and Doll
first drew attention to the exponential growth pattern and linear rise
of most cancer incidence rates on a log rate by log age graphic scale
(Armitage and Doll, 1954, 1957). This observation provided the theo-
retical foundation for the concept of long-​term and multistep carcino-
genesis (i.e., tumor initiation, promotion, progression). In this context,
“chronological age” has emerged as a surrogate for “biological age,”
which affects both the risk of cancer developing and the specific biol-
ogy of the tumors that emerge.
Each phase of the life course is related to specific tumor types, which
in turn reflect critical etiological factors that are operative during these
 27

Morphological and Molecular Classification of Human Cancer 27

Table 3–​2. Approaches for Classifying Cancers

Method of Categorization Illustrations Strengths Limitations

Age at diagnosis Pediatric vs. adult; age at onset; Defines important patterns in large Cancers with similar biology may present at
menopausal status population-​based data sets different periods of life
Genetic factors High penetrance genes, familial or Reflects strong causative mechanisms Unknown status for many individuals
sporadic
Environmental Radiation, complications of prior Defines important etiological factor with Modified by other exposures; specialized
exposures treatment, natural or man-​made public health implications application
disasters, carcinogens
Mode of detection Screen detected vs. interval vs. Important for clinical translation Subject to undetected biases
symptomatic
Pathology Histologic type, degree of Routinely available Imperfect reproducibility and limited
differentiation (i.e., grade) mechanistic implications
Molecular pathology DNA, RNA, protein and integrated Provides detailed snapshot of biology Costs and effort, may reflect current biology
classifications rather than mechanisms of development,
intratumoral heterogeneity
Clinical behavior Aggressive vs. indolent Clinically determined Reflects complex interaction between
individual and cancer biology; affected by
method of detection and clinical care
Molecular treatment Somatic mutations or pathways Reflects mechanisms required for tumor Inconstant relationship with etiology and
targets growth with important treatment pathogenesis
implications (i.e., predictive markers)

periods of a person’s lifetime (Figure 3–​7). Absolute incidence rates
of all pediatric cancers are low in the general population; moreover,
childhood cancers are dominated by leukemias, brain tumors, and sar-
comas (Ward et al., 2014). In contrast, these tumor types are compar-
atively uncommon among adults relative to the greater incidence of
carcinomas. Certain tumor types, such as acute lymphoblastic leuke-
mia and rare solid tumors composed of undifferentiated cells (often
referred to as “blastomas”; e.g., neuroblastoma, hepatoblastoma, etc.),
are almost exclusively diseases of young children, suggesting the
likely importance of heritable syndromes, genetic defects, or carcino-
genic exposures in utero as etiologic factors.
Other cancer types that demonstrate a strong predilection for occur-
ring during late childhood and early adulthood include germ cell
tumors, specific subtypes of lymphoma, such as Hodgkin lymphoma,
and sarcomas such as osteogenic sarcoma (Parsons et  al., 2008).
These relationships may reflect exposures associated with puberty and
post-​pubertal development. The temporal association between osteo-
sarcoma and the growth spurt is consistent with the higher incidence of
these tumors among African American than white children (reflecting
earlier onset of puberty), boys than girls (greater increase in height
and weight), and its predilection to affect large dog breeds (Ottaviani
and Jaffe, 2009).
Some cancers with a peak incidence during adolescence have a
bimodal age distribution, which includes a second wave of later onset
tumors superimposed on an underlying primary non-​neoplastic dis-
ease. For example, the development of osteosarcoma at older ages is
sometimes related to preexisting Paget’s disease, a benign bone abnor-
mality, or therapeutic radiation for a preceding cancer (Ottaviani and
Jaffe, 2009). The biology of osteosarcomas and response to chemo-
therapy differ by age, with best outcomes among youngest patients.
Similarly, leukemias and lymphomas that may be related to cancer
treatment may differ biologically and clinically from spontaneously

A: Females B: Males
500 1000
Breast Prostate
Lung and Bronchus Lung and Bronchus
Colon and Rectum Colon and Rectum
Rate per 100,000 women/men per year

Melanoma Melanoma of the Skin

400 Cervix 800 Testis

300 600

200 400

100 200

0 0
0 20 40 60 80 100 0 20 40 60 80 100
*******************Age at diagnosis (years) ********************

Figure 3–​7.  Age-​specific incidence patterns for different types of cancers by sex.

28
28 Part I:  Basic Concepts
occurring tumors. Understanding risk factors for treatment-​related
tumors may help define factors that predispose to the development of
de novo disease (Bueso-​Ramos et al., 2015).
Among adult onset cancers, age may be interrelated with histo-
pathologic subtypes and markers suggestive of specific etiologic
mechanisms. The identification of subsets of tumors that occur in
earlier adulthood than expected, particularly when multiple, involv-
ing more than one organ site and/​or occurring among multiple fam-
ily members, has contributed to the identification of a carcinogenic
role of heritable high-​penetrance mutations in BRCA1/​2, mismatch
repair genes that cause Lynch syndrome and other cancer syndromes.
Further, cancers that are related to inherited mutations demonstrate
stereotypical biological and clinical features, and potentially improved
treatment responses to targeted therapies (e.g., PARP inhibitors and
ovarian/​tubal high-​grade serous carcinomas among BRCA1 carriers
[Bao et al., 2016] and immunologic treatments for colon carcinomas
among Lynch syndrome patients [Le et  al.,  2015]). Identification of
associations between specific germline mutations and cancers has led
to recognition of the importance of somatic alterations in the same
genes or molecular pathways among individuals who are not carriers
of germline mutations, especially in the context of genes involved in
DNA repair (Jacinto and Esteller, 2007).
Studies of breast cancer age-​specific incidence exemplify the power
and limitations of age-​specific models (reviewed in Anderson et  al.,
2014). Breast cancer rates increase rapidly during early reproductive
life, plateau near age 50 years (a surrogate for menopause), and then
rise again at a slower pace. Pike and colleagues introduced the concept
of “tissue aging” or biologic aging, as opposed to chronologic aging,
to account for effects of risk factors upon the peculiar shape of the
breast cancer age-​specific incidence rate curve (Pike et al., 1983). This
model may be conceptualized in three phases:  (1)  puberty to meno-
pause, when women are exposed to factors that increase breast cancer
risk and incidence rates rise at an accelerating pace; (2)  menopause
transition, when the influence of these factors wanes and the rate of
rise of breast cancer incidence slows; and finally (3) menopause, when
rates increase (albeit at a slower rate than at earlier ages) in response
to new exposures and conditions. Differences among women with
respect to risk factors means that women of the same “chronological
age” may have different “tissue ages” and, consequently, different can-
cer risks. However, Pike’s early conceptualizations of aging and can-
cer incidence did not account for etiologic heterogeneity. Thus, what
appears as a single age-​specific incidence rate pattern may result from
the confluence of two or more independent age incidence patterns (see
Chapter 45 on breast cancer).
Lilienfeld and others provided evidence that the overall breast can-
cer incidence rate curve represents the confluence of two distinctive
incidence rate patterns, prompting a search for molecular pathologic
correlates of these two types (De Waard et  al., 1964; Lilienfeld and
Johnson, 1955). As the specificity of data available in cancer registries
such as National Cancer Institute’s Surveillance, Epidemiology, and
End Results (SEER) Program has increased, the potential for complex
tumor subtype analyses has grown, substantiating the hypothesis that
overall breast cancer incidence patterns are misleading in that they
represent the combined effects of two or more very different cancer
subtypes (Anderson et al., 2014).
Registry datasets are suited to teasing apart effects of age, but
individual-​level data for patients and tumor pathology are typically
limited. However, the large sample sizes and lengthy periods of cov-
erage enable assessment of calendar-​ period effects (which reflect
interventions such as screening) and birth-​cohort effects that are more
closely linked to etiology (risk factors) (Rosenberg and Anderson,
2011). Just as chronological age may not adequately reflect biologi-
cal age, the implications of attained age may vary by year of birth or
calendar year of diagnosis. Analyses of registry data have consistently
shown that younger-​onset and older-​onset tumors are biologically and
etiologically distinct in breast cancer and other tumor types.
Nonetheless, given that age at diagnosis is simply a surrogate of
complex biology, it is rarely sufficient to define a highly homogeneous
set of cancers. An exception in breast cancer that proves the rule might
be medullary breast cancer, which show a unimodal age distribution,
and is strongly associated with mutations in BRCA1 (Anderson et al.,
2006, 2014). In summary, age categories (or life-​course periods) define
groups of certain cancers that are enriched for particular phenotypes,
but these age-​defined groups rarely specify pure categories.
Classifying Cancer by Environmental Exposures
Cancers may be classified according to specific environmental expo-
sures, particularly if these exposures result in distinctive tumor biology.
Examples include radiation-​or chemotherapy-​induced cancers, can-
cers associated with infection (hepatitis B, HPV, Helicobacter pylori),
and cancers associated with powerful carcinogens (e.g., aflatoxin,
smoking) that produce specific molecular signatures (Alexandrov
and Stratton, 2014). The identification of such connections between
exposures and outcomes can aid in population surveillance and
cancer control. For example, transplant recipients may develop hema-
tologic cancers that respond to lowering immunosuppression, but they
develop squamous cell carcinomas of the skin that are more likely
to recur and metastasize than those occurring among non-​transplant
recipients. Geographically defined exposures (atom bomb, chemical
or nuclear power plants, etc.) may aid in the recognition of exposure-​
specific morphologic or molecular patterns. Further, population-​
restricted exposures may reveal links that transcend individual organ
sites and present possibilities to identify characteristic molecular sig-
natures (Hoadley et al., 2014). For example, smokers are at markedly
elevated relative and absolute risk of developing bladder, lung, and
head and neck cancers, and molecular analysis has revealed common
genetic alterations.
High-​throughput genomic platforms (methylation, copy number,
mutation, RNA and protein expression) in the Cancer Genome Atlas
Project (TCGA) have helped link molecular changes with the causal
importance of smoking. In TCGA, molecular analysis of cancers origi-
nating at 12 different sites (organs) demonstrated strong relationships
between molecular alterations and site of origin. However, TCGA also
identified a group of cancers, termed “squamous-​like,” which included
squamous cell carcinomas from different sites (and divergent squamous
differentiation, not matching that of native epithelium), including the
head and neck, lung, and bladder. This group could reflect similar his-
topathology and/​or common etiologic exposures. Furthermore, the vast
majority of bronchial squamous cell carcinomas show a squamous-​
like/​smoking-​associated molecular pattern (206/​238, 87%), as do head
and neck carcinomas (302/​305, 99%), as compared with only 31 of
120 of bladder cancers (30%) (The Cancer Genome Network, 2012;
Hoadley et al., 2014). While TCGA has emphasized histopathology in
naming cancers with this molecular profile (terming them “squamous-​
like”), it is striking that these three sites are those with the strongest
links to smoking, and that the strength of the smoking association is
roughly proportional to the percentage of site-​specific cancers that
are included in the squamous-​like cluster. Other epidemiological data
support the classification of a smoking-​related etiologic grouping that
transcends site of origin (referred to in TCGA as “convergence”).
While all major histologic types of lung cancer are strongly smoking
related, adenocarcinomas occur notably more frequently among a sub-
set of women who are non-​smokers (Pesch et al., 2012). As such, the
lung adenocarcinoma samples in the TCGA study clustered separately
from the other smoking-​associated cancers (Cancer Genome Atlas
Research, 2012, 2014; Hoadley et al., 2014).
If smoking-​ related cancers could be identified more accurately
across sites, surveillance for these etiologically related cancers could
be unified and risk stratification might be improved. The potential to
pool data for smoking-​related cancers defined by molecular signatures
might enable identification of risk factors and interactions among them
that apply across tumor sites and could identify a target population for
preventive interventions. In population surveillance, “lumping” etio-
logically related cancers could improve the ability to detect incidence
trends more quickly and appreciate the public health importance of
such changes at the population level. The utility of this approach is
exemplified in analysis of second smoking-​associated cancers in which
lung (stage I), bladder, kidney, and head/​neck cancers were combined
 29
Morphological and Molecular Classification of Human Cancer 29
as a single case definition in an analysis that demonstrated that smok-
ers who survive a first smoking-​related cancer have an increased risk
of developing a second smoking-​related tumor (Shiels et al., 2014).
The value for cancer surveillance, cancer control, and public health
policy is more clearly demonstrated when the attributable fraction of
an exposure for a particular tumor type is high, as in smoking-​related
cancers. For example, an analysis of data for 1976–​2005 demonstrated
that lung cancer incidence rates or deaths among women increased in
18 states, 16 of which were located in the South or Midwest, where the
prevalence of smoking is higher and annual percentage rates of dis-
continuation were lower than in other parts of the United States (Jemal
et  al., 2008). Future analyses might also consider combining cancer
subtypes in analyses to assess smoking-​related deaths and evaluating
lung cancers for smoking-​related molecular signatures.
A similar concept has been considered with respect to human papil-
lomavirus (HPV)-​related cancers, which account for nearly all ano-
genital cancers and a proportion of head and neck cancers, and may
be preventable through prophylactic HPV vaccination. Given that the
incidence of HPV-​related cancers is comparatively low in the United
States, pooling might offer an important increase in the statistical
power to recognize early trends (Jemal et al., 2013).
Another example of etiologically related convergence of multiple
sites is the associations between hormonal exposures and women’s
cancers. Following the report from the Women’s Health Initiative of
a link between use of combined estrogen and progestin menopausal
hormone replacement and increased risk of breast cancer and non-​
neoplastic diseases, use of these products declined precipitously in the
United States, and incidence rate patterns of hormone-​associated can-
cers among postmenopausal women changed rapidly. The associations
were organ and histopathologic subtype specific:  for breast cancers,
declines were found in ER-​positive breast cancers, including specific
histopathologic subtypes, such as lobular and tubular carcinomas
(Ravdin et  al., 2007), whereas for ovarian cancers, reductions were
greatest for tumors that are linked to endometriosis, including endo-
metrioid and clear cell carcinomas (Yang et  al., 2013). Since 2002,
endometrial cancer rates have increased among women aged 50–​
74 years, particularly for subtypes most strongly linked to hormonal
exposures (Wartko et al., 2013).
Potential reasons for the increasing rates of endometrial cancers in
the face of declines in rates for cancers arising at other organ sites
could reflect etiological differences, such as differences in risk asso-
ciations for obesity and/​or the risk modification of obesity by exog-
enous hormone use, although multiple other explanations are possible
(Cote et al., 2015). Obesity increases the risk of both postmenopausal
breast cancer and endometrial cancer; however, exogenous proges-
tins increase risk of the former, while lowering the risk of the latter
(Anderson et  al., 2003; Brinton and Felix, 2014; Chlebowski and
Anderson, 2014; Collaborative Group on Epidemiological Studies of
Ovarian Cancer et al., 2015; Dobbins et al., 2013; Hou et al., 2013).
Classifying Cancer by Mode of Detection
Among organ sites for which there is population-​based cancer screen-
ing, mode of detection has important influences on the morphologi-
cal and molecular classification of cancer and cancer precursors that
are diagnosed. Screen-​detected cancers are more often slow grow-
ing and indolent compared with those that present symptomatically
(Weiss, 2003). In the extreme, the detection of more indolent cancers
by screening (length time bias) leads to over-​diagnosis, the discovery
of tumors that would never have manifested symptomatically. This
impact of screening can lead to a number of paradoxical effects (Jatoi
and Anderson, 2005), including increased cancer incidence rates,
impression of longer survival (lead time bias), and apparently better
treatment responses. Healthy volunteer effects among screened indi-
viduals may also skew results toward favorable outcomes and are a
concern in clinical trials and cohort studies (selection bias).
The effect of screening on the tumor types identified varies with the
technology employed and patient characteristics. For example, mam-
mography can identify suspicious calcifications that are common in
DCIS, and mass lesions produced by most types of invasive cancers,
which demonstrate ductal histology. However, invasive lobular carci-
nomas, which grow diffusely, may produce fewer radiologic footprints
and are harder to detect. Further, factors such as higher mammographic
density, which is associated with younger age and lean body mass,
may obscure small lesions, increasing the probability of an interval
cancer (Boyd et al., 2007).
In colon cancer screening, distal tumors are more readily detectable
because they arise within exophytic polyps and are more easily identi-
fied by digital rectal examination, sigmoidoscopy, or colonoscopy. In
contrast, right-​sided cancers, such as those that develop in the more
expansive cecal lumen, may be less readily detected, and such tumors
may differ histologically from their left-​sided counterparts (Brenner
et al., 2014). Similarly, prior to the development of better sampling and
HPV DNA testing methods, the movement of the cervical transforma-
tion zone posteriorly with age resulted in a higher frequency of false
negative results at older ages (Sherman et al., 2003).
Defining tumor types that are less readily detected with current
screening methods may prompt the development of alternative early
detection approaches or may refocus approaches for cancer prevention
and control (Miglioretti et al., 2015). Awareness of mode of detection
may also have implications for external validity in epidemiological
analyses because adjustment for pathology variables may not fully
negate the influence of screening on the representativeness of tumors
detected. This may have profound importance in international stud-
ies that include comparisons across extremely variable health systems,
leading to false conclusions that observed data reflect etiology, when
mode of detection is an important contributor.
USING PATHOLOGY TECHNIQUES
TO CLASSIFY CANCERS
Histopathology in conjunction with clinical history provided the
basis for the early development of tumor classifications. Introduction
of electron microscopy and histochemical and immunohistochemi-
cal stains expanded the armamentarium of diagnostic technologies
beyond pure visual assessment.
Methods to prepare reagent monoclonal antibodies with specificity
against protein epitopes that are adequately preserved in routinely pre-
pared formalin-​fixed paraffin-​embedded tissue sections transformed
diagnostic pathology from a discipline based on visual interpretation
alone to one that integrates microscopy with cell-​based assessment
of biomarker expression. Improved antigen retrieval protocols, sig-
nal amplification methods, and labeling of antibodies (fluorescence
and chromogenic tags) have increased the sensitivity and specificity
of immunohistochemical assays. Further, in situ hybridization meth-
ods can enable visual assessment of RNA or DNA species that reflect
gene amplifications, translocations, or other alterations. Novel meth-
ods allow identification of co-​expression of biomarkers within cells,
interaction of markers, and simultaneous detection of different types
of molecules, such as nucleic acid and protein.
Despite advances, various tissue assay methods have strengths and
limitations that reflect sample preparation, storage, and other factors.
Analytical specificity and sensitivity of immunohistochemical stains
and other approaches that combine morphology with molecular probes
continue to present challenges, which are often magnified in epidemio-
logical studies, which include tissues prepared at different laboratories
using variable methods of fixation and processing.
Performance of immunohistochemical assays may be impaired by
multiple technical issues related to fixation, processing, staining, and
interpretation (True, 2014). Guidelines for reporting prognostic mark-
ers to improve the quality of reported research have been promulgated
as the “REMARK” criteria, which may be required by journals for
publication (McShane et al., 2005).
Strengths of immunohistochemistry include substantial experi-
ence with the method, availability, microscopic assessment of marker
expression by cell type and intracellular compartment, and identifica-
tion of heterogeneity of expression within a sample. Although non-​
specificity may be a problem with some assays, pathologists can often
30

30 Part I:  Basic Concepts

identify these problems when patterns of expression are inconsistent
with established knowledge.
Quantification of protein expression by immunohistochemistry
is challenging (Pozner-​Moulis et  al., 2007), and in most diagnostic
applications, cell identification (e.g., distinguishing carcinoma from
lymphoma) or gross scoring of negative or positive is the main goal
(e.g., ER in breast cancer). Immunofluorescence is considered to pro-
vide more accurate quantitation of markers than immunohistochemis-
try. Fluorescence offers advantages for multi-​probe labeling, and this
approach is employed in methods that combine probes to define cell
types and cellular compartments (e.g., membrane, nucleus, cytoplasm)
in which the target probe is measured. For example, by simultane-
ously applying an anti-​keratin reagent antibody to identify epithelial
cells, DAPI (DNA stain) to define the nuclear compartment within
these cells and an anti-​ER antibody, ER expression can be quantified
in breast cancer cells by comparing the nuclear ER and DAPI signals
within keratin-​positive cells (Camp et  al., 2002). However, working
with fluorescent markers has trade-​offs, including reduced ability to
characterize morphology and issues related to preparation of reagent
antibodies and loss of fluorescence over time. Novel methods that Figure  3–​8. Tissue microarray demonstrating immunohistochemistry
combine metal tagged reagent antibodies with multi-​plexed ion beam staining for ER in breast cancer samples.
imaging have also been developed to enable quantification of multiple
markers per cell (Levenson et al., 2015).
In contrast with microscopy-​ based methods, high-​ throughput
sections, such as dipping in paraffin, placing sections in anhydrous or
molecular techniques typically evaluate markers (e.g., DNA, RNA)
anoxic environments, and cold storage, provide unpredictable preser-
derived from mixed cell populations and cannot assess co-​expression
vation of antigenicity and that minimizing the interval from cutting
or topographic localization. The importance of cell-​ type specific-
to staining is the best strategy. Standardized handling and batching
ity depends upon the degree to which tumor cells and surrounding
are critical in studies designed to sensitively measure changes in bio-
benign cells are admixed, whether analyses are discovery-​oriented
marker expression in serial samples, such as neoadjuvant trials.
or hypothesis-​driven, the sensitivity of the assay, and the power of
Improvements in digital scanning technology, web-​based software
analytic methods to separate signals from mixed cell populations. In
for image viewing and scoring, and automated image analysis enhance
tumors that infiltrate into benign tissues (e.g., breast), the challenges
the utility of TMAs in large studies. However, the utility of TMAs
are more pronounced than in circumscribed cancers. If the goal is to
is limited by the same considerations that apply to all immunohisto-
understand tumor biology, signals from the surrounding stroma may
chemical assays: (1) representativeness of tissue samples; (2) represen-
be informative. In contrast, if one wishes to define a cancer-​specific
tativeness of the individual cores (typically 0.6–​1.0 mm); (3) quality
biomarker that may also be found in blood (e.g., circulating tumor
of tissue fixation and preservation of target antigens; (4)  specificity
DNA), identifying markers specific for cancer cells may be of greater
of reagent antibodies; (5) performance of staining protocols; (6) accu-
interest.
racy, and reproducibility of scoring and required effort; and (7) issues
related to data recording, managing, and integrating with other types
of participant data. In research studies, typically only one block per
Tissue Microarrays tumor is available, and some markers may show topographic hetero-
geneity; areas of tumor that are more widely separated may be more
The development of tissue microarray (TMA) technology has poten-
likely to capture variability (Rimm Lab) (Chung et al., 2007). Finally,
tiated opportunities for analysis of immunohistochemistry, in situ
TMAs are best suited to studies of cancer tissues, although TMAs
hybridization, and related methods in large epidemiologic studies
specifically prepared to study cancer precursors, normal structures,
(Kononen et  al., 1998). TMAs are prepared by matching up micro-
stroma surrounding cancer, or immune infiltrates can be prepared
scope slides and blocks to enable localization, removal, and transfer
(Yang et al., 2006).
of tissue cores from targets in many donor blocks into a single recip-
ient block that can be sectioned for immunohistochemistry, thereby
facilitating batch staining and analysis of multiple tumors (Figure Scoring and Interpretation of Immunostains
3–​8). If the sample set is large and/​or multiple immunostains are
planned, this approach can reduce effort and costs. However, multiple Automated scoring of immunohistochemical assays offers potential
cores per tumor are generally prepared and placed in separate blocks advantages, including standardization and quantification. In automated
because any one section typically lacks some cores or contains cores analysis, cancer cells may be identified visually or by computer algo-
with inadequate representation of well-​preserved evaluable cells. Use rithm based on morphometric features and/​or staining for markers.
of TMAs has highlighted critical issues related to sectioning formalin Interactive approaches are less efficient because each sample requires
fixed paraffin-​embedded tissue blocks and loss of immunoreactivity on visual review, whereas in fully automated systems, up-​front effort to
cut sections (Fergenbaum et al., 2004). Loss of immunoreactivity on “tune” the algorithm enables the computer to score all cases without
cut sections is a greater problem than loss of antigenicity in paraffin input, although quality-​control reads of a subset are highly advisable.
blocks (Combs et al., 2016). When blocks are sectioned, the first sec- Analysis of tissues processed in different laboratories that use
tions that are cut are not perfectly parallel to the surface of the block variable tissue preparation, sectioning, and staining protocols poses
and are usually discarded because they do not represent the entire tis- challenges for automated image analyses of immunostains because
sue in the block (referred to as “facing”). Thus, each time a block is algorithms may perform differently in these samples. In multi-​center
sectioned, there is wastage. Accordingly, given that batch sectioning studies, comparing results among laboratories where samples were
conserves tissue, it is advantageous to plan forward by cutting multiple prepared may identify problems. Comparison of scores from replicate
sections at one session and applying validated immunohistochemical cores in tissue microarrays with different results may help identify
protocols as quickly as possible. Loss of antigenicity varies with condi- images requiring visual review. In the end, standardization and optimi-
tions related to tissue fixation and block preparation, the antigen target, zation are essential for generating usable data.
and the immunohistochemical reagent antibody and assay procedures. A comprehensive overview of all possible morphological classifica-
Most pathologists agree that strategies to preserve antigenicity in cut tions of cancer is beyond the scope of this chapter and is accessible
 31
Morphological and Molecular Classification of Human Cancer 31
in existing texts related to oncology and pathology or in site-​specific
chapters in this text. Many such writings relate morphological tumor
subtyping to clinical considerations or molecular characteristics, but
concepts to consider in epidemiological research have received less
attention. Examples of general principles are provided in the follow-
ing, emphasizing several of the most common types of cancers.
Anatomic Tumor Location
Intra-​individual asymmetries in paired organs are common, as are sys-
tematic differences in cancer incidence by laterality (Roychoudhuri
et al., 2006). These differences may reflect biological factors or detec-
tion biases, but convincing explanations are lacking. For example,
breast cancer incidence varies by quadrant of the breast, and while
this may represent a biological difference in the amount or composi-
tion of tissues by anatomic location, this remains unproven. Low-​dose
computed tomography (CT) lung cancer screening may be less sensi-
tive in detecting squamous cell carcinomas, which tend to occur in the
central portion of the lung, than adenocarcinomas, which are relatively
more frequent in the better visualized periphery of the lung (National
Lung Screening Trial Research et al., 2013). Given that smoking risks
are higher for squamous cell carcinomas than for adenocarcinomas,
performance of screening may vary among populations with different
percentages of smokers.
The frequency of other specific tumor types varies by anatomic loca-
tion. In the upper esophagus, squamous cell carcinomas predominate,
whereas adenocarcinomas predominate in the lower part of the organ,
often arising in metaplastic and dysplastic Barrett’s mucosa. Cancer
incidence is low in the small intestine, particularly for adenocarcino-
mas; however, the anatomy, physiologic function, and luminal con-
tents of the intestines change radically beyond the junction between
the small and large intestine, a frequent site of cancer development in
Western populations.
Although most colon carcinomas arise in adenomatous polyps,
tumors that arise in the context of mismatch repair deficiency (i.e.,
Lynch syndrome) are distinctive, often arising in serrated polyps that
were unrecognized historically (Patai et  al., 2013; Snover, 2010).
Microscopically, these cancers are typically high-​grade, mucinous,
and associated with lymphoid infiltrates. Historically, Lynch syn-
drome cancers have been proposed to have a predilection for the right
colon, although some part of this excess could reflect delayed identifi-
cation and eradication of precancerous polyps. Right-​sided tumors are
more frequently exophytic, and therefore tend to remain asymptom-
atic, whereas tumors arising in the narrower left colon may affect bowl
habits and produce symptoms.
In pancreatic adenocarcinoma, tumors that arise in the tail of the
organ are nearly always detected when metastatic, whereas a subset
of adenocarcinomas arising in the head of the pancreas at the junction
of the biliary system and small intestine (ampulla of Vater) may cause
biliary destruction, leading to jaundice and earlier detection (Bond-​
Smith et al., 2012).
Microscopic Patterns Associated with Carcinoma
Many carcinomas are proposed to arise in the context of field effects
that comprise regions of molecular alterations (e.g., genetic, epige-
netic, telomere shortening, and other changes) that provide a back-
drop against which additional changes that initiate tumorigenesis are
superimposed (Chai and Brown, 2009). Accordingly, recurrence fol-
lowing tumor excision, even with microscopically clear margins, may
result from residual “benign appearing” epithelium that retains pre-
cancerous changes. Molecular mapping of cancers and surrounding
tissues represents a promising approach to explore the evolution of
cancer, although the sequence with which molecular alterations occur
(and therefore causality) cannot be determined from cross-​sectional
samples.
In the cervix, anus, and bronchi, squamous cell carcinomas arise
at sites of squamous metaplasia. In the stomach, adenocarcinomas
composed of well-​formed glands commonly develop in the setting
of atrophic gastritis associated with glandular metaplasia and dyspla-
sia (Yakirevich and Resnick, 2013). In contrast, diffusely infiltrating
signet ring cell adenocarcinomas are not associated with metaplas-
tic changes, and have been linked to CDH1 mutations. Increases in
esophageal adenocarcinoma are occurring worldwide and have been
attributed to an increased prevalence of Barrett’s mucosa, which is
characterized by replacement of squamous epithelium by glandular
epithelium, typically in the lower esophagus (Runge et al., 2015).
Macroscopic and Microscopic Growth Patterns
of Carcinoma
Carcinomas that form masses that project from a mucosal surface into
a cavity or lumen of an organ are described as exophytic or polypoid.
Whereas some carcinomas grow as polypoid masses, others develop
within preexisting benign polyps, which undergo malignant change, as
is recognized in the colon and uterus. Polypoid lesions are often asso-
ciated with cysts or found in viscera with cavities (i.e., uterus) or tubu-
lar anatomy (colon). Cysts, which are defined as benign fluid-​filled
structures lined by epithelium, are extremely common throughout the
body and rarely undergo malignant change, whereas “cystic change”
(often necrotic cavitation, rather than true cyst formation) in malignant
tumors is common. Gross architectural patterns are important because
they affect clinical presentation, detection by screening, and epide-
miologic associations. In the Prostate, Lung, Colorectal and Ovarian
(PLCO) cancer screening trial, cysts detected by transvaginal ultra-
sound were not associated with ovarian cancer risk factors, suggesting
that ovarian cancers do not arise typically from benign cysts, as histor-
ically supposed. (Hartge et al., 2000). The lack of association between
benign cysts lined by ovarian surface epithelium and carcinoma may
account for the poor performance of transvaginal ultrasound as an
ovarian cancer screening test (Buys et al., 2011; Jacobs et al., 2016).
Carcinomas exhibit patterns of differentiation, including squa-
mous, glandular, neuroendocrine, and mixed; patterns of differ-
entiation are associated with specific clinical features, and in some
instances, with molecular alterations that represent therapeutic targets.
Histopathologic typing of well-​differentiated carcinomas is reliable,
but distinguishing histopathologic type becomes increasingly difficult
as tumors become less differentiated. Special stains may help distin-
guish squamous cell carcinoma from adenocarcinoma of the lung,
which is important because further testing of adenocarcinomas may
identify specific mutations that predict responses to targeted therapies.
In 2011, a new multidisciplinary classification of lung adenocarci-
noma was proposed to reflect increasing understanding of the biologi-
cal complexity of these tumors (Travis et al., 2011).
Heterogeneity in the Pathology
of Adenocarcinoma: Etiologic and
Clinical Associations
The distinction of different patterns of adenocarcinoma can relate to
etiologic associations and differences in clinical behavior. Selected
examples include the following:
• Endometrial carcinoma:  endometrioid adenocarcinomas are
strongly related to hormonal influences and generally have a favor-
able prognosis, whereas serous carcinomas occur at older ages, are
less strongly related to hormonal factors, and spread aggressively
like their ovarian/​tubal homologues (Brinton et al., 2013).
• Gastric carcinoma: gland-​forming adenocarcinomas are associated
with atrophic gastritis and metaplasia, whereas diffusely infiltrat-
ing carcinomas have a different risk-​factor profile and presentation,
and are linked to germline or somatic CDH1 mutations (E-​cadherin)
(Yakirevich and Resnick, 2013).
• Breast carcinoma: lobular carcinomas grow diffusely as single can-
cer cells or in small linear arrangements, and are more difficult to
detect mammographically than ductal carcinomas (Johnson et  al.,
2015). Lobular carcinomas are linked to CDH1 mutations, as are
similar appearing diffusely infiltrating gastric carcinomas (“signet
ring” cell adenocarcinomas); ductal carcinomas form glands or solid
32
32 Part I:  Basic Concepts
masses and have variable risk-​ factor associations, depending in
part on estrogen receptor status (Acs et al., 2001). (Note: given that
pathologists may use immunostains for e-​cadherin to diagnose lobu-
lar carcinoma, the morphologic distinctions between lobular versus
ductal and e-​cadherin negative or positive are blurred.)
• Ovarian/​tubal carcinoma:  these include multiple histologic types,
some of which have been linked to endometriosis and tend to pres-
ent with stage I  disease (endometrioid and clear cell carcinomas),
whereas high-​grade serous carcinomas typically present with stage
III of IV disease and ascites (Kurman and Shih Ie, 2016).
• Lung carcinoma: tumors measuring up to 3 cm that coat preexist-
ing benign pulmonary architecture (“lepidic growth”) are referred to
as “adenocarcinoma in situ” to emphasize the excellent prognosis;
most adenocarcinomas form masses that destroy underlying benign
architecture (Travis et al., 2011).
Neuroendocrine Carcinomas
Carcinomas showing neuroendocrine differentiation occur throughout
the body, although adenomas and well-​differentiated carcinomas that
produce abundant secretory products occur most frequently within
neuroendocrine organs, sometimes as part of a multiple endocrine
neoplasia syndrome. Neuroendocrine tumors (carcinoids, islet cell
tumors, thyroid medullary carcinomas, etc.) generally appear as uni-
form tumor cells, containing small round nuclei with fine chromatin,
arranged in geographic islands, surrounding by a vascular network.
High-​grade neuroendocrine carcinomas composed of small ovoid
or elongated cells with hyperchromatic nuclei growing in solid sheets,
with frequent mitoses and necrosis, may occur throughout the body.
These “small cell carcinomas” characteristically present with meta-
static disease that responds initially to chemotherapy and radiation, but
later recurs. Cervical small cell carcinomas are more strongly associ-
ated with HPV 18 than squamous cell carcinomas, in which HPV 16 is
numerically predominant (Atienza-​Amores et al., 2014).
Tissue Morphology as Putative
Intermediate Endpoints
Biomarkers may be useful as intermediate or surrogate endpoints.
Establishing that a biomarker is on the causal pathway is powerful
because preventing the intermediate may portend a benefit in cancer
prevention. Intermediates also develop more quickly than cancer, and
therefore can provide more rapid approaches for demonstrating effi-
cacy in prevention studies. However, intermediates often fall short
of expectations because the associations with cancer are not always
strong, and blocking one carcinogenic pathway may not prevent carci-
nogenesis by alternative mechanisms (Schatzkin and Gail, 2002).
In some carcinomas, cancer precursors may serve as useful inter-
mediate markers, although not every precursor lesion will progress
to invasion, and some cancers may arise from multiple different
precursors. Dysplastic changes, such as may occur in inflammatory
bowel disease, may also serve as intermediates and help guide sur-
veillance for colon cancer. At anogenital sites, detection of persistent
type-​specific HPV DNA infection may provide a useful intermediate
biomarker, and serve as an endpoint in screening and prevention stud-
ies (Lowy et al., 2015). Although not every persistent infection pro-
gresses, it is commonly held that all HPV-​related cancers are linked to
a persistent infection.
The Tissue Life Cycle: Practical Consideration
in Planning Analysis of Tissue Biomarkers
in Epidemiology
Increasingly, epidemiologic studies involve multiple centers; conse-
quently, performing central pathology review and molecular analy-
ses in a single laboratory using common validated methods may
improve the consistency of cancer classification. Securing improved
standardization entails costs, logistical concerns, collaborations, and
appropriate internal review board (IRB) approvals.
Agreement between clinical and central research testing results is
high for some markers, such as ER and PR in breast cancer (Badve
et al., 2008); however, for other markers, such as HER-​2, assessing the
status is more complex (Perez et al., 2014). Knowledge of the repro-
ducibility of biomarker studies has potential utility in determining the
value of repeating assays centrally to reduce misclassification.
Diagramming the “tissue life cycle” provides a blueprint for
planning pathology components in epidemiologic studies (Figure
3–​9) (Sherman et  al., 2010). Patient specimens are removed by
clinicians to diagnose the cause of a specific symptom, clinical
finding, radiologic abnormality, or test result, and thus the aims
of diagnostic pathology efforts are narrowly focused. Methods
of obtaining samples vary by method used to localize the target,
access to technology, and indication, which affect the quality and
size of the sample.
Within studies, the characteristics of participants with available tis-
sue should be compared with those for whom samples are unavailable
to address representativeness and possible selection bias. For some
cancer types (i.e., breast), the smallest tumors may be insufficient for
research, whereas for other cancers (pancreatic or lung) the diagno-
sis may be made without surgical removal, limiting the availability
of research samples. These biases could affect analyses of risk-​factor
associations or prognosis by molecular tumor classification.
A comprehensive review of all considerations is beyond the scope
of this writing, but a list of candidate questions for consideration is
provided here.
• Who collected the sample? Specifically, what was the subspecialty
of the clinician who removed the sample? This may be related to the
technique for collection, the clinical setting, geographic setting, and
participant characteristics.
• What tissue was removed? Was the tissue removed for biopsy diag-
nosis, or was the whole organ removed for known cancer?
• Why was the tissue removed? Did the patient have symptoms or
a positive screening test, reflected in an abnormal imaging study,
biochemical or molecular test? Was the surgery performed for risk
reduction in a high-​risk individual?
• Where was the tissue removed? Tissues removed outside the hospi-
tal are often sent to the laboratory fixed, whereas tissues removed
in the hospital may arrive fixed or fresh. Does the setting represent
a general practice setting, high-​risk clinic, or referral for a second
opinion? In international studies, it is important to understand how
clinical practices vary by country and by center within country,
which can profoundly influence quantity, type, and quality of tissues
available for research.
Tissue
Sampling Fixation
Subject Storage with
Optimal Processing
Risk Preservation
Prognosis
Database
Analyses Scoring Assay
Figure 3–​9. Tissue life cycle. Permission and citation may be needed.
Figure 1 adapted from Sherman ME, Howatt W, Blows FM, Pharoah P,
Hewitt SM, Garcia-​Closas M. Molecular pathology in epidemiologic stud-
ies: a primer on key considerations. Cancer Epidemiol Biomarkers Prev.
2010 Apr;19(4):966–​972. doi:10.1158/​1055-​9965.EPI-​10-​0056.
 3
Morphological and Molecular Classification of Human Cancer 33
• When was the tissue removed? Molecular preservation of frozen tis-
sue is generally optimal, but fixed tissues (if well prepared) may be
useful for many assays decades later. Changes in clinical practice,
environmental/​lifestyle factors, and pathology practices over time
may affect assay feasibility and results.
• How was the tissue removed? Was the tissue removed as a small
biopsy that was targeted with direct visualization, or was it image-​
guided? If surgically removed, was an open approach used with
intact removal, or was a minimally invasive procedure used that led
to removal of tissue in fragments without orientation?
Larger tissue specimens received in the diagnostic pathology labora-
tory are sampled for histopathologic examination based on the clinical
context and gross appearance. Selected tissue fragments are used to cre-
ate formalin fixed paraffin-​embedded tissue blocks that are sectioned
(approximately 5 um), mounted on glass slides, stained, and reviewed
microscopically. Each block can yield dozens of tissue sections, and the
uncut material in the block is general archived in pathology laboratories
for variable numbers of years, although a minimum of 10 years is gen-
erally required for laboratory accreditation in the United States.
Pathologists review sections microscopically and formulate diag-
nostic reports that provide information required for management
and assessing prognosis. Pathology reports generally include tumor
size, histopathologic subtype, grade, and clinical biomarker test-
ing. Abstracting pathology reports poses challenges related to non-​
standardized protocols, idiosyncratic differences among specimens,
and variation in formatting and systems of alphanumeric coding for
specimens and individual blocks. Differences in diagnostic terminol-
ogy may necessitate translation to common nomenclature to permit
aggregation of data across study centers. Over the years, standardiza-
tion of pathology reports has increased, which often includes synoptic
reporting that systematically includes all major features related to a
particular cancer type.
Changes in the specificity of diagnoses reported in pathology prac-
tice poses challenges for assessing temporal trends in cancer incidence
rates or analytic studies of cancer incidence in long-​term cohort stud-
ies using cancer registry data. Nomenclature may also evolve to reflect
revised understanding of the clinical behavior of pathologic entities, as
was found for the encapsulated follicular variant of papillary thyroid
carcinoma. Based on a lack of adverse outcomes for individuals with
these cancers, an expert panel recommended renaming these lesions as
“noninvasive follicular thyroid neoplasm with papillary-​like nuclear
features,” thereby revoking the cancer status of such tumors (Nikiforov
et al., 2016). Of note, despite this designation, many of these tumors
show clonal mutations in genes linked to cancer, supporting the view
that molecular testing, like morphologic classification, may have limi-
tations for predicting tumor biology.
EVOLUTION OF HIGH THROUGHPUT MOLECULAR
METHODS FOR CLASSIFYING CANCER
Molecular testing for single or limited panels of prognostic and predic-
tive markers to stratify patients with respect to prognosis and to iden-
tify optimal treatment is an established and growing part of clinical
medicine. With technological advances in array technology and, more
recently, next-​generation sequencing, the biomarker field has moved
into more comprehensive molecular characterization of tumor samples.
As costs for sequencing decline, this trend is anticipated to continue,
although bioinformatic challenges remain limiting. Table 3–​3 reviews
some of the current technologies for analyzing RNA, DNA, DNA
methylation, and protein, highlighting strengths and weaknesses.
The move toward classifications of cancer based on comprehen-
sive molecular characterization began with the development of DNA
microarrays (previously referred to as cDNA microarrays) for measur-
ing gene expression in the late 1990s to early 2000s. Early microarray
studies classified cancer samples into “subtypes” sharing similar gene
expression, as determined by agnostic statistical methods, such as
hierarchical clustering (Alizadeh et al., 2000; Perou et al., 2000; Sorlie
et al., 2001). Enthusiasm for this research was driven by recognition
that cancer subtypes defined by these methods extended classifications
based on robust clinical markers by providing additional prognostic
information. The Human Genome Project accelerated progress by pro-
viding the framework for designing probes to evaluate the transcrip-
tome (Lander et al., 2001).
In breast cancer, DNA microarrays were used to identify an “intrin-
sic gene list.” The early arrays were performed on macrodissected
samples of tumor cells, stroma, immune cells, and adipose tissue.
The intrinsic gene list identified genes that were inherent to the tumor
because they showed similar expression between multiple samples of
the same tumor or tumor/​metastasis pairs. This approach identified five
robust breast cancer subtypes, which were repeatedly identified, sug-
gesting that these categories reflected fundamental divisions in breast
cancer (Perou et al., 2000). This classification distinguished a category
with a good prognosis (luminal A) from classes with poorer outcomes,
designated as luminal B, HER2, and basal-​like (Sorlie et  al., 2001).
This taxonomy has been reproduced in multiple populations and using
different RNA-​based technologies, which has transformed thinking
about breast biology and treatment (Dunbier et  al., 2011; Hu et  al.,
2006; Huo et  al., 2009; Rouzier et  al., 2005; Sorlie et  al., 2001; Yu
et al., 2004).
Improved technology has expanded expression profiling to include
more genes and non-​coding RNAs, and has improved production of
more specific stable probe sequences with quality control. RNA label-
ing and hybridization are relatively easy and can be performed in
2  days. Data analysis can be performed on desktop computers with
widely available packages, including those freely available from
Bioconductor (Gentleman et al., 2004).
Microarrays are useful for measuring expression of many genes
concurrently; however, the outputs are relative gene expression val-
ues that are based on hybridization and fluorescent values, which are
semi-​quantitative. These methods also depend upon amplification and
synthesis of cDNAs, which can be challenging for fragmented RNAs,
such as those extracted from formalin fixed paraffin-​embedded tissues.
Further, these methods can only detect probes represented on arrays,
limiting discovery. New technologies, such as RNA-​counting meth-
ods (e.g., Nanostring; Geiss et al., 2008), do not rely on amplifying
the RNA and can count the number of RNA molecules directly for
up to 800 genes using a barcoded system. These methods can detect
fragmented RNAs, and therefore can be applied to both fresh frozen
and formalin fixed paraffin-​embedded tissues and samples with low
(cellularity) yields.
In the late 2000s, use of RNA sequencing further increased analyti-
cal capabilities, including more sensitivity for detecting lower levels
of transcripts. Further, sequencing can detect uncharacterized RNA
sequences that can be mapped to the genome to identify novel genes,
assess alternative splicing, find somatic gene fusions, and measure
expression levels of mutations.
Next-​Generation Sequencing
Next-​generation sequencing of somatic tissues offers advantages over
earlier generation Sanger Sequencing, including greater through-
put, partly enabled by parallel read detection, increased capacity to
sequence bases, and reduced costs per base. Using newer methods
has enabled detection of new mutations of clinical consequence. For
example, Sanger sequencing of mutations in 601 selected genes in 91
glioblastoma multiforme tissues and matched blood samples identi-
fied genes that were recurrently mutated in glioblastoma multiforme
(Cancer Genome Atlas Research, 2008). Using next-​generation meth-
ods to sequence the genome of only 22 glioblastoma multiforme,
another group identified IDH1 mutations, which emerged as impor-
tant in understanding the pathogenesis of glioblastoma multiforme,
with potential for predicting prognosis and improving treatment
(Parsons et al., 2008). IDH1 and IDH2 mutations are found frequently
in lower grade gliomas and are associated with better survival (Brat
et al., 2015).
Next-​generation DNA sequencing methods include whole genome
sequencing (WGS), whole exome sequencing (WES), and targeted
34

34 Part I:  Basic Concepts

Table 3–​3. Strengths and Weaknesses of Selected Molecular Methods for Classifying Cancers

Analyte Technology Strengths Limitations

RNA RT-​PCR Sensitive quantitative Low throughput; requires gene sequence

Nanostring Good dynamic range; suitable for FFPE Medium throughput; limited number of targets
Minimal bioinformatics
Microarrays High throughput; low cost Low dynamic range; not suitable for FFPE
Quick Genes detected limited to specificity and selection
Minimal bioinformatics of probes
RNAseq (mRNA, miRNA, High throughput; large dynamic range Expensive; time intensive
total RNA) Suitable for FFPE Requires intensive bioinformatics support
DNA Whole genome sequencing Mutations, structural variations, copy number Expensive; time intensive
(WGS) variation, for both coding and non-​coding regions Requires intensive bioinformatics support
More uniform coverage
Whole exome sequencing Mutations (SNVs, indels) for coding regions; less Limited to coding regions in capture set; variability
(WES) expensive than WGS in capture efficiency
Changes in capture kits over time
Variable detection of structural or copy number
variations
Targeted sequencing Less expensive; mutations Limited to regions captured by probes
High coverage of selected regions
Copy number arrays Quick and inexpensive Not full genome; resolution is about a marker every
Copy number and LOH 700bp
SNP information
DNA methylation Arrays High throughput; less bioinformatics demand Inexpensive; analysis limited to selected probes
(currently up to 450K)
BiSulfite sequencing Whole methylome; high sensitivity Expensive; low throughput
Intensive bioinformatics analysis
Protein Western blots Can detect bands based on molecular weight Low throughput; dependent on antibodies
Reverse phase protein High throughput samples ~150 antibodies Antibodies must be specific; proteome incompletely
arrays (RPPA) covered
Mass spectrometry Large number of proteins quantified; good for Expensive; limited sample throughput
known or novel proteins De novo methods not always accurate
Not all peptides visible
Intensive bioinformatics

sequencing (TS), which differ predominately in the amount of the
genome that is sequenced. Methodologic differences related to nucleic
acid preparation and amplification prior to sequencing may affect results
between studies, posing challenges for data pooling. WGS aims to
sequence the entire genome and can find variants in both coding and
non-​coding regions, detect structural variations, and determine copy
number states. Typically, coverage is around 30X, although the purity
of the sample might require additional sequencing to sensitively detect
alterations, and deeper reads may also be required to identify sub-
clones. Applications of WGS have been constrained by cost, but these
have dropped dramatically from ~$10  million for a whole genome
in 2007 to $1000–​$4000 in 2015. WES sequences the exomes (cod-
ing regions), which comprise about 1% of the human genome. WES
reduces the amount of genomic regions sequenced, and therefore cov-
erage is typically higher, approximately 30X–​100X. Finally, TS usu-
ally includes smaller gene panels for focused analyses, and coverage is
usually 500X–​1000X.
DNA sequencing methods have also been used for classification.
TCGA analyses of melanoma resulted in a proposed classification
based on mutations—​BRAF, RAS, NF1, and Triple-​WT (The Cancer
Genome Network, 2015). DNA sequencing can yield mutational spec-
tra that may ultimately be linked with etiological exposures that are
linked to a specific somatic mutation, such as UV induced, APOBEC,
POLE, age, and smoking signatures (Alexandrov et  al., 2013; Nik-​
Zainal et al., 2012).
Analysis of DNA Methylation
Epigenetic alterations, such as DNA methylation, can play an
important role in regulating gene expression. Two platforms used
currently to assess DNA methylation include arrays, which evalu-
ate up to 450,000 probes, and bisulfite sequencing, which can cover
most of the CpG and methylation sites in the genome, but with
lower throughput and at a significantly higher price. Molecular clas-
sification using DNA methylation has played a major role in sev-
eral tumor types. A CpG island methylator phenotype (CIMP) was
first characterized in colorectal cancers (Toyota et  al., 1999)  and
subsequently in other tumor types. TCGA established CIMP in gli-
oma, which was associated with younger age at diagnosis, proneu-
ral subtype, IDH1 mutations, and improved outcomes (Noushmehr
et al., 2010).
Proteomics
To date, most molecular classifications of carcinomas have been
developed using RNA analysis, but proteomic data are important in
targeted drug development. Immunohistochemistry and Western blots
have practical limitations for assessing expression of many different
proteins in large studies. Reverse phase protein arrays (RPPA) allow
detection of ~200–​300 proteins and phosphoproteins in up to 1000 dif-
ferent samples with higher sensitivity than Western blots (Tibes et al.,
2006; Zhang et al., 2009). Mass spectrometry methods can detect more
proteins, but have limited sample throughput. Protein-​based methods
are sensitive, but can be problematic for large studies because stored
samples are susceptible to protein degradation.
RESEARCH APPLICATIONS OF BIOMARKERS
While most current research has focused on translating genomic
discoveries to clinical applications (e.g., prognosis and treatment
response), biomarkers may be measured in cancer tissues to address
different research aims. Other purposes include early detection,
screening, and etiology; general issues are covered in Chapter 6, but
we highlight a few examples here, in particular those related to diag-
nosis and classification.
 35
Morphological and Molecular Classification of Human Cancer 35
Multifunctional Biomarkers: HPV DNA and ER
Biomarkers may serve singular functions in early detection, prognosis,
or prediction, but many useful biomarkers function in multiple capaci-
ties, such as HPV 16 DNA in the cervix and ER in breast cancer. The
cervix is susceptible to infection with over 13 carcinogenic HPV types,
the vast majority of which occur among young women and become
undetectable within 2  years (Moscicki et  al., 2012). However, HPV
16 genotypes are more virulent, with a greater tendency to progress
to cervical cancer than other genotypes, accounting for approximately
50% of these cancers overall. As a result of its importance as an eti-
ologic agent and prognostic marker, clinical guidelines recommend
immediate colposcopy for women who test positive for HPV 16 (or
18) DNA, whereas for all other carcinogenic HPV types, triage with
cytology is acceptable (Huh et al., 2015).
ER status of breast cancers delineates etiologically distinct tumor
subtypes, as defined by risk-​factor associations, incidence rate pat-
terns, and molecular profiles (Althuis et  al., 2004; Anderson et  al.,
2014; Perou et al., 2000). Positive ER status predicts improved out-
comes among postmenopausal women (especially in early follow-​up);
ER therefore represents a single-​gene molecular marker that is a useful
classifier across the spectrum from etiology and prediction (response
to treatment) to prognosis (survival) (Henderson and Patek, 1998). ER
status also demonstrates the blurring of prognosis and predictive mark-
ers. Prior to the introduction of tamoxifen, a highly effect adjuvant
therapy for ER-​positive breast cancer, the hazard rates of both ER-​
positive and ER-​negative cancers were more similar, with a sharp peak
in the first years following diagnosis, followed by a marked decline.
Following introduction of adjuvant tamoxifen therapy, the hazard rate
of ER-​positive breast cancers flattened, but remained above baseline
for many years (Berry et al., 2006).
Single Biomarkers
Clinical testing for many single biomarkers is important for assessing
prognosis and determining management, as outlined throughout this
chapter; however, recognition that none of these biomarkers performs
flawlessly has prompted searches for expanded panels to improve
performance. For example, KRAS, BRAF, and NRAS are important
prognostic indicators in colon cancer, and may predict responses to
EGFR-​targeted therapies; however, predictions are limited by molecu-
lar redundancy in the EGFR pathway (Tran et  al., 2015). In breast
cancer, ER-​positive status predicts responses to endocrine therapies,
but treatments may fail because of ER mutations, alterations in other
growth pathways, or other reasons (Zhao and Ramaswamy, 2014).
Ovarian/​tubal serous carcinomas with BRCA1/​2 dysfunction resulting
from germline mutations or somatic alterations respond favorably to
platinum chemotherapy or PARP inhibitors, but such tumors are rarely
cured (Bao et al., 2016).
Development of more accurate multi-​gene molecular classifiers has
been enabled by the availability of high-​throughput methods for geno-
mic characterization. While some biomarker panels are standardized
and commercialized, other tests performed for research or clinical
management are considered “laboratory-​developed tests,” which are
intended for “in-​house” use only. As precision medicine advances, the
need for such tests will likely increase, raising concerns about vali-
dation (accuracy, analytical sensitivity and specificity, and reproduc-
ibility), clinical predictive performance, and quality assurance, with
implications for regulation and insurance coverage.
Biomarker panels that assess multiple carcinogenic pathways may
provide improved assessment of critical mechanisms (e.g., prolifera-
tion, apoptosis, etc.) by assessing processes with several related mark-
ers (“metagenes”). Several multi-​gene biomarker panels for breast
cancer have been approved as clinical tests, and it may be possible
to repurpose the results to study etiological questions (Gyorffy et al.,
2015). Developing gene signatures that reflect function of pathways
may represent powerful approaches for understanding carcinogene-
sis and improving prevention and treatment strategies. For example,
loss of TP53 functions, as a consequence of mutation, copy number
variation, methylation, or even amplification or overexpression of
other TP53-​regulatory genes, is a cardinal feature of many cancers.
A  TP53 signature based on gene expression that reflects the down-
stream effects of alteration in TP53 function, rather than the underly-
ing molecular mechanisms, has been developed as a useful classifier
(Troester et al., 2006).
High-​Throughput Genomic Classification
The Cancer Genome Atlas (TCGA), a National Cancer Institute–​
sponsored project to develop molecular taxonomies of cancers arising
at multiple organ sites, provides the gold standard for high-​dimensional
genomic cancer classification based on multi-​ platform molecular
profiling data (see Chapter  4). Further, TCGA has provided unique
opportunities to assess molecular genomic and epigenomic changes
across tumors of different organ sites, demonstrating unexpected and
potentially important biological relationships among cancers through-
out the body. For example, data suggest common genomic alterations
for serous carcinomas of the pelvis and basal carcinomas of the breast,
including a high prevalence of mutations in TP53 and a similar pattern
of copy number alterations (The Cancer Genome Network, 2012).
TCGA has resulted in landmark achievements in molecular clas-
sifications; nonetheless, the results of the project are not optimal for
addressing all types of scientific questions. For example, TCGA was
not designed to investigate etiological heterogeneity, prognosis, or pre-
diction of treatment. The study does not represent a population-​based
sample and tends to over-​represent larger and more aggressive tumors.
Moreover, TCGA includes only limited risk factor information, and
although the data sets have been used to analyze outcomes, follow-​up
is not mature and available treatment data are minimal. Importantly,
the study was designed to collect optimally preserved tissue samples,
and therefore, the tumors may not be representative of those occurring
in the general population, at least with regard to frequency of occur-
rence. Therefore, TCGA provides an important biomarker discovery
engine, but molecular epidemiology and clinical research are pivotal
for applying biomarkers to answer important translational research
questions.
Integrated multi-​platform molecular analysis, while providing the
most detailed molecular classifications, is expensive and unaffordable
in most epidemiological studies. However, anticipated reductions in
sequencing costs may increase the feasibility of these approaches in
the future. Further, molecular panels based on immunohistochemistry,
DNA sequencing, or mRNA expression that approximate classifica-
tions based on comprehensive molecular analysis can be applied in
many epidemiologic projects, particularly as methods for analyzing
paraffin embedded tissues improve (Tyekucheva et al., 2015). TCGA
is currently leveraging methods, such as elastic nets and LASSO, to
identify the minimal number of features needed to distinguish tumor
classes identified with the full data. These types of studies are a neces-
sary next step in translating the TCGA findings to large population-​
based studies. Given power requirements that result in part from
multiple comparisons, future research in this area will likely require
consortia of multiple studies. These approaches will necessitate either
standardization of methodology or demonstration of comparability in
classification across genomic platforms.
INTEGRATION OF CLASSIFICATION SCHEMA
Researchers addressing the challenge of developing useful cancer clas-
sifications rely on different types of data, ranging from population-​
based incidence rates through intensive molecular profiling. Each
approach offers strengths and weaknesses, but none is likely to fully
capture the heterogeneity of cancer from every perspective: etiological,
biological, and clinical. Consequently, integrating information from
multiple disciplines may improve the utility of cancer classifications.
Classification of breast cancer provides an illustrative example of
where different approaches reinforce one another to provide a coherent
picture of carcinogenesis. In breast cancer, from a clinical perspective,
36
36 Part I:  Basic Concepts
there are three primary types: hormone receptor positive, HER2 over-
expressing, and a third group encompassing all other tumors. Etiologic
hypotheses based on descriptive population-​based statistics suggest
that breast cancer may represent two main types: an early-​onset can-
cer, enriched for ER-​negative cancers with a peak incidence at age
50 years, and a larger group of late-​onset tumors, which is mainly ER-​
positive and peaks at age 70 years (Anderson et al., 2014). In analytical
epidemiology, cancers are often split based on age and menopausal
status, relationship to estrogenic risk factors, ER status, and associa-
tion with mutations in high-​penetrance genes (e.g., BRCA1/​2) (Althuis
et  al., 2004; Anderson et  al., 2014; The Cancer Genome Network,
2012; Yang et  al., 2011). Basic biologists that embrace a stem cell
model of carcinogenesis might envision two main types:  luminal or
basal, reflecting proposed progenitor cells of origin.
Following the identification of the breast cancer intrinsic subtypes
based on expression profiling, TCGA extended the characterization of
breast cancer using multiple genomic platforms (mRNA and miRNA
gene expression, DNA sequencing, DNA methylation, copy number
variation) (The Cancer Genome Network, 2012), which affirmed the
validity of the original classification. Further, the data demonstrated
that the three most prevalent somatic mutations in breast cancer are
TP53 (37%), PIK3CA (36%), and GATA3 (11%), and that the preva-
lence of these mutations differ by subtype. Almost 80% of basal carci-
nomas showed a mutation or loss of TP53, and those that did not share
these defects showed defects in other TP53 pathway members, such
as the TP53 negative-​regulator MDM2. Compared with basal carcino-
mas, a lower percentage of luminal breast cancers demonstrate TP53
defects, whereas the percentage of PIK3CA and GATA3 mutations was
much higher (The Cancer Genome Network, 2012). Approximately
35 genes were mutated with appreciable frequency in breast cancers.
However, little is known about associations between these mutations,
risk factors, and prognosis. Thus, additional analyses encompassing a
multidisciplinary perspective are needed.
Subsequent studies have shown that genomic data and epidemio-
logic data can be integrated, yielding improved inferences. In a TCGA
report that evaluated multiple genomic platforms from 12 different
cancers, the differences in the genetic characteristics of luminal versus
basal breast cancers were on the order of differences between sites
(e.g., bladder vs. kidney) and were greater than differences between
some sites (e.g., colon and rectum) (Hoadley et al., 2014). This under-
scores, from a genomic perspective, that the two breast cancer sub-
types are best considered as distinct diseases. Further, basal breast
cancers and high-​grade tubal/​ovarian serous carcinomas shared an
unexpectedly high number of molecular similarities.
CHALLENGES AND FUTURE DIRECTIONS
Classical Pathology Methods
Histopathology was the mainstay of cancer classification for many
years. Ongoing research seeks to overcome the inherent subjectivity,
inconsistency, and variability of visual assessment, while preserving
the rich data that morphology provides by reflecting the composite
dynamic effects of complex biology over time. When pathologists
score histopathological features, they are relying on a visual, men-
tal database of thousands of images and applying pattern recognition
skills and diagnostic criteria. This process is at best semi-​quantitative,
and often merely descriptive. Differences in pathologists’ biases and
experiences may contribute to subtle, and sometimes more than subtle,
differences in interpretation. Further, these opinions may be reinforced
among pathologists who work together and strive for reproducibility.
A number of objective, automated algorithms have been developed to
address these concerns.
Automated algorithms and computer-​based image analysis offer
inherent strengths, including the ability to count events and measure
features, neither of which is readily achieved visually. However, algo-
rithms are often challenged to make distinctions that are readily made
by pathologists, such as identifying artifacts and distinguishing cell
types. Simple computer algorithms can count the number of positive
nuclei with a particular immunohistochemical stain and measure stain
intensity in each nucleus, but cannot distinguish invasive cancer cells
from CIS and benign cells without applying sophisticated algorithms.
Interactive image analysis can sometimes be used to harness the visual
identification skills of pathologists and the ability of computer pro-
grams to count and measure morphological features. For some pur-
poses, this synergistic power may enable improved morphologic
classification. Further, results of image analysis may lead to improve-
ments in diagnostic criteria used by pathologists.
An important application of morphologic classification is that it can
be merged with molecular testing to assess relationships of cells within
intact tissues and co-​expression of proteins within individual cells. To
achieve these goals, several methods are being developed to enable
labeling with dozens of probes on a single section. If combined with
quantification of signals from target probes, this approach may iden-
tify various subclones within cancers and map these topographically to
assess intratumoral heterogeneity, and potentially its regional drivers.
Finally, in large studies of cancer that are assessing robust markers,
automated analysis may provide standardized reads more quickly than
might be achieved by visual interpretation. However, the advantages of
this approach are tempered by the upfront effort to develop and apply
algorithms and the need to perform quality assurance.
Molecular Classification
Many epidemiologic studies attempt to link known cancer risk fac-
tors to cancers of particular organ systems, stratified by molecular
tumor subtypes, as defined using marker panels. This approach can
be expanded to evaluating etiologic heterogeneity based on subtypes
defined by molecular profiling, and further, to relating risk factors or
exposures to expression of individual genes, gene mutations, cytoge-
netic changes, or molecular signatures. Relating risk factors to causal
mechanisms and strongly associated biomarkers may offer opportuni-
ties for early detection and prevention.
Assessing risk factors in relation to increasingly complex tumor
classifications poses challenges for achieving sufficient statistical
power to distinguish true associations from chance findings found
among multiple comparisons. Addressing these issues will require
large data sets compiled in collaborative consortia or data pooling, an
approach that will pose complexities related to differences in sample
preparation, profiling methodologies, logistics, and cost. Ideally, once
biomarker associations are identified, they should be independently
replicated in different studies to support their validity, and then evalu-
ated in diverse populations to assess generalizability. Further, for
many cancers, subtypes of particular etiologic interest may comprise
a minority of tumors (e.g., basal breast cancers, endometrial serous
carcinomas, etc.).
Attempting to relate risk factors to specific changes at the DNA or
RNA level may prove challenging because numerous stochastic events
related to genetic instability, an intrinsic property of cancer, may prove
difficult to distinguish from changes related to cancer etiology or
pathogenesis. Complex biostatistical analysis of multiple samples per
tumor may be required to distinguish driver from passenger molecular
events in established cancers, but such samples are rarely available and
the work is costly. Analysis of cancer precursors could reduce difficul-
ties related to distinguishing molecular drivers from passengers related
to genetic instability (Campbell et al., 2016), but once tissues are sam-
pled, the natural history of such lesions may be unknown with regard
to progression to invasive cancer, regression, or dormancy. Further,
precursor lesions are typically asymptomatic, and the types of such
lesions may vary with screening methods.
Another possible approach to improve the distinction of molecular
alterations causally related to carcinogenesis is to study field effects
surrounding cancers, cancer precursors, or normal tissues (Chai and
Brown, 2009). Further, integrating such findings in the context of
epidemiological studies may be useful for understanding the “etio-
logical field effect,” which links molecular alterations in tissues to
potential carcinogenic exposures (Lochhead et  al., 2015). Although
such cross-​sectional studies cannot distinguish whether a specific
 37
Morphological and Molecular Classification of Human Cancer 37
molecular alteration preceded or followed cancer development, it
may aid the identification of biomarkers that could be tested in other
sample sets without cancer (e.g., tissues removed for diagnosis) and
known outcomes in follow-​up. The development of a pre-​TCGA
project may enable this research in the future, although technical
challenges remain, related to molecular studies of small samples,
the likely need to work with fixed tissues, and difficulties related to
knowing the natural history of lesions once removed (Campbell et al.,
2016). Nonetheless, such research may distinguish etiological factors
and mechanisms involved in initiation from those that may be related
to later phases of carcinogenesis, such as clonal expansion, invasion,
and metastasis.
Cancer risk factors that are genetic or related to development may
operate by shaping normal tissues to make them more susceptible to
cancer initiation. In the breast, data suggest that differences in physi-
ological exposures, ranging from attained age or age at menarche and
menopausal status to recent pregnancy and childbirth, may alter the
microanatomy, molecular characteristics, and function of normal cells,
resulting in a spectrum of “molecular histology” (Figueroa et al., 2014;
Sherman et al., 2012).
Changes in molecular histology may represent prevention targets
in healthy populations. Well-​developed surrogate endpoint biomark-
ers have been identified for some cancers (Schatzkin and Gail, 2002),
but for most cancers, such endpoints are lacking. Identification of
surrogate endpoints could facilitate evaluation of novel prevention
approaches in clinical trials and allow monitoring of the effectiveness
of established approaches in clinical practice.
CHALLENGES AND FUTURE DIRECTIONS:
CLINICAL RESEARCH
As our understanding of the molecular biology of cancer advances,
important topics with translational implications are emerging. Recent
research has emphasized the key role of intratumoral (within tumor)
spatial or temporal heterogeneity. A central translational goal of can-
cer classification is optimized, targeted treatments, which requires
accurate clinical subtyping. Clinical subtyping has historically uti-
lized single tissue samples collected at diagnosis and selected based
upon high tumor viability and cellularity. However, tumors may have
mixed phenotypes or may be spatially heterogeneous, and this could
confound accurate clinical subtyping and treatment. Understanding
intratumoral genotypic and phenotypic heterogeneity is a critical topic
of cross-​disciplinary concern, although to date, this has received most
attention with regard to predicting therapeutic responses (Alizadeh
et al., 2015).
As an example of the importance of intratumoral heterogeneity,
consider the estrogen receptor, arguably the most important prog-
nostic/​predictive biomarker in breast cancer clinical care. Tumors
that express ER strongly in every cell tend to be well differentiated,
indolent, and more readily cured; however, many tumors classified as
ER-​positive include substantial subpopulations of ER-​negative cells
(at least based on immunohistochemical assays performed at any
given time point), and the behavior and treatment response of such
tumors is less predictable. Understanding which ER-​positive tumors
are composed of biologically diverse clones is critical because initial
treatments may inadvertently select for tumor subpopulations that are
resistant to targeted therapy. Thus, identifying cancers with clonal
diversity and developing algorithms to classify such tumors are critical
to the success of precision medicine; tailored treatments should target
the Achilles’ heel of all potentially clinically significant clones, not
merely the dominant one.
Spatial heterogeneity ultimately arises from temporal heterogeneity
(i.e., because tumors change through clonal expansion and “evolution”
over time), but spatial heterogeneity is particularly important because
initial treatment success, based on accurate molecular characterization
and appropriate treatment selection at diagnosis, is the best predictor
of treatment outcome. Spatially, some tumors are homogeneous, and
such tumors might be anticipated to respond more uniformly, portend-
ing a more indolent course. Previous studies have shown that the risk
of cancer progression is highest among lesions with the highest degree
of regional genetic heterogeneity (Merlo et al., 2010).
Among heterogeneous tumors, there are at least two types of hetero-
geneity, which may have different consequences. Heterogeneity can
be stochastic and dispersed, reflecting genetic instability across the
tumor. In a dispersed heterogeneous tumor, various clones show fitness
and/​or become extinct via a linear, randomly evolving (stochastic),
time-​variant process. Heterogeneity can also be segregated or hierar-
chical, possibly defined by key geographic landmarks or microenvi-
ronmental zones, with tumor cells found in one area showing distinct
evolutionary pressures and therefore distinct genetic characteristics.
The latter type of heterogeneity was termed “allopatric” in reference
to ecologic speciation that is branched due to geographic segregation
(Burrell et al., 2013).
Segregated heterogeneity is particularly problematic for molec-
ular diagnostics. Sampling of one “species” or zone of a hetero-
geneous tumor would not represent the tumor’s overall biological
potential and could lead to treatments that lack the breadth of
effects required to inhibit all driver molecular pathways. Thus,
tumors could be of at least three types: (1) homogeneous; (2) het-
erogeneous, dispersed; and (3) heterogeneous, segregated. Despite
the potential for prognostic and/​or treatment decision differences
between the first two categories, both homogeneous and heteroge-
neous, dispersed tumors could reliably be characterized by assaying
samples from a single location. Recognition of dispersed heteroge-
neity may have important prognostic and predictive implications,
but at least sampling is straightforward. Segregated molecular
heterogeneity would require multiple samplings to be adequately
described and targeted.
Another area of contemporary interest is in further characterizing
tumors according to the characteristics of their microenvironments.
This can mean characterizing stromal or immune cell infiltrations
around a tumor, but can also encompass better understanding of the
systemic milieu of the person with disease. For example, obesity-​and
diabetes-​associated cancers may have different metabolic or tissue
characteristics that affect their growth (Gucalp et al., 2016). Similarly,
recent pregnancy may affect the milieu in which a reproductive or
breast cancer arises, resulting in distinct tumor characteristics, modu-
lated by the post-​pregnancy microenvironment, as suggested in animal
models (Lyons et  al., 2011). Tumors associated with local immune
responses may be more amenable to immunotherapy, as has recently
been demonstrated for colon carcinomas associated with microsatellite
instability, a defect that may produce multiple tumor antigens that are
recognizable by the immune system and breast cancer (Le et al., 2015;
Savas et al., 2016).
Implications for Cancer Epidemiology
Historically, cancers were analyzed purely by site of origin. As appre-
ciation of the biological heterogeneity of cancer increased, etiologi-
cal research expanded to assessment of cancer subtypes, first based
on histology, and then on limited numbers of key biomarkers. As the
capacity for high-​throughput molecular analysis has increased, and the
costs for performing such analyses have decreased, questions arise as
to the best approach for tumor classification. In tandem with the arrival
of the “molecular age,” clinical practice has moved toward using less
invasive biopsy methods, which remove smaller samples that are often
consumed by intensive molecular testing. Further, neoadjuvant therapy
has rendered many surgically removed tissues less useful for etiologic
studies. Consequently, obtaining “residual” tissue for research has
become more difficult, which poses challenges for conducting large
epidemiological studies.
As suggested in this writing, optimal classification may depend on
the research questions posed: etiological, mechanistic, prognostic, or
predictive. At the extreme, every cancer might be viewed as a “one of a
kind,” but this approach is not amenable to understanding associations
using statistical methods. Accordingly, efforts to define the optimal
parsimonious biomarker panels, which group cancers that are highly
similar biologically, even if not identical, are needed. To accomplish
this goal, molecular epidemiologists will move increasingly into the
38
38 Part I:  Basic Concepts
world of trans-​disciplinary research, partnering with both laboratory
scientists at the cutting edge of technology, and bioinformaticists and
biostatisticians who can provide guidance in interpreting enormous
amounts of data.
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4 Genomic Landscape of Cancer
Insights for Epidemiologists
CHRISTOPHER J. MAHER AND ELAINE R. MARDIS
OVERVIEW
The past decade has seen rapid advances in the study of cancer
genomics using next-​generation or massively parallel technology
for DNA sequencing. The resulting knowledge has transformed our
understanding of the genetic underpinnings of cancer susceptibility,
onset, and progression. New technologies have increased the speed
and have lowered the cost of DNA sequencing, and have enabled
high-​volume characterization of RNA, DNA methylation, DNA-​
protein complexes, DNA conformation, and a host of other fac-
tors that, when altered, can lead to cancer onset and progression.
Technological advances have greatly expanded research on somatic
changes in tumor tissue, revealing both the singularity of individual
cancer genomes and the commonality of genetic alterations that
drive cancer in different tissues. Regulatory processes involve not
only changes in nucleotide sequence but also functionally relevant
effects mediated through epigenetics, transcription factors, non-​cod-
ing RNAs, and chromatin packaging. Combined with our enhanced
understanding of cancer cell-​specific alterations in the genome is a
growing understanding of how our constitutional genome impacts
cancer susceptibility. Hence, the introduction to the current frame-
work of cancer genomics we provide here will inform future studies
of the genetic epidemiology of cancer.
INTRODUCTION
Over the past 10  years, the study of cancer genomics using next-​
generation or massively parallel technology for DNA sequencing
has transformed our understanding of the genetic underpinnings
of cancer susceptibility, onset, and progression. Expanding beyond
the detection of genomic alterations, methods development aimed
at characterizing RNA, DNA methylation, DNA-​protein complexes,
DNA conformation, and a host of other aspects of cancer-​altered
nucleic acids has resulted from the increasing throughput and
decreasing cost of DNA sequencing. One vital component of this
progress was the initial sequence, and ever-​improving completion, of
the human reference genome that provides the framework for inter-
preting the data generated by these increasingly complex methods
to evaluate changes that are contributing to the onset and progres-
sion of cancer. The human reference genome (International Human
Genome Sequencing, 2004) is indispensable in this new era of cancer
genomics discovery since the short read lengths produced by mas-
sively parallel sequencing (MPS) instruments require alignment of
sequencing reads to the reference genome as a first step to data anal-
ysis. In other words, rather than being able to assemble the individual
chromosomes from the sequencing data reads, one must first align
to the fixed reference genome and then use a variety of interpreta-
tional algorithms to evaluate the data according to the experimental
“question” being asked by the upfront preparatory assays (Mardis,
2013). Hence, by using this general paradigm for data generation and
analysis, cancer genomics efforts have tremendously enhanced our
understanding of the differences between tumor and normal genomes
across the breadth of adult and pediatric tissue sites commonly (and
in some cases rarely) affected by cancer. Indeed, several discover-
ies have indicated surprising new genes and pathways that, when
altered, lead to cancer onset and progression. For example, spliceo-
some proteins, cohesin complex genes, and metabolic enzymes have
been identified as predominantly mutated in certain tumor types and
have been shown by follow-​on functional experiments to contrib-
ute to carcinogenesis. There also have been surprises regarding the
germline contribution to cancer susceptibility. Several studies have
demonstrated the contribution of de novo mutations in known can-
cer susceptibility genes to the onset of disease. These discoveries
indicate that, while a predisposition to cancer as ascertained by fam-
ily history provides important clinical data, the absence of family
history cannot solely rule out a germline contribution. Finally, by
comparing genomic alterations across different tissue sites, so-​called
pan cancer analyses have demonstrated the commonality of genomic
alterations across cancer genomes and yet have emphasized in sin-
gularity that each patient’s cancer genome is composed of a unique
set of genomic alterations. Beyond genes and their alterations, a
richer understanding of gene regulatory mutations and other types of
regulatory alterations has been revealed using genome-​wide assays
that are read out by MPS to characterize the cancer epigenome.
These efforts include studies of newer types of non-​coding RNAs
that are only beginning to be classified as overexpressed in cancers
and to have associated regulatory roles. Taken together, the cancer
genome landscape is incredibly complex and varied, yet these newer
approaches are increasing our knowledge with each new study.
THE IMPACT OF TECHNOLOGY
Massively Parallel Sequencing
Following completion of the human genome reference sequence in
2004 (International Human Genome Sequencing, 2004), capillary
sequencing technology was used to study mutations in known cancer
genes following directed polymerase chain reaction (PCR) ampli-
fication of the gene’s exons. Increasing the numbers of PCR prim-
ers across all annotated exons of every human gene was possible,
but there were significant challenges due to the cost of sequencing,
the scalability of the molecular biology, and the need for extraordi-
narily large amounts of DNA from the tumor to accomplish many
thousands of PCRs done individually. As such, most early studies
of cancer genomes focused on known genes in relatively large num-
bers of tumors, or sequenced large numbers of genes (or all of them)
in a small number of tumors (Ding et  al., 2008; Ley et  al., 2003;
Wood et  al., 2007). In the first decade of the 2000s, new sequenc-
ing technologies were introduced that were called “next-​generation”
or “massively parallel” sequencing instruments. These technologies
were distinctly different from the combination of Sanger sequenc-
ing and capillary electrophoresis-​based separation and detection of
reaction products because, rather than a decoupled set of reactions to
produce sequencing fragments that were subsequently separated and
detected on the sequencing instrument, these instruments permitted
sequencing and detection in situ, without the need for electrophoretic
43
4
44 Part I:  Basic Concepts
fragment separation. As such, one could combine, for example, all
PCR products resulting from primer-​directed amplification in indi-
vidual reactions, and produce sequencing data for all products at
once. The result was a massive increase in throughput and a dramatic
decrease in the cost of the sequencing reactions, but still required
large amounts of tumor-​isolated DNA to feed the upfront PCRs.
The alternative approach, prior to 2009, was to sequence the entire
genome of the tumor using these new instruments, but the large
amount of data produced by this approach, the expense of producing
that data, and the lack of a computational analysis method to make
sense of the hundreds of millions of short read–​length sequences
made the analysis seem implausible. In 2008, however, the first such
study was reported for a single patient whole genome, comparing
the acute myeloid leukemia (AML) genome to the matched skin-​
derived normal genome (Ley et  al., 2008), using the Solexa (now
Illumina) technology. In this study, as in all to follow, the human
reference genome provided the template against which short reads
were aligned and variants detected, and then algorithm-​driven com-
parison approaches were used to identify somatic alterations unique
to the tumor. Many aspects of the data provided by MPS have
changed since this early study, including read-​length increases (cur-
rently Illumina produces 150 bp), the capability to produce sequence
data from both ends of each library fragment (“paired-​end reads”),
and the instrument throughput (coverage for multiple whole human
genomes can be produced in a few days per instrument). Due to these
types of improvements, algorithms that examine the aligned reads to
identify different types of alterations have also been developed and
applied to tease out focused insertions or deletions of one to several
nucleotides (“indels”), to identify either increased coverage indica-
tive of an amplified chromosomal region or decreased coverage at
deleted regions, as well as structural variations (inversions, trans-
locations) based on paired end reads that do not map as anticipated
onto the genome.
Exome Hybrid Capture
In 2009, several groups developed methods based on nucleic acid
hybridization that acted to “subset” the genome by capturing only
the coding portions (the “exome”) of known genes (Bainbridge
et al., 2010; Gnirke et al., 2009; Hodges et al., 2009). Exome hybrid
capture is accomplished by synthetic DNA or RNA probes that
are designed to hybridize library fragments from a whole genome
library based on nucleic acid sequence similarity. The synthetic
probes have biotin molecules covalently linked to them during syn-
thesis, permitting a post-​hybridization pull-​down of probe:library
hybrids by mixing in streptavidin-​coated magnetic beads to bind
the biotin and subsequently applying a magnetic field. Captured
library fragments are reclaimed by denaturing them away from the
probes, after which they are quantitated and sequenced to provide
the exome data. In practice, hybrid capture is performed for each
tumor and matched normal exome, whereby increasing throughput
on sequencing instruments has enabled pools of hybrid capture frag-
ments from many such exomes to be mixed prior to hybrid capture
and sequencing. The use of a DNA barcode on each library adapter
set permits downstream computational binning of sequences derived
from individual patient samples for separate alignment and analysis
of somatic alterations. In essence, the exome capture technique pro-
vides a focused and readily interpretable data set that is smaller and
less expensive to produce than a whole genome data set and is easier
to analyze and interpret. The disadvantage of exome sequencing is
that structural variants are extremely difficult to identify, copy num-
ber analyses are possible but at very low resolution, and regulatory
variants are missed since they commonly lie in non-​coding regions
of the genome. Further subsetting of the exome is possible only if a
discrete set of genes is of interest, rather than all known genes. For
example, hybrid capture reagents that target genes linked to can-
cer susceptibility are commercially available for research and also
are offered as commercial CLIA (Clinical Laboratory Improvement
Amendments) assays.
RNAseq
RNA can be sequenced using massively parallel approaches as well,
following an initial conversion to DNA by reverse transcriptase
(Mortazavi et al., 2008). This can be accomplished from total RNA,
which subsequently is treated prior to sequencing to subtract ribo-
somal RNA (rRNA) sequences due to their incredible abundance in the
human transcriptome. rRNA subtraction takes a number of forms and
can include the use of an exome hybrid capture step, described earlier,
or a number of other selection approaches. When RNA is abundant, an
initial step to isolate polyadenylated mRNAs from total RNA can be
accomplished with poly-​T labeled magnetic beads that hybridize the
polyadenylated mRNAs and isolate them from solution by applying a
magnetic field. After washing away the non-​polyadenylated RNAs, a
sequencing library is generated from reverse transcriptase-​converted
sequences prior to sequencing. Since gene-​coding RNAs are not the
only RNAs of potential value to study in comparing cancer to nor-
mal tissues, as outlined later in this chapter, a variety of approaches to
generate libraries from non-​coding RNAs has evolved in the context
of MPS to permit the characterization of different classes of ncRNAs,
such as microRNAs and lncRNAs. In all RNA studies of tumor tissue,
the challenge of data interpretation lies in placing results into context,
which typically requires an appropriate and parallel study from a com-
parative (i.e., adjacent, non-​malignant) normal tissue.
LARGE-​SCALE CANCER GENOME DISCOVERY
Data Deluge
The result of these rapidly developing methods and the decreasing
cost of MPS has been an explosion in our characterization of can-
cer genomes, exomes, and transcriptomes, revealing catalogs of new
mutations and other somatic alterations in genes and alterations in
transcription that can lead to cancer onset or progression. In particular,
two large-​scale cancer genomics studies that are investigating adult
cancers are The Cancer Genome Atlas (TCGA; www.cancergenome.
nih.gov) and the International Cancer Genome Consortium (ICGC;
www.icgc.org). TCGA is a largely US-​based project that was funded
by the National Cancer Institute (NCI) and the National Human
Genome Research Institute (NHGRI). This project has studied over
10,000 cancer samples, but due to cost limitations, most were stud-
ied only by exome sequencing, with only around 10% of each cancer
type sequenced by whole genome methods. By contrast, ICGC is an
international project that requires individual groups to ascertain fund-
ing to pursue genomic discovery in specific cancer types. Their aim
is to have 50 cancer types studied from over 25,000 patients. Most
ICGC projects use whole genome sequencing (WGS) to characterize
the genome. The two projects also are cooperating in a pan-​cancer
analysis, currently underway, that includes data from over 2000 can-
cers across many tissue sites that were profiled by WGS, RNAseq,
and other types of next-​generation sequencing (NGS)–​based analyses
as well as proteomics (www.dcc.icgc.org). Cumulatively, these large
projects have effectively defined the catalog of cancer-​specific changes
that occur across most common and some rare tissue sites, and have
led to remarkable discoveries of the genetic contributors to can-
cer’s development. Another large-​scale project, the Pediatric Cancer
Genome Project (PCGP; https://​www.stjude.org/​research/​pediatric-​
cancer-​genome-​project.html) was a privately funded collaborative
project carried out by St. Jude Children’s Research Hospital and the
Genome Institute at Washington University. This 5-​year project, now
completed, focused on genomic discovery in pediatric cancer types
and resulted in sequencing of nearly 1000 cancer and paired normal
samples by WGS in comparison to a matched normal. The final 2 years
of this project included RNAseq of the tumor, and whole genome
bisulfite sequencing data to elucidate somatic methylation changes.
While the matched normal genome is most commonly used as a
comparator to help define what is truly somatic, a separate analysis
of only the normal genome has also provided insights regarding the
genetic susceptibility to cancer (Lu et al., 2015; Zhang et al., 2015).
 45
Genomic Landscape of Cancer 45
In addition to susceptibility, a data mining study of TCGA solid tis-
sue germline exomes, derived from peripheral blood lymphocytes,
led to an interesting series of observations regarding the increased
presence of rare truncation variants and known hotspot variants in
cancer genes in these blood normal (Xie M et al., 2014). The study
demonstrated a positive correlation between blood-​specific mutations
in leukemia/​lymphoma genes and age of the individuals, and deter-
mined that these mutations were detectable largely due to the growth
advantage they conferred on the hematopoetic stem cell that carried
them and its subsequent clonal expansion. These results were verified
in a non-​cancer data set from the National Heart, Lung, and Blood
Institute (NHLBI) exomes study’s WHISP (Women’s Health Initiative
Sequencing Project) cohort. McCarroll’s group reported a similar
finding in 10% of persons older than 65 when analyzing exome data
for 12,380 Swedish persons that were blood derived (Genovese et al.,
2014). Here, health outcomes analysis from 2 to 7 years following
blood sampling showed that clonal hematopoiesis was a strong risk
factor for subsequent hematologic cancer.
Remaining Challenges
One clear challenge that accompanies the data deluge that is result-
ing from large-​scale cancer genomics data is a means to predict the
functional consequences of the many discovered somatic variants on
the final protein produced in the cancer cell. This conundrum has led
to improved computational algorithms that consider a variety of lines
of evidence to predict functional consequences (Gonzalez-​Perez et al.,
2013; Schroeder et al., 2014; Tamborero et al., 2013). Such methods
typically are implemented as a first classifier of functional predic-
tion for novel mutations without supporting evidence of the resulting
mutant protein function, mainly because defining this impact by bio-
logical measures is a daunting task, given the magnitude of the somatic
alteration data that now exists and continues to grow. However, biolog-
ical data that demonstrate the impact of altered amino acid sequence
on protein function remain the gold standard.
Functional Studies
While newer tools for genome editing, such as TALENs and Crispr/​
Cas9, are enabling scalable functional studies of specific mutations,
supporting data sets have been generated to provide resources for func-
tional predictions. Two early efforts that provided a resource for cor-
relating cancer cell genome mutations and function were published
in 2012. One study was the Cancer Cell Line Encyclopedia (CCLE),
published by Garraway and colleagues (Barretina et al., 2012). This
study compiled gene expression, chromosomal copy number, and
exome sequencing data from 947 cancer cell lines and released the
data to public availability. Furthering the correlation of mutational pro-
files and drug responsiveness, these authors also studied 24 anticancer
drugs across 479 of the cell lines to catalog drug sensitivity in the
context of genotype and gene expression-​based prediction. Coincident
publication of a similar study of 639 human tumor cell lines by Benes
and colleagues (Garnett et al., 2012) determined the genotypes of 64
commonly mutated cancer genes obtained by NGS, with copy num-
ber analysis from single nucleotide polymorphism (SNP) microarrays
and expression profiling by microarrays. In this study, 130 drugs were
screened to determine drug sensitivity and dose–​response curves. One
challenge in sequencing cancer cell lines is that the comparator nor-
mal cell line or DNA source is largely not available, so the resulting
genotypes are no doubt predominantly, but not exclusively, somatic.
Regulatory Region Functions
Beyond functional aspects of mutations relating to the resulting pro-
teins, there are higher-​level impacts of somatic mutations that lie out-
side of known gene coding sequences in the genome. Namely, some
mutations may alter RNA expression and hence interfere with normal
cellular control of growth and division by disrupting gene regulatory
regions, such as promoters or enhancers. Such regions have typically
not been identified by large-​scale cancer genomics studies, due to the
preponderance of exome versus WGS data, the difficulty of delineat-
ing the putative functions of these loci, and their imprecisely defined
boundaries and functional regulatory components. One large study
that attempted to better define the regulatory genome of human is
ENCODE (Encyclopedia of DNA Elements), which utilized human
cell lines including cancer cell lines (e.g., HeLa, K562) and a variety
of assays like chromatin immunoprecipitation (ChIP) and RNAseq,
to characterize the functional portions of the non-​ coding genome
(Consortium, 2012). These assignments are based on the evaluation of
protein: DNA binding for specific transcription factors, on chromatin
packaging by different histones with differential methylation status,
and by correlative analyses that link different DNA configurations to
the resulting RNA expression data for the genes at these loci. Further
refinements of the ENCODE data have ensued, including a cancer-​spe-
cific functional analysis approach devised by Gerstein and colleagues
(Khurana et al., 2013). Here, the initial approach combined ENCODE
regions with data from the 1000 Genomes Project individuals to define
regulatory regions that are particularly sensitive to mutation or that
clearly disrupt transcription factor binding. The resulting patterns
identified were then used to develop a computational tool (FunSeq)
to examine data from ~90 cancer whole genome sequences, revealing
around 100 candidate non-​coding drivers. While the amount of data in
whole genome data sets can provide large numbers of possible non-​
coding drivers using these approaches, in a refined version of FunSeq,
called FunSeq2 (Fu et al., 2014), Gerstein and colleagues devised a
prioritization scheme that reduces the number of highly likely func-
tional drivers one might need to pursue with biological studies to
support their ability to impact tumor biology. Certainly the increas-
ing numbers of whole genomes being sequenced in cancer discovery
efforts will improve the identification of significantly mutated regula-
tory drivers in the future (Piraino and Furney, 2016). Perhaps the most
common regulatory alteration known to occur across multiple tissue
sites is in the promoter region of the TERT gene. This gene encodes a
ribonucleoprotein polymerase that maintains telomere ends by addi-
tion of the telomere repeat TTAGGG. The promoter mutations create
a new binding motif for Ets transcription factors and ternary complex
factors (TCFs) near the transcription start site of the gene, resulting
in increased gene expression levels. Two groups initially reported
the TERT promoter mutations: one studying a family with inherited
melanoma predisposition by linkage analysis approaches coupled with
NGS (Horn et al., 2013), and a second studying melanoma somatic
alterations by NGS-​based WGS approaches (Huang et al., 2013). This
provides an interesting and likely not unique example of how con-
stitutional and somatic alterations can lead to the same disease and
highlights yet another discovery from large-​scale comparative cancer
genomics: namely, the large degree of overlap between germline sus-
ceptibility genes and their mutations with the common somatically
mutated genes in human cancer genomes.
To this end, Snyder and colleagues have evaluated WGS data
from 436 patients in TCGA to identify point mutations in regulatory
regions with evidence for positive selection in transcription factor
binding sites. Their efforts have identified recurrently mutated sites
across these individuals that include the known non-​coding regulatory
mutations at the TERT promoter, as well as several new sites (Melton
et al., 2015).
RNA Expression Resource
One final resource worth mentioning in the context of correlative
genomic and RNAseq data is the Genotype-​Tissue Expression (GTEx)
resource (https://​commonfund.nih.gov/​GTEx/​index) that aims to
provide a combination of genomic data and RNAseq-​based expres-
sion data and analyses from healthy human tissues. This consortium
recently published their pilot analysis of gene regulation in humans
(Consortium, 2015), presenting their analysis of RNA sequencing data
in the context of tissue site and genotype from 1641 samples across 42
tissues from 175 individuals. While the clear aim of this resource is to
46
46 Part I:  Basic Concepts
help put genomic variation into context relative to its impact on gene
expression, GTEx data already have proved valuable as a resource by
which to gauge the cancer-​specific RNAseq expression data that often
are lacking comparative RNAseq data from an adjacent non-​malignant
tissue.
DEEPER INSIGHTS FROM CANCER GENOMICS
Genomic Heterogeneity
Beyond enhancing our understanding of the genomic underpinnings
of cancer, the use of NGS in these studies has shed light on aspects
of cancer that were long suspected, based on other data, including
microscopy-​based staining (e.g., immunohistochemistry). One such
area is genomic heterogeneity in cancer samples. While it is intuitive
that as cancer cells rapidly grow and divide during disease progres-
sion, daughter cells will acquire, in addition to the initial set of found-
ing mutations that led to the cancer phenotype, new mutations that
may confer additional growth advantage, may be neutral, or may aid
in treatment resistance once therapy begins. The unique characteristic
of NGS data that has led to improved abilities to identify such genomic
heterogeneity is the digital nature of the data. In particular, when DNA
is isolated from a tumor mass, the isolate contains genomic representa-
tion from each cell’s genome in that mass. Since each DNA fragment
in this isolate contributes to the sequencing library, and each result-
ing sequencing read originates from one unique genomic fragment,
the data are in essence quantitative, or digital in nature. One way to
illustrate this is by evaluating copy number altered regions, where the
magnitude of the amplification is exactly proportional to the (-​fold)
increase in data coverage of the amplified chromosomal region once
the data are aligned to the reference genome (Figure 4–1). In the con-
text of genomic heterogeneity, we can simply examine the level of data
coverage for each identified somatic variant and calculate the number
of sequencing data reads that represent the variant and those that rep-
resent the wildtype (or unmutated) allele. The percentage of variant-​
containing reads for each variant is referred to as the variant allele
fraction (VAF), whereby the founder variants carried in every cancer
cell have a VAF of around 50% (since most variants are heterozygous).
Using a variety of approaches to group or cluster all identified variants
with shared VAFs, the heterogeneity of the cancer cell population con-
tributing to the genomic DNA isolate can be characterized. Estimates
of genomic heterogeneity are improved by increased coverage depth,
which enables more sensitive detection of low proportion cell popu-
lations or “subclones” and by increasing numbers of variants, where
WGS with high coverage at variant sites yields higher confidence clus-
tering of VAFs due to the larger number of somatically mutated sites.
Temporal or spatial changes in heterogeneity also can be evaluated
if the appropriate samples exist. For example, the differences between
Figure 4–1.  An indicated HER2 locus amplification from whole genome sequencing (WGS) of a human breast cancer genome. The panel provides data on
the focal amplifications along chromosome 17. This patient had a known HER2 amplification by conventional clincopathologic assay (HER2 fluorescent
in situ hybridization).
primary and recurrent disease can be striking, especially taken in the
context of a specific treatment. One example is shown in Figure 4–2,
comparing an AML patient genome at diagnosis and after treatment
by induction chemotherapy, consolidation therapy, and a greater than
1-​year disease-​free remission. As evidenced by Figure 4.2, the recur-
rent disease is significantly less heterogeneous than the primary, where
one minor subclone has survived the chemotherapy regimen and has
emerged with additional genomic alterations as the predominant clone
in the recurrent disease presentation (Ding et al., 2012).
In addition to advanced computational methods and visualization
tools (Grundberg et al., 2013; Hajirasouliha et al., 2014; Miller et al.,
2014; Nik-​Zainal et al., 2012; Roth et al., 2014) to calculate and dis-
play genomic heterogeneity, the pursuit of heterogeneity in cancer has
resulted in a multitude of interesting findings. Studies of intratumoral
heterogeneity have evaluated the comparative clonal architecture of
tumors from the same tissue site, sampled at different locations in
the tumor, and also have evaluated the somatic mutations for their
likelihood of response to a targeted therapy (a.k.a. “druggability”)
(Gerlinger et al., 2012; Gerlinger et al., 2014; Haffner et al., 2013;
McGranahan et al., 2015; Zhang et al., 2014). The latter provides
insights into whether single core or needle biopsy assays for targeted
therapy susceptibility are likely to provide sufficient information upon
which to base treatment decisions, and establishes the proportion of
variants identified or missed based on single versus multiple samples/​
assays of different tissue biopsies. While such studies have only been
conducted in a limited number of tissue sites, in general most studies
have advocated for more than one biopsy being assayed per tumor in
the clinical setting (i.e., druggability).
Intertumoral heterogeneity data have emerged as a natural conse-
quence of thousands of tumors being studied by NGS-​based genomics
and have illustrated the myriad combinations of driver mutations,
tumor suppressor alterations, germline susceptibility, and other non-​
DNA-​ based (methylation, chromatin configuration, RNA over-​or
underexpression absent obvious copy number alteration) somatic
changes that lead to cancer. As intertumoral heterogeneity studies have
progressed and have begun to compare primary to recurrent disease
changes in heterogeneity (de Bruin et al., 2014; Johnson et al., 2014;
Xie T et al., 2014) across multiple patients’ samples, we have come to
understand that primary tissue sites can display a panoply of combina-
tions of different subclones in the temporal samples taken at metasta-
sis, most of which are discernable in the primary tissue. This temporal
comparison of heterogeneity becomes increasingly interesting in the
context of targeted therapy and acquired resistance (Awad et al., 2013;
Juric et al., 2015; Katayama et al., 2012; Pao et al., 2005; Poulikakos
et al., 2011; Sequist et al., 2011; Wagle et al., 2011). One critical clin-
ical question that remains to be answered is whether primary tumors
that are more heterogeneous predict a worse outcome for the patient
in the setting of a consistent therapeutic approach to the disease (e.g.,
standard of care). Large-​scale analyses across cancer types indicate
 47

Genomic Landscape of Cancer 47

Figure 4–2.  Changes in tumor heterogeneity over time. This figure illustrates the changes in AML tumor cell genomes in the primary compared to the
relapse population. Effectively, the initial or founder mutations develop in a hematopoetic stem cell (HSC) to provide a growth advantage. As this popula-
tion of cells rapidly grows and divides, additional mutations are added to a subpopulation of cells, creating a subclone. Each subclone of cells carries a
genotype that includes the founder clone mutations and mutations unique to that subclone. After chemotherapy treatment, the patient suffers a relapse that
represents a minor subclone from the primary disease presentation that has acquired additional mutations and a chromosomal translocation, expanding to
represent the single homogeneous cell population in the relapse disease.

that heterogeneity can impact outcomes (Andor et  al., 2016; Morris
et  al., 2016). Understanding the role of heterogeneity in the context
of outcome for similarly treated cancers may be impactful within the
clinical setting of disease treatment, especially in the context of tar-
geted therapy and acquired resistance.
Single Cell Studies
One technology-​based pursuit of genomic heterogeneity that has been
enabled by NGS and specific devices is the isolation and characteri-
zation of the genomes of single cells. This interesting question about
how genomic heterogeneity can be characterized at the single cell level
is a technical challenge, since the amount of DNA from each cell is
below the limit of the amount required to make an NGS library or
even for site-​specific PCR and sequencing of known hotspot muta-
tions, for example. As a result, these studies require an initial step of
whole genome amplification (WGA) to increase the amount of geno-
mic DNA prior to library construction. However, the WGA procedure
is enzymatic and thus introduces biases during amplification that result
in semi-​random areas that are not amplified completely (“amplifica-
tion dropout”) (Navin, 2014). Initially, yields from WGA were insuf-
ficient for high coverage sequencing suitable for mutation detection,
so only copy number-​based comparisons were possible (Navin et al.,
2011). As library methods have improved to enable low DNA input,
sufficient depth of coverage for mutation calls has resulted (Hughes
et al., 2014; Wang et al., 2014). However, although tens to hundreds of
cells from each tumor typically are studied, it is often unclear whether
mutations that are not seen in every cell are representing heterogene-
ity or are false negative results due to amplification dropout. While
increasing numbers will add statistical confidence to estimates of het-
erogeneity, the cost of single cell sequencing across hundreds of cells
calls into question the value of this approach when compared to high-​
depth NGS coverage of mutated sites in DNA isolated from a tumor
mass, as discussed earlier (Hughes et al., 2014).
Pan-​Cancer Genomics
Large-​ scale cancer genomics discovery also has fundamentally
changed our notions about the uniqueness of cancer in terms of its
tissue site specificity. While tissue biology remains an important con-
sideration to treatment paradigms (Prahallad et  al., 2012), we also
know that many cancer genes are frequently mutated in different tissue
sites, and in some cases, cancers driven by the same mutations will
respond to treatment with an appropriate targeted therapy. In princi-
ple, the shared nature of druggable targets across tissue sites conflicts
with the typical clinical trial and drug approval paradigm by which
therapies are tested one tissue site at a time. As evidence mounts for
the shared nature of alterations in specific cancer genes across tissue
sites (Cancer Genome Atlas Research et  al., 2013; Hoadley et  al.,
2014; Leiserson et al., 2015), the practice of treating cancer based on
data from a genotyping assay to help determine the treatment for each
patient is becoming increasingly common. For example, 3%–​4% of
human breast cancers are driven by point mutations in HER2 rather
than by its amplification (Bose et al., 2013), and 1%–​2% of prostate
cancers are driven by the BRAF mutations so common in human mela-
nomas (Palanisamy et  al., 2010). By profiling somatic alterations in
tumor tissues, we also have discovered that several known cancer sus-
ceptibility genes (BRCA1/​2, TP53, NF1) are also germline mutated
in multiple tissue sites (Lu et al., 2015; Schrader et al., 2016; Zhang
et al., 2015). This fact emphasizes the need for comparing tumor to
normal DNA in cancer genotyping assays because the nature of the
mutation is critically important for determining both treatment and the
need for genetic counseling (Jones et al., 2015).
While the individual combinations of altered genes in any one human
cancer are highly unique, by layering the information about genes that
are activated or inactivated by their alterations onto known biological
pathways, we can identify that there is a common set of biological
pathways that are frequently altered in cancer. Initially described in
2001 (Hanahan and Weinberg, 2000), our growing knowledge about
cancer genomics that emerged from large-​scale studies resulted in the
addition of several new pathways in a revised “hallmarks” manuscript
in 2011 (Hanahan and Weinberg, 2011).
DNA Damage
Another discovery from large-​scale genomic studies is the identifi-
cation of DNA damage signatures that can be attributed to specific
mutagens or mutational influences. In particular, the DNA from
smoking-​associated lung cancers has not only a characteristic signa-
ture from benz-​pyrene adduct formation with the DNA, but also an
extraordinarily elevated mutation number across the genome due to
the long-​term exposure typical of these patients (Pleasance et  al.,
2010). Never-​ smokers, by contrast, have relatively few mutations
in their tumor genomes (Govindan et al., 2012). Similarly, UV light
leaves a characteristic pattern of damage due to thymine dimerization
and repair, and hence UV-​induced melanomas and basal cell carcino-
mas have the highest mutation numbers of all cancers due to lifelong
sunlight exposure (Alexandrov et al., 2013). By contrast, melanomas
in protected areas do arise (e.g., bottoms of feet) yet have a paucity of
mutations and no characteristic signature of UV damage. In studies
48
48 Part I:  Basic Concepts
comparing treatment-​naive primary to post-​treatment recurrent tumors
where a DNA-​damaging chemotherapy was utilized following the
primary diagnosis, several studies have demonstrated a characteristic
increase in a specific DNA damage motif or signature (Ding et  al.,
2012; Johnson et al., 2014) in the post-​therapy tumor genome, as well
as an elevated mutation number.
Targeting the Cancer Genome
Coincident with our increasing knowledge of genomic alterations that
result in cancer development or progression is the increasing shift
away from broad-​spectrum cytotoxic chemotherapy toward target-
ing specific genes known to frequently develop mutations that acti-
vate the corresponding protein, disrupt normal cellular processes and
controls, and drive cancer development. In this approach, designing
small molecule inhibitors to specifically bind to and inhibit the acti-
vated variant protein (or protein family members) can bring dramatic
results to metastatic cancer patients with a significant disease bur-
den. Initially, the targets of many small molecule inhibitors were not
known, but in 2004, three studies were published that illustrated how
genomic approaches could help to identify markers of response. Here,
the research groups utilized the newly completed human genome
sequence, which had provided precise locations and annotations to
many of the cancer-​related tyrosine kinase oncogenes. Their work
studied specific tyrosine kinase genes in small numbers of patients
who had enrolled in clinical trials and either did or did not respond to
small molecule tyrosine kinase inhibitor drugs. These studies identi-
fied that most lung non-​small-​cell adenocarcinoma (NSCLC) patients
with a response to a tyrosine kinase inhibitor carried specific somatic
mutations in the tyrosine kinase domain of the gene encoding epider-
mal growth factor receptor (EGFR) (Lynch et  al., 2004; Paez et  al.,
2004; Pao et  al., 2004). While these were painstaking studies done
by PCR amplification and sequencing of suspect target genes, the
widespread use of massively parallel sequencing has vastly increased
our understanding of target genes, mutations, and their relationship to
therapeutic response (Dienstmann et  al., 2015; Meador et  al., 2014;
Wagner et al., 2016), and even has identified frequent genetic changes
that result in acquired resistance to small molecule inhibitor therapies.
In particular, these approaches have accelerated the identification of
patients most likely to respond to a targeted therapy such that first-​line
treatment with a tyrosine kinase inhibitor in newly diagnosed NSCLC
patients carrying the corresponding EGFR mutations is now FDA
approved in the United States. In fact, the large number of somatic
alterations now recognized for driving NSCLC development and their
corresponding therapies have made the case for testing multiple genes
and fusion gene/​protein drivers in patients diagnosed with the disease
(Figure 4–3) using NGS and computational analysis to detect drug-
gable gene targets.
Diagnostic Multi-​Gene Assays
Such multi-​gene assays or panels take on a wide ranging number of
genes and different types of somatic alterations that can be remarka-
ble in their scope and breadth, from testing tens of genes to all known
human genes (the exome) and assaying for all mutation types from
point mutations to structural rearrangements that produce targetable
fusion gene drivers (Hyman et al., 2015; Siu et al., 2015; Van Allen
et al., 2014). Clinically, these assays are more conservative of precious
tumor tissue biopsies than performing multiple single-​gene tests, and
the results are more quickly and cheaply obtained. Furthermore, given
the relatively large number of frequently mutated genes now identi-
fied as being shared across multiple tissue sites, NGS-​based multiplex
gene assays are achieving analytical and clinical validity as diag-
nostics. Downsides include the fact that these assays also will reveal
so-​called VUS (variants of unknown significance) in genes that are
cancer-​related yet for which the impact of the variant, especially on
drug response, is unknown for that tissue site (or for any site) (Andre
et al., 2014; Van Allen et al., 2014). Reimbursement of the costs asso-
ciated with these assays also has been slower to emerge, and more
Double mutations 3%
EML4-ALK BRAF 2%
8%
Unknown
KRAS 25%
EGFR 17%
Unknown/no mutation detected EGFR KRAS EML4-ALK
Double mutations BRAF MET ROS1 MET
NRAS AKT1 PIK3CA HER2 MEK1
Figure  4–3. Genomic drivers of cancer development in non-​small-​cell
adenocarcinoma of the lung. The pie graph illustrates that a large propor-
tion of the genomic drivers of NSCLC have been identified by large-​scale
cancer genomics discovery efforts. Many of the driver alterations can be
targeted by specific therapies.
practical challenges do still remain with respect to this molecular pro-
filing paradigm. In particular, not all metastatic sites are readily biop-
sied, and insurance may not cover the cost of re-​biopsy if there is no
demonstrated clinical benefit. Also, while the number of targeted ther-
apies is growing, the number of gene targets remains relatively small.
Furthermore, depending upon the number of genes or sites tested, only
around 25%–​40% of patients have a clearly indicated therapeutic tar-
get in their tumor genome that might qualify them to be treated with
that drug or class of drugs. If a trial is available and accruing patients,
they may not be eligible due to other factors, such as their performance
status, the number of prior therapies, or other qualification metrics. If
they are eligible, patients sometimes do not have the financial means
to pay for their own costs of travel and hotel stays required to partici-
pate in the trial.
CANCER EPIGENOMICS
Another significant area of large-​scale research has been to under-
stand functionally relevant changes to the genome that do not involve
a change in the nucleotide sequence but can ultimately alter gene
expression, such as DNA methylation or histone modifications, yet
are essential for fully understanding many biological processes and
disease states. This can be exemplified by international collaborations
such as The ENCODE (http://​www.genome.gov/​encode/​) Consortium
and the National Institutes of Health (NIH) Roadmap Epigenetics
Project (http://​www.roadmapepigenomics.org). These pioneering
efforts highlight how epigenetic information complements genotype
and expression analysis and its potential importance in cancer. They
further emphasize the need for discovery genomics centered on epi-
genetics (gene regulation) that has resulted in a variety of novel tech-
niques coupled with specific analytical methods according to different
epigenetic marks that can be evaluated. Here we highlight several
recent technological advances that have facilitated high-​throughput
assessment of functional regulatory elements that may act across a
range from proximal (i.e., within the promoter region) to distant, and
provide examples of their application to cancer epigenomic discovery.
DNA-​Protein Binding
Currently, there are numerous strategies to interrogate chromatin
biology. One of the initial applications for determining how proteins
 49
Genomic Landscape of Cancer 49
interact with DNA to regulate gene expression is chromatin immuno-
precipitation (ChIP) coupled with massively parallel DNA sequenc-
ing, referred to as ChIP-​Seq. To date, it has been widely used to
map precisely the genome-​wide binding sites for proteins (transcrip-
tion factors, modified histones, RNA polymerase, etc.). As one of
the earlier applications developed for epigenetic discovery, there
already exist ChIP-​seq guidelines and best practices released by
ENCODE (Landt et al., 2012) to maximize performance. Likewise,
there are numerous open-​source tools for ChIP-​seq data analysis
(Fejes et al., 2008; Qin et al., 2010; Zhang et al., 2008). However,
for the remainder of applications discussed, often the availability of
experimental and analytical resources is much more limited. A sig-
nificant advancement in the application of ChIP-​Seq has been the
transition from initial cancer studies focusing on cell lines to study-
ing the epigenomes of human tissues. This transition enables gen-
erating epigenetic maps across patient cohorts to understand how
epigenetic changes correlate with clinical and epidemiological data.
Such an approach is exemplified by a breast cancer study focused on
understanding the differences in estrogen receptor (ER) binding in
primary breast cancers during the progression to distant metastases.
Notably, the resulting data demonstrated that patients resistant to ER
agonist therapies still have active recruitment of ER to chromatin.
Additionally, patients more likely to progress to metastatic disease
acquired ER binding to unique genomic regions not bound by ER in
patients reported to have good clinical outcomes (Ross-​Innes et al.,
2012). Overall, this study demonstrates the biological and clinical
importance of studying the epigenome in broader patient populations
with corresponding clinical data.
Proximal Chromatin Conformation Epigenomics
As chromatin is tightly packaged into an array of nucleosomes, the nucle-
osome positioning plays a significant regulatory function by facilitating
the “openness” or accessibility of binding sites to transcription factors
(TFs) and to the general transcription machinery. Therefore, chromatin
accessibility assays have been developed to correlate regulatory DNA
sequences that coincide with open or accessible genomic DNA. In con-
trast to ChIP-​seq, chromatin accessibility assays do not require anti-
bodies specific for the DNA binding protein of interest, and the results
can directly report the effect of chromatin structure alterations on gene
transcription. Currently, there are three common methods to assay open
chromatin. The first approach, DNase-​seq, allows for the global discov-
ery of nucleosome-​free genomic regions that are hypersensitive to nucle-
ase treatment with the non-​specific double strand endonuclease DNase I,
also known as DNase I hypersensitive sites (DHSs) (Boyle et al., 2011;
Hesselberth et  al., 2009). The second method, formaldehyde-​assisted
isolation of regulatory elements, or FAIRE-​Seq (Bianco et  al., 2015),
uses phenol-​chloroform to separate nucleosome-​bound from free geno-
mic DNA. The last method, assay for transposase-​accessible chromatin
with high-​throughput sequencing (ATAC-​seq), measures open chroma-
tin through the ability of hyperactive Tn5 transposase to integrate into
active or open chromatin regions (Buenrostro et al., 2015). As the most
recently introduced approach, ATAC-​seq has been used the least to date.
However, it is an appealing strategy due to the simplicity of the method,
its sensitivity, and the fact that the method does not require a large quan-
tity of genomic DNA, which is often a limiting factor when studying
clinical samples. While the application of these assays has primarily
focused on single gene studies in cell lines, already the results of these
studies have led to the discovery of critical epigenetic changes respon-
sible for differential gene expression in cancers. For instance, by inte-
grating DNase I hypersensitivity and expression data, we have gained a
deeper understanding of the interplay between chromatin accessibility
and androgen receptor (AR) function, which is particularly important in
prostate cancer. As expected, AR binding is associated with chromatin
accessibility, and ultimately this affects gene expression following hor-
mone induction. However, in contrast to other previously studied DNA-​
binding proteins, AR binding appears to have multiple modes. In fact,
half of the AR binding sites identified by this study were not accessible
to DNase I  cleavage prior to hormone induction, suggesting that AR
binding following hormone therapy increases chromatin accessibility
(Tewari et al., 2012).
Distant Chromatin Conformation Epigenomics
To this point we have focused on applications commonly used for
understanding regulatory processes occurring in close proximity to a
gene. However, recent advances have made it possible to understand the
contribution of the three-​dimensional organization of chromatin to reg-
ulating gene expression. The first such high-​throughput method, called
chromatin conformation capturing (3C), is used to study the nuclear
organization in the native cellular state ((Miele et al., 2006); Splinter et
al., 2004). In brief, 3C involves (1) cross-​linking proteins and DNA that
are in close proximity in the nuclear space, (2) a restriction digest to
separate cross-​linked from non-​cross-​linked DNA fragments, (3) DNA
ligation under conditions favorable to ligate junctions between cross-​
linked DNA fragments, (4) reversal of cross-​links, and (5) quantifica-
tion (PCR, microarray, high-​throughput sequencing). This method also
spurred the development of circularized chromosome conformation
capture (4C) (Zhao et al., 2006) and carbon-​copy chromosome confor-
mation capture (5C) (Dostie and Dekker, 2007). One advantage of 4C
is that it enables a genome-​wide screen for interactions with a specific
locus of interest; 5C builds upon this approach by enabling parallel
analysis of interactions with a selected set of loci. The application of
these technologies can be witnessed by our improved understanding
of hormone regulation in prostate and breast cancer. In the context of
breast cancer, it was observed that estrogen is able to induce chromatin
“looping” by bringing two genes not normally located near one another
in the genome into close spatial proximity (Hu et al., 2008). Such find-
ings have been replicated in prostate cancer studies that couple 3C with
ChIP (ChIP-​3C), to explore AR-​induced chromatin “looping.” Multiple
studies have reported distal AR binding sites capable of regulating
well-​known target genes through chromatin looping, some of which
have been shown to be directly involved in promoting cell growth in
castration-​resistant prostate cancer (Chen et al., 2011; Wang et al.,
2007, 2009). In addition to gene regulation, AR has been implicated
in the formation of gene fusions, which commonly occur in prostate
cancer. Notably, androgen treatment appears to induce the co-​localiza-
tion of TMPRSS2 and ERG, to generate the most common gene fusion
in prostate cancer, and also activates TMPRSS2 transcription (Mani
et al., 2009; Wang et al., 2009). Taken together, a deeper understand-
ing of three-​dimensional chromatin organization has offered profound
insights into gene regulation.
Methylation Epigenomics
DNA methylation is a process by which methyl groups are added to
cytosine nucleotides in DNA and is an important regulator of gene
transcription. Aberrant DNA methylation patterns in cancerous tis-
sue genomes by comparison to normal tissues have been identified as
recurrent in a large number of human malignancies. The two common
states are (1) hypermethylation, or enhanced DNA methylation in the
promoter region, which results in gene silencing; and (2) hypometh-
ylation, or reduced methylation, which results in gene overexpression
and globally has been associated with tumor development and progres-
sion. Unlike many genetic mutations in cancer, aberrant DNA meth-
ylation can be reversed, therefore making it an appealing therapeutic
target. Currently there are a number of approaches for identifying
methylation changes that can be divided into three main categories.
DNA is either pretreated with a restriction enzyme, is enriched for
methylated DNA using an affinity based approach (i.e., anti-​methyl-
cytosine antibodies), or is treated with sodium bisulphite to convert
unmethylated cytosines to thymines. Initial high-​throughput methods
utilized arrays to monitor methylation changes (i.e., MeDIP [Weber
et al., 2005]; MCA [Estecio et al., 2007]; MIRA [Rauch et al., 2006])
before being adapted for NGS (i.e., MeDIP-​Seq [Harris et al., 2010];
and MIRA-​Seq [Choi et al., 2010]). Whole genome shotgun bisulfite
sequencing (WGBS-​seq) is currently the most exhaustive approach for
monitoring the whole methylome landscape, although it is also the
50
50 Part I:  Basic Concepts
most costly. WGBS-​seq has been successfully used to map the com-
plete methylomes of several cancer samples (Berman et al., 2012;
Hansen et al., 2011), demonstrating that hypermethylated domains
occur primarily at CpG islands and are concentrated within regions
of long-​range hypomethylation that span across greater than 100 kb.
These same hypomethylated regions coincide with attachment sites to
the nuclear lamina, leading to the hypothesis that widespread DNA
methylation changes in cancer cells are linked to gene silencing pro-
grams according to three-​dimensional chromatin organization in the
nucleus (Berman et al., 2012).
Long Non-​Coding RNA Regulation
For decades, cancer genetics research has largely focused on the impor-
tance of protein-​coding genes, such as oncogenes and tumor suppres-
sors that can serve as biomarkers and therapeutic targets. The more
recent discovery of microRNAs (miRNAs) and of long non-​coding
RNAs (lncRNAs) have led to multiple discoveries regarding the role of
non-​coding RNAs in gene regulation. LncRNAs are typically greater
than 200 nucleotides in length, transcribed with RNA polymerase II,
and produce transcripts that are 5' capped, polyadenylated, spliced
(like mRNAs), lack coding potential, and only recently have emerged
as critical regulators in tumorigenesis. As part of the ENCODE proj-
ect, the GENCODE consortium has already manually curated 9227
human lncRNAs (Derrien et  al., 2012). However, by leveraging the
unbiased view of RNA transcription products offered by transcriptome
sequencing (RNA-​Seq), many additional lncRNAs have been detected,
resulting in the annotation of greater than 50,000 expressed lncRNA
genes, many of which had eluded discovery by microarray-​based strat-
egies (Cabanski et al., 2015; Iyer et al., 2015; Simonetti et al., 1989).
Overall, the characterization of RNA species, elucidating their func-
tion, and assessing their clinical applicability have become a major
area of biological and clinical importance in cancer research.
While many classes of non-​coding RNAs have been implicated
in cancer, lncRNAs are still largely unexplored and recently have
emerged as a new aspect of biology. Several well-​described examples,
such as HOTAIR (Gupta et al., 2010) and ANRIL (Yap et al., 2010),
indicate that lncRNAs may be essential actors in cancer biology,
typically facilitating epigenetic gene repression through chromatin-​
modifying complexes. Importantly, newer methods have enabled a
deeper understanding of lncRNA-​based regulation, both by determin-
ing the proteins with which different lncRNAs interact and where
lncRNAs bind chromatin to epigenetically regulate gene expression.
There are two major strategic approaches that have developed over
the past few years. The first strategy focuses on identifying spe-
cific proteins that interact with lncRNAs by using antibodies to pull
down a protein complex and its associated lncRNAs. These methods
include RNA-​immunoprecipitation (RIP; Zhao et al., 2010) and UV-​
crosslinked immunoprecipitation (CLIP) coupled with transcriptome
sequencing (Murigneux et al., 2013). While the identification of pro-
tein partners can implicate an lncRNA in a specific functional mecha-
nism or biological process, it requires a priori knowledge of the protein
to be studied and a corresponding high-​specificity antibody. In con-
trast, the second strategy takes an lncRNA-​centric approach by focus-
ing on studying the interactions occurring with a specific lncRNA of
interest. Here, oligonucleotides are designed to tile across the entire
target lncRNA transcript, enabling the selective hybridization of RNA
or DNA to the lncRNA. Subsequently, the lncRNA-​bound interactors
can undergo sequencing to identify either the RNA transcripts that
interact with it or to reveal where the lncRNA was bound to chromatin
throughout the genome.
Two widely adopted methods of this type include chromatin isola-
tion by RNA purification (ChIRP; Chu et al., 2011) and RNA antisense
purification (RAP; Engreitz et al., 2015). While largely similar meth-
odologies, ChIRP uses 20-​mer oligonucleotide probes, whereas RAP
uses much longer probes (120 nucleotides). The RAP strategy was
used to successfully elucidate how HOTAIR interacts with chromatin
to promote breast cancer metastasis (Gupta et al., 2010).
CONCLUSIONS
Taken together, the combination of clever molecular biology
approaches with massively parallel sequencing and genome-​ scale
analyses have provided a rapid and remarkable improvement in our
understanding of the role of the genome in cancer development and
progression. This chapter has attempted to introduce some of these
approaches and the resulting breadth of knowledge gained from them
to date. There is undoubtedly still much to learn. However, we already
are seeing evidence that these methods and the results obtained from
them are beginning to make inroads to large-​scale epidemiological
studies, to our understanding of how environmental factors such as
exposure to known carcinogens and mutagens are represented in the
resulting tumor DNA, and to further defining the correlation between
epigenetic changes and cancer development.
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 53
5 Genetic Epidemiology of Cancer
KATHRYN L. PENNEY, KYRIAKI MICHAILIDOU, DEANNA ALEXIS CARERE,
CHENAN ZHANG, BRANDON PIERCE, SARA LINDSTRÖM, AND PETER KRAFT
OVERVIEW
Cancer is a genetic disease at the cellular level. Tumors occur when
variations in DNA sequence and aberrant gene expression disrupt the
normal cellular processes that control cell division, survival, clonal
growth, and migration. Most of the genomic variants that affect can-
cer growth and progression are somatic mutations in tumor tissue that
are acquired rather than inherited (see Chapter 4). At the same time,
genetic variants inherited in germline DNA can affect susceptibility to
cancer. This chapter reviews the evidence linking inherited genetic var-
iation to cancer incidence and mortality. The literature includes studies
of rare variants in high-​risk families, risk concordance in twins, and
association studies of unrelated individuals in search of common, less
penetrant susceptibility loci. Despite considerable variability across
cancers, most cancers exhibit familial clustering, driven partly by a
small number of known rare variants that powerfully affect risk and a
larger number of common variants that, in combination or at the popu-
lation level, could significantly affect risk. We discuss the implications
of these findings for clinical care, public health, and basic biology. We
close with a discussion of open questions, most notably the puzzle of
“missing heritability”: the fact that—​despite tremendous advances in
our understanding of the genetic epidemiology of cancer over the last
10 years—​multiple lines of evidence suggest that many specific risk
variants, both rare and common, have yet to be discovered.
EVIDENCE SUPPORTING INHERITED SUSCEPTIBILITY
TO CANCER
Scientists have long reported that cancer aggregates in families. Paul
Broca described a large family with a high burden of various cancers in
his 1866 book, Traité des Tumeurs (Figure 5–​1) (Broca, 1866). At least
three types of systematic studies provide evidence for an inherited
genetic contribution to risk of cancer: studies showing that relatives of
cancer cases have a higher risk of cancer than the general population;
studies comparing cancer incidence patterns across different types of
relative pairs (e.g., comparing concordance rates in monozygotic ver-
sus dizygotic twins); and studies that test whether the inheritance of
cancer in extended pedigrees is consistent with a simple Mendelian
model for genetic inheritance, such as autosomal dominant or reces-
sive. These studies also shed light on the genetic architecture of differ-
ent cancers, that is, the number of distinct genetic loci that influence
cancer risk, their allele frequencies, and the distribution of the magni-
tude of their effects.
Close relatives of cancer cases are themselves at increased risk of
cancer. For example, a woman with a first-​degree female relative with
breast cancer has a 2-​fold higher risk of developing breast cancer com-
pared to a woman without a family history (Collaborative Group on
Hormonal Factors in Breast, 2001; Kharazmi et  al., 2014; Pharoah
et al., 1997). Men whose father had prostate cancer are more than twice
as likely to develop prostate cancer (Kicinski et al., 2011). Individuals
with a first-​degree relative with colon cancer have a approximately
one-​third increased risk of developing the disease (Slattery et  al.,
2003). Table 5–​1 shows the sibling recurrence risk ratio λs for a range
of cancers. (λs is the ratio of the incidence in siblings of a cancer case
to the incidence in the general population.) For most cancers, λs falls
between 1.5 and 2.5, although there are exceptions: testicular cancer,
for example, has λs = 8.6. For comparison, the λs for early-​onset dis-
eases or diseases that affect fitness can be much larger than for most
cancers: the λs for type 1 Diabetes is 13.7 and for schizophrenia is
9.0 (Wray et  al., 2010). The lower λs for many cancers may reflect
that they are late-​onset diseases that typically affect men and women
after reproductive age, so that most (but not all) alleles associated with
cancer risk may not be under strong negative selection, and hence do
not exhibit the strong biological effects typical of negatively selected
alleles.
There is also evidence that having a relative with cancer of one type
increases risk of other types of cancers. For example, first-​degree rela-
tives of cases with prostate cancer are at 1.1-​fold increased risk of colon
cancer and 1.3-​fold increased risk of thyroid cancer (Amundadottir
et al., 2004). Fraternal (dizygotic) twins of individuals with any type
of cancer are at 1.1-​fold increased risk of any cancer, while identical
(monozygotic) twins of individuals with any type of cancer are at 1.4-​
fold increased risk.
Some of the increased risk of cancer among family members may be
due to shared environmental risk factors. However, in order to explain
most of the familial aggregation, the magnitude of environmental
effects and strength of the correlation of exposures among family
members would have to be much larger than is empirically observed
(Khoury et al., 1988). This suggests that much familial aggregation is
due to inherited genetic factors.
Twin studies are one tool that can help disentangle inherited genetic
susceptibility from shared environmental exposures. Under certain
mathematical modeling assumptions (Falconer, 1965; Falconer and
Mackay, 1996; Khoury et al., 1988; Sham, 1998)—​for example, that
an individual’s cancer risk is determined by an unobserved, normally
distributed “liability,” which is made up of independent genetic and
environment components—​the difference in the proportion of disease-​
concordant monozygotic (identical) twin pairs and the proportion of
disease-​concordant dizygotic (fraternal) twin pairs can be used to esti-
mate the inherited genetic contribution to familial aggregation, as dis-
tinct from shared environmental factors. In particular, such studies can
estimate the heritability of different cancers, defined as the proportion
of total variance in liability due to genetic factors. The genetic contri-
bution can range dramatically for different cancers. A  recent analy-
sis of 203,691 individual twins from the Scandinavian twin registries
(Mucci et al., 2016) determined overall cancer heritability to be 33%
(95% confidence interval [CI]: 30%, 37%). A high degree of heritabil-
ity was seen for several specific cancers, including melanoma (58%;
95% CI:  43%, 73%), prostate cancer (57%; 95% CI:  51%, 63%),
ovarian cancer (39%; 95% CI: 23%, 55%), kidney cancer (38%; 95%
CI: 21%, 55%), and breast cancer (31%; 95% CI: 11%, 51%). These
results provide evidence for an inherited genetic contribution to these
cancers and a rough guide to the relative importance of inherited ver-
sus acquired factors to risk. However, heritability values should be
interpreted with care, because procedures for estimating heritability
are sensitive to modeling assumptions (Falconer and Mackay, 1996;
Lewontin, 1995; Sham, 1998; Visscher et al., 2008), and because her-
itability is defined in the context of a particular mathematical model
and need not have direct biologic or epidemiologic interpretability
53
54

54 Part I:  Basic Concepts

Mrs. Z
b 1728
d 1788
Mrs. D
b 1773
d 1827
Mrs. C
b 1763
d 1814

d 55 d 61
d 40 d 47
1848 1856
1822 1837
Liver
Abdomen

Figure 5–​1.  Portion of a pedigree describing breast and other cancers running in Paul Broca’s family. Broca (1866).

(Hoover, 2000; Visscher et al., 2008). In particular, a high heritability
does not imply that there are no environmental risk factors for disease
or that most cases are due to genetics alone: heritability should not be
interpreted as a population attributable fraction. Nor do differences in
heritability across populations imply that the genetic contribution to
disease is necessarily greater or smaller in one population or the other
(Hoover, 2000): differences in the distribution of environmental risk
factors likely account for much of the differences in heritability.
GENETIC MODELS FOR CANCER RISK
studies (Figure 5–​2). Linkage studies (described in more detail later
in the chapter) use the co-​segregation of disease status and alleles at
specific loci within families to identify genomic regions harboring
causal variants. Association studies (described later in the chapter)
use population-​level (across-​family) association between an allele and
disease, typically estimated using large series of unrelated cases and
controls. Before reviewing these two approaches in more detail, we
introduce two conceptual models relating genetic variants to cancer
risk: a Mendelian model and a polygenic model. In broad terms, link-
age studies are better suited to identify Mendelian variants, and associ-
ation studies are better suited to identify polygenic variants.

Although the data on patterns of cancer incidence within and across

families suggest that inherited genetic factors influence risk for most Mendelian (Rare Variant Large Effect) Model
cancers, they do not identify particular genetic loci and variants associ-
Under a Mendelian model, the association between disease variants
ated with risk. Identifying cancer susceptibility variants requires meas-
and cancer risk closely follows one of the classical Mendelian domi-
uring and comparing DNA variation across individuals. Over the last
nance patterns, with nearly complete penetrance and few phenocopies.
25 years, two basic approaches have identified most of the currently
(Penetrance refers to the probability that an individual with the risk
known cancer susceptibility variants: linkage studies and association
genotype contracts disease. Phenocopies are individuals diagnosed
with the disease who do not have the risk genotype.) For example, a
risk allele might act in a dominant fashion: those who carry at least
Table 5–​1.  Sibling Recurrence Risk Ratios for Various one copy of the risk allele are at very high lifetime risk of cancer.
Cancers Mendelian risk alleles are presumed to be rare—​typically with an
allele frequency below 1/​500.
Site λs Family-​based linkage studies have been relatively effective at iden-
tifying rare, high-​penetrance Mendelian risk alleles for several rea-
Aerodigestive tract 6.80 sons. First, by focusing on families with multiple affected individuals,
ALL 5.00 they enrich the sample for risk alleles. The sample sizes needed to
Bladder 1.53 detect associations with rare alleles in a population-​based case-​control
Brain/​CNS 1.97 study are much larger, even for alleles with large effects. Second, high
Breast 1.83 penetrance and a low phenocopy rate ensure that disease status is an
CLL 4.50 effective proxy for the unknown and unmeasured risk allele. This
Colorectal 2.54 makes co-​segregation of a measured genetic marker and disease status
Female genitalia 2.22 informative for co-​segregation between the marker and the risk allele.
Granulocytic leukemia 2.94
Hodgkin lymphoma 1.25
Lung 2.55 Polygenic (Common Variant Small Effect) Model
Melanoma 2.10
Multiple myeloma 4.29 Under a polygenic model, disease risk is determined by the cumulative
Non-​Hodgkin lymphoma 1.68 effects of many common alleles, each of which has a small individual
Oral cavity 1.82 effect on disease risk. Although made up of discrete effects, the cumu-
Prostate 2.21 lative polygenic components of risk can be thought of as continuous
Soft tissue sarcoma 2.00 factors with a known correlation structure among relatives. This model
Testicular 8.57 underlies the calculations used to estimate heritabilities from twin and
Thyroid 8.48 other family-​based studies.
Uterine 1.32 Alleles with small effect are difficult to detect using linkage stud-
ies: low penetrance and a large number of phenocopies make disease
status a poor proxy for any single contributing locus. On the other
ALL = acute lymphoblastic leukemia (childhood); CLL = chronic
lymphocytic leukemia; CNS = central nervous system.
hand, because they are common, these alleles can be effectively stud-
Bhat et al. (2015); Chang et al. (2005); Risch (2001). ied in population-​ based case-​control studies, despite their smaller
 5
Genetic Epidemiology of Cancer 55
(a) (b)
44
65 45 39
BD AE BA BD
41 23 39
BA BE DE
Figure 5–​2.  Strategies for localizing cancer susceptibility variants. (a) Linkage studies rely on the co-​segregation of alleles and disease status within a
family. (b) Association studies compare allele frequencies between samples of unrelated cases and controls.
effects. The relative efficiency of association approaches relative to
linkage approaches for common risk alleles with modest effects was
one of the main arguments justifying the expansion of genetic associ-
ation studies over the last 20 years.
Genetic Architecture of Cancer
Genetic architecture refers to the number of risk alleles that influence
a particular cancer and the distribution of their frequencies and effect
sizes. The genetic architecture will influence the relative efficacy of
different study designs (Bodmer and Bonilla, 2008). For example, if
both common and rare variants contribute to cancer risk, but the effect
sizes for both common and rare variants are modest, then linkage stud-
ies will be less effective than association studies at identifying risk
loci (and very large sample sizes will be needed to reliably identify
rare variants). On the other hand, if Mendelian mutations account for
most cases, association studies looking for common risk alleles may
be ineffective. Patterns of disease segregation within families and con-
cordance rates across different degrees of relationship provide some
information about the genetic architecture. However, these data are
rarely strong enough to rule out either a Mendelian or polygenic com-
ponent, and suggest that both rare variants with large effects and com-
mon variants with smaller effects contribute to many cancers. As we
review in the following, findings from linkage and association studies
are consistent with this mixed genetic architecture, combining both
rare and common risk alleles (Figure 5–​3).
LINKAGE STUDIES
One of the short-​term goals of the Human Genome Project when it
was launched in 1990 was the development of a panel of microsatellite
markers spaced across the genome. Over the next decade, research-
ers used linkage studies to track co-​segregation of disease with these
markers to identify broad regions of the genome that harbored rare,
high-​penetrance cancer predisposition genes. Linkage studies have
focused on families with an often striking aggregation of disease.
Owing to this method of case ascertainment, successful investigations
of these families have typically yielded rare genetic mutations confer-
ring a moderate to high risk of particular cancers. (Relative risks for
those with high-​risk genotypes range from approximately 3 to > 100
[Nagy et al., 2004].) However, while the identified mutations are often
limited in relevance to specific families or ethnic groups, the genes
identified have in most cases had broad application to other families
with similar phenotypes. To date, over 114 such cancer predisposition
AT
AT AT
AA AA AA
AA AT
AT TT
AT
AA
AA AA
AA AT
fT,cases = 0.33
fT,controls = 0.17
genes (CPGs) have been discovered, and together account for at least
3% of cancer diagnoses worldwide (Rahman, 2014).
CPGs employ a diversity of molecular mechanisms. Most function
normally as tumor suppressors: gatekeepers or caretakers in the cell
cycle that inhibit cell proliferation and prevent tumor development
(Oliveira et al., 2005). The best known of these is TP53, which encodes
a tumor suppressor active in many human tissues. Dominantly inherited
loss-​of-​function mutations in TP53 lead to Li-​Fraumeni syndrome, a
notable cancer syndrome characterized by both rare and common can-
cers, with pediatric and adult onset, and multiple primary cancers over
the lifespan (Kamihara et al., 2014). It is the tumor suppressor class of
CPGs (and the RB1 gene in pediatric retinoblastoma, in particular) that
formed the basis of Knudson’s two-​hit hypothesis—​that is, that carci-
nogenesis requires accumulation of loss-​of-​function mutations in both
copies of a tumor suppressor gene, and that familial cancers develop
at younger ages because genetically predisposed individuals start out
with the first “hit” already present in all germline cells, with the second
hit occurring in the tumor (Knudson, 1971). Carcinogenesis addition-
ally requires the activation of proto-​oncogenes, and a small number of
CPGs (e.g., RET, associated with familial medullary thyroid cancer)
fall into this category, predisposing to cancer when germline gain-​of-​
function mutations cause constitutional activation of the gene product
(Kouvaraki et al., 2005).
At the family level, a majority of CPGs exhibit autosomal dominant
inheritance (e.g., BRCA1/​2, causing hereditary breast and ovarian can-
cer syndrome), while a sizable minority are autosomal recessive (e.g.,
MUTYH: colorectal polyposis), and a handful are X-​linked (e.g., WAS
[Wiskott-​Aldrich syndrome]), Y-​linked (SRY:  gonadal dysgenesis
and cancers of the underdeveloped gonadal tissues), or show parent-​
of-​origin effects via differential methylation (e.g., SDHD: hereditary
paraganglioma/​pheochromocytoma syndrome) (Bardella et al., 2011).
Gene dosage effects are variable: for example, while homozygous or
compound heterozygous mutations in BRCA1 are unobserved and are
assumed to be lethal in utero (Gowen et al., 1996), double mutations
in BRCA2 lead to Fanconi anemia, a condition characterized by cer-
tain physical features, bone marrow failure, and childhood cancers
(Howlett et al., 2002).
Familial cancer clusters caused by CPG mutations share some or
all of the following features:  early age at diagnosis (e.g., colorec-
tal cancer in adolescence); multiple primary tumors in one individ-
ual (e.g., bilateral breast cancer, or both breast and ovarian cancer
diagnoses); uncommon sex distribution (e.g., breast cancer in men);
rare tumors (e.g., adrenocortical cancer) or an unusual constella-
tion of features (e.g., renal cancer and pneumothorax); and multi-
ple affected individuals across generations. These unique patterns of
56
56 Part I:  Basic Concepts
CDH1
TP53
10
STK11
Relative Risk
PALB2
PTEN
1
0.000001 0.00001 0.0001
Allele frequency
Figure 5–​3.  Relative risk and frequency of known breast cancer risk alleles. BRCA1 and BRCA2 were discovered via linkage studies. The highlighted
alleles in the lower right-​hand corner were discovered via genome-​wide association studies (GWAS). Modified from a figure courtesy of Peter Devilee
and Douglas Easton.
disease—​distinguishable even against the backdrop of cancer as a
common disease of older age—​make high-​risk cancer families ame-
nable to identification and systematic classification (Fitzgerald et al.,
2010; Umar et al., 2004). These families have historically served as a
fruitful resource for genetic studies, particularly those employing link-
age analysis (Hall et al., 1990; Khan et al., 1988).
Linkage analysis relies on the co-​segregation of a measured genetic
marker and an unmeasured disease allele, and uses statistical methods
to test for and measure genetic linkage between the marker and the
causal allele. In this way, linkage analysis can provide both (a) a test-
able marker to predict disease risk status by proxy when the CPG itself
is not known, and (b) physical mapping of a CPG to a particular chro-
mosomal region, through repeated linkage analyses with increasingly
proximate markers. To date, linkage analysis has led to the identifica-
tion of at least 59 CPGs (Rahman, 2014).
Linkage analysis requires two sets of data: first, accurate documen-
tation of family relationships and phenotype in affected and unaffected
relatives; and second, genetic samples from all available relatives,
genotyped for at least one highly polymorphic genetic marker. Highly
polymorphic markers are essential because it is the variability in marker
status that permits tracking of the marker through a family. (Highly
polymorphic markers are genetic variants with many relatively com-
mon alleles—​say, each with frequency greater than 1%. Most individ-
uals in the population will be heterozygous for these markers: they will
have inherited two different alleles from their parents.) Homozygous
individuals (e.g., marker genotype = AA) will be uninformative, while
a marker with only two or three possible alleles (e.g., A, B, C) may be
difficult to track if there are many matings between people with the
same combination of alleles (e.g., AB & AB) (Figure 5–​4).
Informally, one can often visually track disease and marker sta-
tus in a pedigree and identify the likely disease-​linked marker, as in
Figure 5–​4. Formally, linkage analysis uses likelihood ratios to test
Linkage
BRCA1
BRCA2
CHEK2
ATM
GWAS
Risk SNPs
0.001 0.01 0.1 1
for genetic linkage and estimate map distance. Map distance, distinct
but related to physical distance on a chromosome, reflects the tight-
ness of linkage between two loci, and is estimated by recombination
frequency (ϴ). When two loci are unlinked, they are inherited inde-
pendently of each other, and ϴ = 0.5; when two loci are linked, they
are more often inherited together, and ϴ < 0.5. The recombination
fraction ϴ is typically estimated using maximum likelihood meth-
ods:  LOD (“logarithm of the odds”) scores are then computed for
each value of ϴ, comparing the likelihood of observing the family
data assuming the loci are linked to the likelihood assuming the loci
are unlinked. Positive LOD scores favor linkage, and a LOD score of
+3 or greater has traditionally been considered strong evidence that
two loci are linked. The ϴ value with the highest LOD score is con-
sidered the best estimate of ϴ.
For rare phenotypes, a model-​based (parametric) method of link-
age analysis is typically used, which assumes a particular mode of
inheritance. Another critical assumption is that a single genetic locus
is responsible for the phenotype in the family, so the utility of linkage
analysis is determined by the extent to which having the phenotype is
strongly predictive of having the underlying risk allele. A limitation of
linkage analysis is that it may be less effective for clusters of common
cancers with probable phenocopies, where multiple genes and/​or envi-
ronmental factors contribute to risk. Extensions of linkage analysis to
these situations typically make use of non-​parametric methods that are
agnostic about mode of inheritance, and make no assumptions about
the number of risk loci that contribute to a trait. The utility of linkage
analysis is further limited, however, by small family size, unavailabil-
ity of relatives’ genetic samples, and the general work-​intensive and
costly nature of a procedure involving dozens to hundreds of individ-
ual samples and case histories (Klein, 2005). Today, linkage analysis
is largely being supplanted by other technologies (e.g., whole exome
sequencing) in the field of CPG discovery.
 57
Genetic Epidemiology of Cancer 57
(a)
71 31 45 36
DD EH BC ED EH FG
28 29 48 43 37 40
EB AH EB HC HC EF HF
25
EA
Figure 5–​4.  Co-​segregation of breast cancer and alleles for a marker on chromosome 17q21 near BRCA1 (Hall et al., 1990). In family (a), the E allele
and the breast cancer risk allele are inherited together (denoting absence of recombination); in family (b), the B allele and the risk allele are inherited
together.
ASSOCIATION STUDIES
Association studies are typically conducted as case-​control studies, in
which genotype frequencies are compared between unrelated patients
with the disease of interest (cases) and individuals who are free of the
disease (controls). Cases may be drawn from population-​based studies
(prospective cohorts or cancer registries) or from hospital/​clinic (retro-
spective)–​based series (Cordell and Clayton, 2005; Newton-​Cheh and
Hirschhorn, 2005). Cohort studies are conducted when a large number
of individuals are recruited and a comprehensive collection of baseline
data are collected. Individuals are followed, and those who develop the
disease of interest are considered cases in the association analysis. The
cost of genotyping an entire cohort is usually prohibitive, so cohort
studies are typically analyzed as nested case-​control studies. Such a
design is particularly useful if other (non-​genetic) risk factors, which
may not be reliably assessed in retrospective case-​control studies, need
to be taken into account (Cordell and Clayton, 2005; Newton-​Cheh
and Hirschhorn, 2005). In hospital-​based retrospective case-​control
studies, cases are ascertained by disease status, and other phenotypic
characteristics are also collected (Cordell and Clayton, 2005; Newton-​
Cheh and Hirschhorn, 2005).
In principle, genetic association studies are a special case of an
observational epidemiologic study: the exposure of interest just hap-
pens to be genetic variation. Accordingly, basic principles of epide-
miologic design for valid inference should be considered (Manolio
et al., 2006). However, in practice, some of the biases that affect obser-
vational studies are not present or are minimized by the nature of the
genetic exposure. For example, exposure suspicion bias (Manolio
et al., 2006) is unlikely to affect genotype measurement, as the expo-
sure is measured using automated techniques by lab technicians who
are blind to the case-​control status of the individual who supplied the
DNA sample. With the exception of population stratification bias,
genetic associations are unlikely to be strongly confounded, because
genotypes are distributed independently of potential confounders
within ancestrally homogeneous, outbred populations. Consequently,
many genetic association studies apply minimal adjustment for covari-
ates, as this adjustment is not needed for valid tests of the null hypoth-
esis of no cancer-​genotype association. In fact, care is required when
deciding which covariates to adjust for, as adjustment for some known
cancer risk factors can reduce power to detect a genetic association
or even create a spurious genetic association (e.g., due to collider
bias) (Aschard et al., 2015; Day et al., 2016; Kuo and Feingold, 2010;
Pirinen et al., 2012). For example, two of the three initial genome-​wide
association studies (GWAS) of type 2 diabetes identified diabetes risk
(b)
44
49
DD
65 45 39
BD AE BA BD
41 23 39
BA BE DE
markers near the FTO gene, while the third study—​which matched
cases and controls on body mass index, unlike the other studies—​
did not (Diabetes Genetics Initiative et  al., 2007; Scott et  al., 2007;
Wellcome Trust Case Control Consortium, 2007). These markers are
strongly associated with body mass index. By conditioning on a medi-
ator of the marker-​diabetes association, the power of the third study
to identify these markers was greatly reduced. Although most GWAS
have been conducted by conditioning on a minimal set of covariates, it
is important to note that in some situations, the inclusion of covariates
as potential effect modifiers may lead to increased power, as discussed
later in this chapter in the section on gene–​environment interactions.
Considering that the initial aim for many genetic association stud-
ies is discovery—​establishing that a genetic variant is associated with
cancer risk—​some investigators have adopted designs that provide
valid tests of the null hypothesis but that have biased measures of asso-
ciation under the alternative, in order to increase statistical power. For
example, many association studies oversample cases with a positive
family history and compare these to general-​population controls. This
approach can improve the power to detect associations, because such
cases are more likely to carry susceptibility alleles, but it can lead to
biased estimates of the effect size (Antoniou and Easton, 2003).
Disease-​free controls need to be drawn from the same population
as the cases (in particular, they need to be of the same ethnicity), or
differences in genotype frequencies between cases and controls may
simply reflect population variation in frequencies. A variety of analytic
methods have been developed to adjust for latent population structure
and cryptic relatedness (Kang et al., 2010; Price et al., 2010); of these,
adjusting for the top principal components of genetic variation is the
most widely used (Price et al., 2006). Controls also need to be repre-
sentative of the spectrum of individuals at risk for disease so that bias
is avoided and appropriate adjustments need to be made to avoid asso-
ciations due to confounders (Pearson and Manolio, 2008; Zondervan
and Cardon, 2007). For example, case-​control studies in prostate can-
cer that used “supernormal” controls (i.e., with very low PSA levels)
identified markers that in subsequent studies in controls alone were
shown to be associated with PSA levels rather than prostate cancer
(Knipe et al., 2014). A well-​defined but non-​representative set of con-
trols can sometimes increase the power of the study, but it can also
introduce selection bias.
An alternative approach for studying low-​penetrance alleles is a
family-​based association design. Rather than utilizing unrelated cases
and controls, family-​based designs involve genotyping relatives. The
most common approach involves genotyping affected cases together
with their parents (“trio design”). An association test is then derived
58
58 Part I:  Basic Concepts
by comparing the frequency of allelic transmission from heterozygous
parents with its expectation (1/​2) (Laird and Lange, 2006; Spielman
et al., 1993). This design has the advantage that, because the case gen-
otypes are matched to the un-​transmitted alleles from the same par-
ents, it is not subject to bias due to population stratification. However,
collecting sufficient parent-​offspring trios can be problematic, espe-
cially for an adult-​onset disease (Laird and Lange, 2006).
Linkage Disequilibrium
The genetic phenomenon of linkage disequilibrium has made associa-
tion studies aimed at discovering novel variants associated with dis-
ease relatively cost-​effective. It also makes association studies more
precise than linkage studies, in the sense that markers associated with
disease tend to be physically closer to the causal variants than mark-
ers that co-​segregate with disease within families. The resolution from
linkage studies is approximately one to two million base pairs, while
the resolution for association studies is on the order of tens of thou-
sands of base pairs (Schaid et al., 1999).
In brief, linkage disequilibrium refers to the correlation between
alleles at two varying sites on the same chromosome. Most common
single nucleotide polymorphisms (SNPs, pronounced “snips”) are
strongly correlated with at least one other SNP, and in some cases,
dozens of SNPs may be in strong linkage disequilibrium with each
other. (SNPs are the most commonly studied markers in genetic asso-
ciation studies. They are single-​base-​pair sites in the genome that vary
across individuals.) Thus, genotyping a carefully chosen subset of
common SNPs can provide useful information about the majority of
common SNPs in a region or across the whole genome.
Patterns of linkage disequilibrium are influenced by a number of fac-
tors, including recombination, selection, and demographics. Because
of this, a SNP that is a good proxy for another in one population may
not be a good proxy in another population. Similarly, the accuracy
of imputation (discussed later) from a fixed set of genotyped SNPs
may differ across populations. In particular, Africans and African
Americans exhibit lower levels of linkage disequilibrium—​on aver-
age, SNPs in Africans are strongly correlated with fewer other SNPs
than SNPs in Europeans or East Asians. As a consequence, more SNPs
need to be genotyped in Africans and African Americans to achieve the
same level of coverage as in Europeans or East Asians.
Candidate Gene Association Studies
Before advances in our catalogs of genetic variation and in genotyping
technology made GWAS feasible, most association studies focused
on particular candidate genes. These studies required investigators to
make several key decisions about which genes to study and what varia-
tion in those genes to measure—​decisions that were constrained by the
available knowledge and technologies (Tabor et al., 2002).
First, the choice of which candidate genes to study should ide-
ally have been driven by biological hypotheses linking gene prod-
ucts to carcinogenesis. DNA repair genes were common candidates,
for example—​over 140 publications on just XRCC1 and lung neo-
plasms are listed in the Centers for Disease Control and Prevention
Genopedia (https://​phgkb.cdc.gov/​HuGENavigator/​home.do)—​as
were steroid-​hormone metabolism genes for hormone-​related cancers
(Hunter et  al., 2005). However, some studies chose candidate genes
primarily because they contained a well-​known and easily genotyped
polymorphism, with a post hoc hypothesis relating the gene to cancer.
Furthermore, the choice of biologically motivated candidate genes was
(and still is) limited by our knowledge of cancer biology. Candidate
gene studies could not systematically explore genes that might have an
unanticipated link to cancer.
Second, after having chosen candidate genes, investigators had
to choose which genetic markers to type in and around these genes.
Even ignoring cost constraints, exhaustively genotyping all com-
mon variation in a gene was not possible; until very recently, with the
advent of large whole-​genome sequencing reference panels like the
1,000 Genomes Project (Genomes Project Consortium, 2015; http://​
www.internationalgenome.org/​home) or the Haplotype Reference
Consortium (McCarthy et al., 2016; http://​www.haplotype-​reference-​
consortium.org), there was no exhaustive catalog of common genetic
variation in humans. Instead, investigators relied on existing databases
such as dbSNP to identify variants that putatively altered the function
or expression of the gene—​primarily non-​synonymous coding SNPs.
(It is worth noting that a variant that is predicted to alter a gene’s pro-
tein product may not change the cancer-​relevant function of the gene;
additional experimental work is needed to establish the downstream
impact of changes in protein structure [Rebbeck et al., 2004].) After
including putative functional variants, investigators might then attempt
to indirectly capture other common variants in or near the gene by
carefully selecting a set of “tag SNPs”: a set of SNPs chosen such that
any variant in the target region is either itself a tag SNP or is in high
linkage disequilibrium with a tag SNP (or a known combination of tag
SNPs). Selecting tag SNPs requires a reference panel of densely geno-
typed or sequenced individuals from a population with similar ancestry
to the study population. (Before the advent of the HapMap, investiga-
tors had to generate these panels for their candidate genes themselves
[Hunter et al., 2005].) Target regions for candidate gene studies typi-
cally included a small amount of sequence up-​and downstream of
the gene (10–​20 kb), so by default—​and often by explicit choice—​
candidate gene studies focused on coding regions of the genes, and did
not investigate medium-​and long-​range gene-​regulation mechanisms.
Because of these constraints, candidate gene studies could only
focus on a small number of genes, and a small number of variants
within those genes, and could not reliably make any claims regarding
the comprehensiveness of these tests: if none of the variants tested
showed any association with disease, it was still possible that an
untyped and unknown variant in the gene was associated with dis-
ease, but was not detected because it was not in strong linkage dis-
equilibrium with any of the typed variants. Despite some success,
e.g., ALDH2 and ADH genes in esophageal cancer; (Brooks et  al.,
2009; Cui et al., 2009; Hashibe et al., 2008; Wu et al., 2012), CHEK2,
PALB2, and CASP8 in breast cancer; (Cox et  al., 2007; Lin et  al.,
2015; Southey et al., 2016), the majority of the associations in these
genes failed to replicate in subsequent independent studies (Ioannidis
et al., 2001), and often candidate gene studies reached apparently con-
tradictory conclusions. There are a number of reasons for these incon-
sistencies and lack of replication (Hirschhorn and Altshuler, 2002;
Kraft et  al., 2009b; NCI-NHGRI Working Group on Replication in
Association Studies et  al., 2007). First, the initial report may have
been a false positive. Many early candidate gene association studies
failed to appropriately adjust significance thresholds for the number
of markers tested. Small sample sizes and implicitly overoptimistic
priors also likely contributed to false positive results (Hirschhorn
and Altshuler, 2002; Hirschhorn et al., 2002; Ioannidis, 2005, 2006;
Wacholder et  al., 2004). Second, replication studies may also have
been underpowered to detect modest true associations. Third, studies
looking at the same candidate gene may also have genotyped different
markers, making comparison of results difficult, especially before the
advent of comprehensive surveys of linkage disequilibrium. Fourth,
differences in allele frequencies or linkage disequilibrium patterns
across populations can lead to non-​replication: a marker that was a
good proxy for the causal variant in the initial population is a poor
proxy in the second. Finally, in principle, differences in non-​genetic
exposures across study populations could modify the effect of the
genetic variant (although in practice, clear examples of this phenom-
enon are rare).
As discussed in the next section, GWAS incorporated some of the
lessons learned from the inconsistencies of candidate gene studies,
including the following: studies should be sufficiently powered; sig-
nificance thresholds should appropriately account for the number of
markers tested or the low prior probability that any particular marker
is associated with disease risk; and standardized genotyping panels
should be used as far as possible to facilitate meta-​analysis. Arguably
most important, GWAS allowed investigators to investigate the entire
genome in a hypothesis-​free manner, enabling them to discover cancer-​
associated variants in genes and pathways not previously hypothesized
to be associated with the development of cancer.
 59
Genetic Epidemiology of Cancer 59
GENOME-​WIDE ASSOCIATION STUDIES:  magnitude > 1.3. More recently identified loci have ORs below 1.2 and
DESIGN PRINCIPLES
In GWAS, the concept of association studies is extended to the whole
genome; an agnostic approach is followed, in which no prior hypoth-
esis about the location or type of genetic variants or genes involved
in the disease of interest is assumed (Evangelou and Ioannidis, 2013;
Hirschhorn and Daly, 2005; Ioannidis et  al., 2009; Marchini and
Howie, 2010; Pearson and Manolio, 2008; Price et al., 2010). High-​
throughput genotyping technologies developed in the first decade
of the 2000s are used, allowing for the simultaneous assay of hun-
dreds of thousands to millions of polymorphisms (Genomes Project
Consortium, 2012; Pearson and Manolio, 2008). GWAS capture the
large majority of genome variation by utilizing the linkage disequilib-
rium structure from publicly available databases such as the HapMap
project or the 1000 Genomes Project (International HapMap, 2005).
SNPs on a GWAS chip are selected so that they “tag” most of the
known common variants across the genome. Hence, rather than geno-
typing all SNPs, GWAS use the genotype for the tag SNPs to give
proxy information about the non-​genotyped SNPs which they tag.
The tagging SNPs on GWAS platforms usually have a population fre-
quency of the minor allele greater than 1%. Based on data from the
HapMap—​a project that genotyped a dense set of markers in reference
samples from multiple ethnicities—​the majority of the commonly
occurring SNPs in European populations can be tagged using a subset
of 500,000–​1,000,000 SNPs (International HapMap, 2005). A similar
number of SNPs is needed for Asian ancestry populations, whereas a
larger number is needed to tag all common variation in African ances-
try populations (International HapMap, 2005).
The 1000 Genomes Project and the Haplotype Consortium data sets
now provide more comprehensive resources, both because they are
based on whole-​genome sequencing and because they include more
individuals across more populations. These panels allow for the bet-
ter tagging of the rarer variants (Genomes Project Consortium, 2012;
McCarthy et al., 2016; Nelson et al., 2013).
Large numbers of samples are needed in order to identify associa-
tions with diseases, as the effects of the variants that are being observed
are usually small: odds ratio (OR) < 1.5, and most of the times < 1.3
(see section on GWAS results later in this chapter). Power is an impor-
tant issue that must be taken into account when designing GWAS.
The first published GWAS identified loci with a moderate number of
cases/​controls since the variants originally identified had larger ORs of
(a) Target power: 80%
1.8
Smallest Detectable Odds Ratio
1.6
n = 1,000
1.4
1.2
n = 5,000
n = 25,000
1.0 n = 125,000
0.0 0.2 0.4 0.6
Risk Allele Frequency
Figure 5–​5.  Smallest detectable per-​allele odds ratios in a case-​control GWAS, assuming 1:1 case:control ratio and a significance threshold of p < 5 ×
10–​8. Panel (a) depicts the smallest detectable odds ratios with 80% power as a function of sample size and risk allele frequency. Panel (b) depicts smallest
detectable odds ratios for a study of 25,000 cases and 25,000 controls as a function of the target power and the risk allele frequency.
even below 1.1, suggesting that samples sizes larger than 10,000 cases
and 10,000 controls will be required to detect additional associations
with such modest effects (Figure 5–​5).
Phenotype Choice and Definition
In GWAS and genetic association studies it is very important to have
well-​defined phenotypes, as this will increase the power of detecting
associations, especially for specific diseases where the classification
is not always straightforward. Misclassification of cases and controls
can largely bias the study results toward no association (Pearson and
Manolio, 2008). The large majority of the GWAS that are conducted
usually take into consideration cases that are representative of the
population-​level disease. This allows for selection of a large number of
samples and is powerful to identify variants that are significantly asso-
ciated in all the different subtypes of the disease. Different disease sub-
types, though, might have different characteristics. Thus restricting the
analyses to specific subtypes can increase power for detecting associa-
tions that predispose to those subtypes (Kraft and Haiman, 2010). For
example, restricting breast cancer cases to samples that carry deleteri-
ous mutations in BRCA1 (which are mainly ER-​negative cases) led to
the identification of further breast cancer susceptibility loci that were
not identifiable in the general population cases (Antoniou et al., 2010).
This strategy has also proven successful in ovarian cancer, as analy-
ses restricted to epithelial ovarian cancer (EOC) and a meta-​analysis
with ovarian cancer in patients with deleterious mutations in BRCA1/​2
(which have a high percentage of EOC) identified further susceptibil-
ity loci that could not be identified using all subtypes (Kuchenbaecker
et al., 2015).
Multiple Testing
GWAS explore thousands to millions of polymorphisms in a large
number of samples. The conventional p-​value < 0.05 for significance
cannot be used in GWAS, as the number of tests is large—​tens of thou-
sands of variants will be flagged as statistically significant using that
threshold, most of which will be false positives, and far too many to
carry on to conventional functional studies. The usual “GWAS signif-
icance” threshold that has been used is 5 × 10–​8, corresponding to a
Bonferroni correction for about one million independent tests (Pearson
and Manolio, 2008). This threshold was determined via simulation
(b) Sample size: n = 25,000 cases
1.20
Smallest Detectable Odds Ratio
1.15
1.10
power = 80%
1.05 power = 25%
power = 1%
1.00
0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0
Risk Allele Frequency
60
60 Part I:  Basic Concepts
and considers all common variants segregating in a European-​ancestry
population (not just the tag SNPs on a GWAS array) and the empir-
ical linkage disequilibrium among them (Dudbridge and Gusnanto,
2008; Hoggart et al., 2008; Pe’er et al., 2008). Thus it is an appropriate
threshold, even when the number of markers tested is larger than one
million (e.g., when more than one million common markers are geno-
typed or imputed; see later discussion in this chapter). Bayesian meth-
ods have also been proposed to select markers that are truly associated
with disease with high posterior probability; considering the low prior
probability that a random common marker is truly disease-​associated
and the small expected effect sizes, these Bayesian methods typically
require large test statistics—​of similar magnitude to those required to
achieve p < 5 × 10–​8—​in order to flag a credible disease-​marker asso-
ciation (Wakefield, 2007, 2012, 2014). Empirically, the p < 5 × 10–​8
threshold has proven very specific: markers that pass that threshold in
a GWAS tend to replicate in adequately powered replication studies.
It is worth noting that such stringent significance thresholds are
driven by the desire to minimize the experiment-​wide Type I  error
rate:  the probability of incorrectly declaring even one marker to be
associated with disease when it is not. This is arguably an appropriate
goal in the context of locus discovery, when one wants to say with
reasonable certainty that yes, this locus is associated with cancer risk,
because one then wants to use that result to make inferences regard-
ing disease biology. In particular, if one plans to conduct additional
expensive and time-​intensive functional studies to better understand
the mechanism linking genetic variation at a cancer-​associated locus to
cancer initiation and development, then one should be certain the asso-
ciation is real before investing considerable resources in functional
studies. That said, requiring such a stringent significance threshold
ensures that some truly cancer-​associated markers will fail to reach
statistical significance (controlling Type I error will increase Type II
error). Multiple lines of evidence discussed in the following suggest
that there are many cancer-​associated loci that show some evidence for
association in GWAS, but do not achieve p < 5 × 10–​8. In some situa-
tions, where there is greater tolerance for false-​positive results, it may
be appropriate to relax the genome-​wide significance threshold (relax-
ing control of Type I error in order to minimize Type II error). This
could be the case in the setting where many promising markers can
be followed up cheaply and quickly—​for example, by genotyping all
independent markers with p < 10–​4 in a large replication set. We cannot
be sure which of the markers with p between 10–​4 and 10–​8 are truly
disease associated, but we can be confident that some of those mark-
ers are truly associated with disease (assuming the GWAS was ade-
quately powered). Similarly, a risk-​prediction model using only those
SNPs that reach genome-​wide significance may be less predictive than
a model that includes SNPs passing a lower significance threshold,
when the signal added by truly associated sub-​genome-​wide signifi-
cant SNPs overpowers the noise from non-​associated SNPs. Thus, it
can be useful to consider the appropriate significance threshold for
genetic association studies as a decision theoretic problem, balancing
the relative costs of false positives and false negatives in a particular
research setting.
Replication and Power in GWAS: The Importance
of Collaboration
Given that many reported associations in early candidate gene studies
failed to replicate, the GWAS community quickly adopted standards to
maximize the chances of successful replication (NCI-​NHGRI Working
Group on Replication in Association Studies et al., 2007). Replication
serves two primary goals: first, to establish that the reported asso-
ciation is real, and not solely due to random sampling; and second,
to establish that the association is consistent across different studies
and does not reflect a bias present in one particular study (Kraft et al.,
2009b).
Given the stringent significance thresholds needed to distinguish
chance from true associations (see previous section), and given
the expected modest effect sizes (see the section “Genome-​ Wide
Association Studies: Results”), large sample sizes are needed to obtain
adequate power to detect true associations. Several different strategies
have been applied to increase power to detect associations. One of the
most common practices is to use a multistage design. In the first stage,
a GWAS is performed using a large number of SNPs and a smaller
set of individuals. In the second stage, the most significantly associ-
ated variants from the first stage are brought forward for replication
in a larger independent set of samples. Three-​and four-​stage designs
are also performed, where the most significant variants in the previ-
ous stages are explored in further independent samples (Pearson and
Manolio, 2008).
We wish to clarify two potential points of confusion regarding mul-
tistage GWAS. First, the approach of only testing “promising” mark-
ers from the first stage of GWAS is primarily a cost-​saving measure.
If GWAS data are available on all the studies that contribute to the
various stages, then the most efficient design and analysis will be to
conduct a genome-​wide meta-​analysis, and to study all markers in all
studies. Early GWAS adopted a multistage design because genome-​
wide genotyping arrays were still many times more expensive than
assays typing tens to thousands of markers. Now that GWAS arrays
are much less expensive, the cost savings from a multistage design are
nil or negligible and arguably are offset by the power gains of running
a GWAS array on as many samples as possible. Second, a study can
meet the goals of replication without conducting a formal replication
(i.e., genotyping the significant SNPs from the GWAS in yet another
set of samples). Most recent large GWAS have been meta-​analyses of
many studies, each of which had been genotyped. Associations that
achieve genome-​wide significance in these studies meet both of the
criteria for replication: they are unlikely to be due to sampling vari-
ability, and they are unlikely to reflect design artifact or other biases
that are restricted to one or a few contributing studies. Genotyping
promising markers in yet another study may not provide much addi-
tional information regarding the robustness of the finding, especially
considering that the size of any study available for replication is likely
much smaller than the original GWAS meta-​analysis.
In order to assemble such large samples sizes and replicate asso-
ciations in diverse studies and populations, investigators from many
studies have organized large, multi-​institutional, and multidisciplinary
consortia. These consortia can pool financial and scientific resources,
coordinate work, and ensure that credit gets apportioned fairly. Aside
from assembling large sample sizes, these collaborations can harmo-
nize phenotype and exposure data, and make prospective decisions
regarding genotyping platforms to ensure data compatibility (Amos
et al., 2016; Bennett et al., 2011). Collaborations across consortia can
also make use of economies of scale when ordering genotyping arrays
and assays.
Figure 5–​6 illustrates the impact the collaborative approach can
have on the pace of discovery, using breast cancer as an example. Over
the first few years, several research groups undertook GWAS of breast
cancer, independently expanding the size of their distinct replication
efforts (both in terms of number of markers studied and sample size)
and publishing separately. This led to a steady stream of discoveries,
so that from 2007 to 2012 approximately 27 independent breast can-
cer risk loci had been discovered. By conducting a meta-​analysis of
existing GWAS and designing a genotyping array to follow up 29,807
promising SNPs in a large replication sample (45,290 cases and
41,880 controls), researchers were able to more than double the num-
ber of identified loci in 2013 (Garcia-​Closas et al., 2013a; Michailidou
et al., 2013). Imputation in the replication sample further increased the
power of the study, so that another 15 loci were discovered in 2015
(Michailidou et al., 2015a). Finally, as part of the OncoArray initiative
(Amos et al., 2016), investigators in more than 90 studies were able to
double the sample size of the largest breast cancer GWAS conducted
to date. This study is projected to almost double the number of known
breast cancer risk loci.
Imputation
Genotype imputation is a method that can be used to estimate geno-
types for SNPs that are not directly genotyped in the study sample
 61

Genetic Epidemiology of Cancer 61

2007
2017 (projected)
Easton (2007) Nature
150 Hunter (2007) Nat Genet
Stacey (2007) Nat Genet
2010
Stacey (2008) Nat Genet

Cumulative number of GWAS-discovered markers

Ahmed (2009) Nat Genet
Zheng (2009) Nat Genet
Thomas (2009) Nat Genet
Turnbull (2010) Nat Genet
100 Antoniou (2010) Nat Genet
2015
2012
Haiman (2011) Nat Genet
Siddiq (2012) Hum Mol Genet
Ghoussaini (2012) Nat Genet
2013 2013
Michailidou (2013) Nat Genet
50 2015
Michailidou (2015) Nat Genet

2012
2010
2007

1,000 10,000 100,000

Number of cases in initial discovery GWAS

Figure 5–​6.  Number of GWAS-​discovered breast-​cancer risk markers as a function of largest initial GWAS sample size. Projected numbers for 2017 are
based on K. Michailidou (2015).

(Howie et al., 2012; Li et al., 2010; Marchini and Howie, 2010; Zheng
et  al., 2011). Imputation in GWAS works because SNPs are often
correlated due to linkage disequilibrium (LD), so that missing SNP
genotypes can often be inferred with high accuracy. Typically, study
samples are genotyped in a large number of SNPs (e.g., in a GWAS),
and missing SNPs are inferred from a reference panel of haplotypes.
To date, the reference populations most widely used are the HapMap
Consortium project data (International HapMap, 2005) and the 1000
Genomes Project data (Genomes Project Consortium, 2012). More
recently, the Haplotype Reference Consortium has released a refer-
ence panel of more than 32,000 sequenced samples (McCarthy et al.,
2016). The 1000 Genomes and the Haplotype Reference Consortium
data are based on whole genome sequencing of large number of sam-
ples. Stretches of shared haplotypes are identified between the ref-
erence panel and the study samples, and missing genotypes for each
sample are then “filled in” by copying alleles in the matching refer-
ence haplotypes (Li et  al., 2009). There are several reasons to use
genotype imputation, but a major use is to facilitate combining results
from different GWAS based on different genotyping platforms, since
results are then obtained for all SNPs in the reference panel. In addi-
tion, it increases the power of association analysis for studies based
on a single platform and fine-​mapping studies, since an imputed SNP
that is only partially correlated with typed SNPs may give a stronger
association than directly genotyped SNPs. Until recently, common
variants (minor allele frequency [MAF] > 0.01) could be reliably
imputed with high accuracy, whereas variants with MAF < 0.01 were
not imputed as well (Howie et al., 2012; Marchini and Howie, 2010).
Improvements to the different imputation algorithms, as well as the
increase in the numbers of the sequenced samples in the reference
panels, have increased the accuracy of the imputation of rarer variants
dramatically; variants down to MAF = 0.1% can now be imputed with
high accuracy (Figure 5–​7) (Genomes Project Consortium, 2015;
McCarthy et al., 2016). In European-​ancestry samples, approximately
9.5 million SNPs can be imputed from commonly used GWAS arrays
with an R2 > 0.8 using the 1,000 Genomes Project Phase 3 v5 ref-
erence panel. (R2 is a metric that estimates the correlation between
imputed SNP genotypes and true SNP genotypes.) Different eth-
nicities produce different qualities of imputation accuracy of com-
mon and rare variants. The HapMap and the 1000 Genomes Project
included samples from different ethnicity backgrounds, whereas the
Haplotype Reference Consortium reference panel consists largely of
samples with mainly European ancestry.
GENOME-​WIDE ASSOCIATION STUDIES: RESULTS
GWAS have been extremely successful at identifying common vari-
ants with modest effects associated with risk of complex disease. As
noted in an early review, “There have been few, if any, similar bursts
of discovery in the history of medical research” (Hunter and Kraft,
2007). Cancer has been no exception. As of November 2016, over 200
published GWAS on more than 30 different cancers were listed in the
NHGRI-​ EBI Catalog of published GWAS (https://​www.ebi.ac.uk/​
gwas/​). These papers reported 938 SNP-​cancer associations at the p <
5 × 10–​8 level of statistical significance. An exhaustive review of these
results is beyond the scope of this chapter—​and any detailed review
would be out of date by the time it is published. Instead, we focus on
general trends, illustrated by a few particular examples.
Effect Sizes for Common Alleles Are Modest
With few exceptions, the per-​allele odds ratio associated with common
risk alleles (frequencies between 5% and 95%) are modest (Figure 5–​8).
Although the relatively small number of low-​frequency SNPs that
have been identified through GWAS tend to have larger effect sizes,
that may reflect the fact that the GWAS to date have only been pow-
ered to detect low frequency variants with large per-​allele odds ratios.
It is an open empirical question whether low frequency and rare alleles
62

62 Part I:  Basic Concepts

(a) One Thousand Genomes Project (b) Haplotype Reference Consortium

31.6 31.6
0.00–0.01
0.01–0.05
0.05–0.10

Number of Markers (millions)

Number of Markers (millions) 0.10–0.20
10.0 0.20–0.35 10.0
0.35–0.50

3.2 3.2

1.0 1.0

0.3 0.3

0.00 0.30 0.50 0.70 0.80 0.95 0.00 0.30 0.50 0.70 0.80 0.95
Rsq Threshold Rsq Threshold

Figure 5–​7.  Performance of imputation using (a) the 1000 Genomes Project (Phase 3) reference panel and (b) the Haplotype Reference Consortium panel,
for samples genotyped using the OncoArray (Amos et al., 2016). The y-​axis denotes the number of markers that can be imputed with estimated accuracy
(imputation R-​squared) at or above the specified threshold. Each line denotes the performance for markers in distinct minor allele frequency bins.

generally have larger effects than common variants (and, if so, how
much larger).
Most Cancers Appear to Include a Polygenic
Component
For most of the cancers with at least one published genome-​wide sig-
nificant association, GWAS have identified at least 10 unique risk SNPs
in a median of seven distinct risk loci (Table 5–​2). For the cancers that
have been studied in the largest sample sizes (breast and prostate cancer),
over 100 independent genome-​wide significant associations have been
reported. The number of risk loci and the distribution of their effect sizes
vary somewhat across cancers, although because of differences in sample
sizes across cancer GWAS it is difficult to say how much the genetic archi-
tecture varies (Table 5–​2 and Figure 5–​9). Of particular note are ALL,
CLL, and testicular cancer, which have larger effect sizes on average (con-
sistent with their larger sibling recurrence risk ratios; see Table 5–​1).
More Common Cancer Risk Alleles Have Yet to Be
Discovered
This is illustrated in Figure 5–​10, which presents results of a series of
simulated GWAS with increasing sample sizes for a cancer with a pol-
ygenic component. None of the 100 loci with a per allele-​odds ratio
of 1.05 was discovered in studies of 1000 or even 10,000 cases, due
to low power. One risk allele reaches genome-​wide significance in the
study with 50,000 cases, and 28 reach genome-​wide significance in
the study with 100,000 cases. There are two things to note from this
example. First, those 28 genome-​wide significant SNPs in the study
with 100,000 cases and 100,000 controls represent the “tip of the ice-
berg.” The power to detect a particular causal SNP in Figure  5–​10
(panel d) is modest (about 25%); some luck was involved for these 28
SNPs to achieve p < 5 × 10–​8. It is likely that SNPs with modest effects
(which had low power to be detected) are drawn from a larger pool
of SNPs, many (or most) of which have gone undetected. Second, as
sample size increases, the distribution of p-​values for causal SNPs

4.0

3.5
Per-Allele Odds Ratio

3.0

2.5

2.0

1.5

1.0

0.0 0.2 0.4 0.6 0.8 1.0

Risk Allele Frequency

Figure 5–​8.  Per-​allele odds ratios of cancer risk alleles from published genome-​wide association studies (restricted to markers with association p < 5 ×
10–​8). Data from Burdett T (EBI), version v1.0 (accessed November 25, 2016).
 63

Genetic Epidemiology of Cancer 63

Table 5–​2.  Summary of Risk Markers from Published Genome-​Wide 2013; de los Campos et al., 2010; Finucane et al., 2015; Gusev et al.,
Association Studies (GWAS) of Cancer 2014; Vilhjalmsson et  al., 2015). Several lines of evidence suggest
that the scenario presented in Figure 5–​10 holds for many cancers,
Site npapers nSNPs nregions σg2 and that more common risk alleles with modest effects remain to be
discovered. Techniques that estimate hg2, the amount of variability in
ALL 8 19 10 0.58–​1.02 disease liability that could be explained by all the SNPs measured in a
Bladder 9 16 15 0.25–​0.17 GWAS, suggest that currently known genome-​wide significant SNPs
Breast 26 107 59 0.47–​0.82 account for a fraction of hg2 (Lu et al., 2014; Sampson et al., 2015).
Cervical 2 7 5 0.07–​0.08 Similarly, inverse-​ probability-​
of-​
discovery methods suggest that
CLL 5 31 23 0.77–​0.89 many common variants with effect sizes similar to those already dis-
CML 1 1 1 0.19–​0.19 covered remain unknown (Chatterjee et al., 2013; Krier et al., 2016;
Colorectal 20 55 39 0.30–​0.33 Park et al., 2011, 2012).
Melanoma 1 7 7 0.04–​0.04
Endometrial 1 1 1 0.02–​0.02
Esophageal 4 21 18 0.37–​0.39 Some Regions Harbor Multiple Statistically
Ewing sarcoma 1 3 3 0.39–​0.39 Independent Signals
Gastric 4 10 7 0.11–​0.18
Glioma 7 23 12 0.33–​0.39 The 8q24 region, for example, contains at least five SNPs that are
Hepatocellular carcinoma 3 5 4 0.19–​0.22 independently associated with prostate cancer risk (in the sense that
Hodgkin lymphoma 5 12 9 0.27–​0.26 the SNPs remain statistically significant after mutual adjustment in a
Lung 15 26 17 0.31–​0.39 multivariable regression model) (Al Olama et al., 2009; Gudmundsson
Lymphoma 8 23 12 0.58–​0.89 et  al., 2007a; Haiman et  al., 2007; Witte, 2007; Yeager et  al., 2007,
Multiple myeloma 3 10 7 0.17–​0.21 2009). This may indicate that there are distinct mechanisms whereby
Non-​melanoma skin 9 31 25 0.63–​0.66 different SNPs disrupt gene function or expression in the region
Ovarian 8 24 22 0.38–​0.37 (allelic heterogeneity), or it may indicate that the SNPs jointly tag a
Pancreatic 5 24 17 0.20–​0.23 rare variant with a larger effect (Anderson et al., 2011; Dickson et al.,
Prostate 24 142 77 0.78–​1.61 2010; Wray et al., 2011). More research is needed to understand the
Renal cell carcinoma 5 8 6 0.08–​0.05 functional mechanisms at these loci.
Testicular 7 24 20 0.89–​1.07
Thyroid 4 8 4 0.27–​0.47
Some Regions Harbor Variants Associated
npapers = number of distinct published GWAS containing at least one genetic association with Multiple Cancers and Other Complex Traits
with p < 5 × 10–​8; nSNPs = number of distinct single nucleotide polymorphisms with p <
5 × 10–​8 in at least one paper; nregions = number of distinct regions (cytobands) containing
The 8q24 region is again an example of this phenomenon, as it con-
at least one SNP with p < 5 × 10–​8 in at least one paper; σg2 = the sum of the effect tains SNPs associated with prostate, breast, colon, ovarian, thyroid,
sizes for the published risk markers, Σi 2 qi (1-​qi) βi2. The range for σg2 is defined by and kidney cancers and glioma (Ghoussaini et al., 2008; Yeager et al.,
first considering only one marker per region (the lower bound), then considering all the 2009). The region near the TERT and CLPTM1L genes also contains
unique markers in the regions, averaging the effect sizes for markers reported more than
once (the upper bound).
SNPs associated with lung, pancreatic, and at least four other distinct
ALL = acute lymphoblastic leukemia (childhood); CLL = chronic lymphocytic cancers (Wang et al., 2014). The HLA region and a region on 11q13
leukemia; CML = chronic myeloid leukemia also contain variants associated with multiple cancers (Chung and
Data from Burdett et al. (2016). Chanock, 2011).
The biological implications of these findings remain unclear.
Some of these regions contain multiple SNPs that are asso-
starts to differ from that of the background “noise” SNPs. This fact ciated with different cancers:  for example, rs4449583 at the
could be leveraged to improve risk prediction models (see later dis- TERT-​CLPTM1L locus is associated with prostate cancer, while
cussion) or to identify functional elements across the genome that rs13170453 at the same locus is associated with lung cancer (the
are more likely to harbor cancer-​associated alleles (Chatterjee et al., two SNPs are in low LD, r2 < 0.10) (Wang et  al., 2014). Some
regions contain individual SNPs that are associated with multiple
cancers: rs4430796 at HNF1B is associated with both prostate can-
cer and endometrial cancer (Gudmundsson et  al., 2007b; Spurdle
ALL et al., 2011). Some alleles that are associated with multiple cancers
CLL increase the risk of one cancer but lower the risk of another:  the
Testicular A allele of rs451360 increases risk of pancreatic and testicular can-
Esophageal cer, for example, but decreases risk of lung cancer (Wang et  al.,
Ovarian 2014). These findings may indicate that variants at these loci affect
Lung multiple cancer-​related pathways, or a single pathway that affects
Pancreatic
different cancers, some in different ways. Further work pinpointing
the causal variants in these regions and how they perturb biologic
Prostate
function is needed.
Colorectal
Cancer risk SNPs also co-​ localize with SNPs associated with
Breast other complex traits. For example, the G allele of rs4430796 near
HNF1B is associated with an increase in risk of type 2 diabetes, but
0.00 0.05 0.10 0.15 0.20 0.25 a decrease in prostate and endometrial cancer risks (Elliott et  al.,
Effect size: 2 q (1–q) β2 2010; Gudmundsson et  al., 2007b; Machiela et  al., 2012; Pierce
and Ahsan, 2010; Spurdle et al., 2011). The T allele of rs505922 is
Figure 5–​9.  Boxplots of effect sizes for cancer risk alleles from published a proxy for the “O” allele of the ABO gene and is associated with
GWAS (restricted to markers with association p < 5 × 10–​8). The effect size lower risk of pancreatic cancer, lower risk of venous thromboembo-
of a risk allele is its contribution to the variance in log odds of disease. lism (Germain et al., 2015; Wolpin et al., 2010), markedly higher lev-
ALL = acute lymphoblastic leukemia (childhood); CLL = chronic lymphocytic els of e-​selectin (Qi et al., 2010), and an increased risk of duodenal
leukemia; q = minor allele frequency; β = log per-​allele odds ratio. ulcer (Amundadottir et al., 2006; Tanikawa et al., 2012). The breast
Data from Burdett T (EBI), version v1.0 (accessed November 25, 2016). cancer risk SNP rs11075995 is located near FTO, but is apparently
64

64 Part I:  Basic Concepts

(a) n = 1,000 cases (b) n = 10,000 cases
12 12
100 causal loci,
10 MAF = 0.10, 10
–log 10 p-value OR = 1.04

–log 10 p-value
8 8

6 6

4 4

2 2
0 0

Position Position
(c) n = 50,000 cases (d) n = 100,000 cases
12 12

10 10
–log 10 p-value

–log 10 p-value
8 8

6 6

4 4

2 2

0 0

Position Position

Figure 5–​10.  Manhattan plots from four simulated GWAS. Each point represents one of 100,000 independent markers; highlighted points represent 100
true causal variants (with a minor allele frequency of 0.1 and per-​allele OR of 1.04); all other markers are assumed to have the same allele frequencies in
cases and controls. The x-​axis denotes order along the genome; the y-​axis is the –​log10 p-​value for association. Dashed line represents the genome-​wide
statistical significance threshold (p < 5 × 10–​8).

independent of the obesity-​related SNPs in that region (Garcia-​Closas
et al., 2013a).
Such findings raise intriguing biological hypotheses. They also
suggest that combining GWAS results across multiple cancers can
increase power to detect SNPs that are in fact associated with multiple
cancers or cancer-​related traits (Bhattacharjee et al., 2012; Fehringer
et al., 2016; Kar et al., 2016). This possibility is supported by cross-​
phenotype heritability analyses. These analyses estimate the correla-
tion in SNP effects across cancers (and between cancers and other
phenotypes). They show that many cancers share a genetic component
with each other and other traits (e.g., lung cancer and smoking behav-
ior), although the genetic correlation is not as strong as that observed
for some psychiatric traits (e.g., schizophrenia and bipolar disease)
(Sampson et al., 2015).
Most GWAS-​Identified Markers Do Not Clearly Tag
Coding Variants
As with other complex traits, the majority of SNPs that are associated
with cancer are not themselves in coding regions, nor are they indi-
vidually in strong linkage disequilibrium with coding variants. Instead,
these SNPs and their strong proxies are mostly found in putative regu-
latory regions (Maurano et al., 2012; Schaub et al., 2012). Heritability
enrichment analyses that use all GWAS markers (not only those reach-
ing genome-​wide significance) to partition the total genetic contribution
to cancer liability across different regions of the genome (e.g., coding,
promoter, UTR, repressed) have consistently found that regulatory ele-
ments explain most of the genetic contribution to cancer risk. The 8q24
region yet again provides a concrete example of this phenomenon. This
region is “gene desert”:  all of the cancer-​associated SNPs there are
about one million base pairs removed from the nearest gene. There is
some experimental evidence suggesting that these SNPs disrupt long-​
range binding between the 8q24 region and MYC, an oncogene.
The Causal Variant(s) at Most GWAS-​Identified Loci
Remain Unknown
Although there is evidence that SNPs in regulatory regions as a class
are associated with cancer risk, identifying the specific variants that
influence cancer development and how they do so remains a difficult
task. While linkage disequilibrium helps identify cancer-​associated
regions (by enabling cost-​effective design and accurate imputation), it
hinders the identification of the relevant functional SNPs within these
regions. SNPs that are in strong LD will be statistically indistinguish-
able due to colinearity, even in large sample sizes. Modern statistical
approaches to “fine mapping” integrate association results from large
studies (typically GWAS meta-​analyses), linkage disequilibrium pat-
terns, and genomic functional annotations in order to identify a (hope-
fully small) set of SNPs likely to contain the causal variant(s) in a
region (Coetzee et  al., 2012; Kichaev et  al., 2014, 2016; Ward and
Kellis, 2016). Still, even when these analyses return a small number
of candidate variants, additional functional analyses will be needed to
confirm that they are biologically related to cancer risk and to under-
stand the mechanism behind the association.
Most Genome-​Wide Association Studies Have Been
Conducted in European-​Ancestry Populations
This creates several important gaps in our knowledge of the genetic
epidemiology of cancer. To begin with, the impact on non-​European
populations of markers discovered in Europeans is less clear. When
SNPs that are significantly associated with cancer in Europeans are
present in other ethnicities, some associations replicate (though often
with weaker magnitude of association), while some do not (Fejerman
et  al., 2014; Han et  al., 2015b; Murillo-​Zamora et  al., 2013; Waters
et al., 2009). Taken in aggregate, the variants discovered in European-​
ancestry populations are typically associated with cancer in other
 65
Genetic Epidemiology of Cancer 65
ethnic groups, although these associations (and hence their ability to
discriminate cases and controls) are generally lower. As an example,
a score composed of 105 known prostate cancer risk SNPs (most dis-
covered in European-​ancestry samples) was tested across multiple eth-
nicities: “Comparing the highest to lowest risk score deciles, the OR
was 6.22 for non-​Hispanic whites, 5.82 for Latinos, 3.77 for African-​
Americans, and 3.38 for East Asians” (Hoffmann et  al., 2015). The
lack of replication, or weaker associations, may be due to differences
in allele frequencies or LD patterns across different ethnic groups.
Moreover, European-​ancestry GWAS are underpowered to discover
variants that are rare in Europeans but common in non-​Europeans.
Studying non-​ European populations can increase power to detect
these loci, identifying variants that are directly relevant to the popu-
lations where they are polymorphic and more generally in terms of
our understanding of cancer biology. Increasing effort is being made
to perform GWAS in non-​European ancestry populations, including
those of African, East Asian, and Latino American ancestry.
APPLICATIONS OF GWAS RESULTS
Although additional epidemiologic studies, bioinformatic analyses,
and biologic experiments are needed to understand the mechanisms
linking genetic variation to variation in cancer risks, GWAS have
already led to biologic insights, and GWAS results may have immedi-
ate clinical implications and may open up new approaches to under-
standing cancer epidemiology. For example, GWAS have highlighted
the importance of regulatory variation relative to protein-​coding varia-
tion, overturning some of the common wisdom from the candidate
gene era. Here we highlight two contemporary applications of GWAS
results: genetic risk prediction and Mendelian Randomization studies.
Risk Prediction
Rare, high-​penetrance variants in cancer predisposition genes (whether
identified via genetic testing or inferred based on family history) have
been used to counsel men and women from high-​risk families regard-
ing their options for cancer screening and prevention for over 30 years
(Biesecker et  al., 1993; Fitzgibbons et  al., 1987; Lynch HT, 1967;
Yandell DW et  al., 1989). Recently, Mary-​Claire King and others
have proposed the implementation of population screening for known
cancer-​related risk variants (regardless of family history) (King et al.,
2014; Manchanda et al., 2015; Metcalfe et al., 2015; Plon, 2015); sep-
arately, there are initiatives to expand standard testing to include less
well-​characterized cancer predisposition genes (Couch et  al., 2015;
Easton et  al., 2015; Kapoor et  al., 2015; Tung et  al., 2015). These
proposals highlight several gaps in empirical data on rare variants in
cancer predisposition genes. First, for known deleterious mutations,
current estimates of lifetime risk are largely based on high-​risk fami-
lies with multiple affected family members. The impact of these muta-
tions in the general population remains unknown. Second, it remains
difficult to predict the impact of novel variants in known predisposition
genes. For example, while only 2% of BRCA1/​2 variants identified in
the context of genetic counseling are variants of unknown significance
(previously unreported variants with a predicted function that could be
deleterious or benign) (Eggington et al., 2014), currently 30%–​40% of
variants identified are of unknown significance when large multi-​gene
panels are employed (Tung et al., 2015). Third, the evidence linking
some proposed predisposition genes to particular cancers is inconclu-
sive. All of these questions are currently active areas of research.
The success of GWAS in identifying common risk alleles raises
the possibility that these alleles could also be used to predict absolute
risk of cancer, especially in the general-​population setting. Although
the effects of these common risk alleles are individually small, taken
together they can describe a larger gradient in disease risk. Typically,
genetic risk models combine information from independent genome-​
wide significant SNPs in a genetic risk score: a sum of the number of
risk alleles an individual carries, weighted by the allele-​specific log
relative risks. Early reports of the genetic risk scores for cancer (and
other complex traits) were criticized for poor discriminatory power
and misleading presentation (conflating the statistical significance of
an association test with clinical utility) (Kraft et al., 2009a). The lim-
ited discriminatory power in early reports was in large part due to the
relatively small number of genome-​wide significant markers known at
the time. Now, for cancers with scores of genome-​wide significant risk
alleles, the discriminatory ability of genetic risk scores is on par with
or surpasses the discriminatory ability of other widely used risk tools
or biomarkers. For example, the discrimination of 86 breast-​cancer
risk SNPs already surpasses that of the Gail model, based on estab-
lished (non-​genetic) breast cancer risk factors (area under the ROC
curve of 0.63 for a model including 86 risk SNPs, compared to 0.59
for the Gail model; Maas et al., 2016). The area under the ROC curve
for 133 prostate-​cancer risk SNPs is 0.68, equivalent to the area under
the curve for prostate-​specific antigen testing (Szulkin et al., 2015b;
Thompson et al., 2005).
Several avenues for improving genetic risk-​prediction models are
currently being explored. First, larger GWAS sample sizes will lead
to greater power to identify new risk loci and sort signal from noise
(Krier et al., 2016; Park et al., 2010, 2011). Second, more advanced
statistical methods can improve risk prediction. Several groups have
proposed models that do not restrict to genome-​wide significant SNPs,
either by raising the p-​value threshold for including markers in a risk
score or by applying penalized regression methods (Chatterjee et al.,
2013; Dudbridge, 2013, 2016; Vilhjalmsson et al., 2015). These meth-
ods can improve discrimination relative to a risk score that includes
only genome-​wide significant SNPs by taking advantage of truly asso-
ciated SNPs that fail to reach genome-​wide significance (Figure 5–​10).
However, large training samples are needed to realize this potential
gain, and care must be taken to avoid overfitting (ideally by reporting
model performance in an independent test data set).
Most genetic prediction models assume that the effects of risk alleles
add within and across loci on the log relative risk scale. Relaxing this
assumption to allow for gene-​gene interactions (non-​additive effects)
might improve model performance. However, the log additive model
appears to be a good fit to empirical data (Hsu et al., 2015; Jiao et al.,
2012; Joshi et al., 2014; Lindstrom et al., 2012; Mavaddat et al., 2015),
and including non-​additive effects (which will require very large sam-
ples sizes to detect and estimate accurately [Zuk et  al.,  2012]) may
not greatly improve model discrimination (Aschard et al., 2012a). It is
important to note that additivity on the log relative risk scale implies
that the relative risk of cancer increases exponentially with the number
of risk alleles carried. This can lead to a small subset of individuals in
the tails of the risk distribution with markedly elevated (or lowered)
risk. For example, the 1% of men with the highest values of a 77-​SNP
genetic risk score for prostate cancer are at 4.7 times the average risk
of prostate cancer (Eeles et al., 2013), and the 1% of women with the
highest values of a 77-​SNP genetic risk score for breast cancer are at 3
times the average risk (Mavaddat et al., 2015).
Finally, it should be noted that the clinical or public health utility
of a genetic risk prediction algorithm cannot be determined by any
one of the usual statistical metrics used to assess model performance
(area under the ROC curve; variance in log relative risks; prediction
r2; etc. [Chatterjee et al., 2016; Gail and Pfeiffer, 2005; Gerds et al.,
2008; Kerr et  al., 2014; Pfeiffer and Gail,  2011]) taken in isolation.
The utility will depend on the balance of risks, costs, and benefits asso-
ciated with a particular application of the risk model. The benefits of
using predictive genetic profiles to define high-​risk subjects who might
receive intervention (and low-​risk subjects who might not) should out-
weigh the costs of the testing and the intervention. This net benefit thus
depends on the specifics of the proposed intervention. (“An expensive
or invasive intervention, such as prophylactic surgery, to prevent a rare
outcome requires a very high specificity. High specificity may not
be as important for a less expensive and less risky intervention, such
as providing additional encouragement to adopt a healthier lifestyle
to individuals at high lifetime risk” [Kraft et al., 2009a]). Moreover,
assessments of clinical or public health utility typically involve param-
eters beyond the risk model itself, such as uptake of testing, adherence
to treatment or screening guidelines given genetic risk results, effi-
cacy of treatment or screening modality (which may itself depend on
6
66 Part I:  Basic Concepts
genetic risk), and so on (Chowdhury et al., 2013, 2015; Marcus et al.,
2016). Modeling the impact of genetic risk prediction in a variety of
settings is currently an area of active interest.
Mendelian Randomization
Epidemiological studies are used to estimate associations between
exposures of interest and cancer risk. However, these associations may
be biased estimates of the effect of an exposure on cancer risk due
to unmeasured confounding and/​or reverse causality. Mendelian ran-
domization (MR) is an approach that can be used to avoid such biases.
MR methods can estimate a causal relationship between an exposure
and a disease if the exposure has a known genetic determinant, which
is used as an instrumental variable (IV) for the exposure (Didelez and
Sheehan, 2007; Lawlor, 2008). Genetic variants serve as good can-
didate IVs because they are time-​invariant and randomly assigned at
conception; thus, they are not susceptible to the effects of potentially
confounding environmental factors and are not affected by disease sta-
tus. Rather than directly estimating the association between an expo-
sure and outcome, MR involves estimating the association between
the IV and the outcome, and using this estimate to infer the effect
of the exposure on the outcome. These inferences are valid under the
assumptions that the IV is (1) predictive of the exposure, (2) indepen-
dent of confounders that bias the exposure–​outcome association, and
(3) independent of the outcome given the exposure and confounders
of the exposure-​outcome association (Didelez and Sheehan, 2007;
Glymour et al., 2012; Lawlor, 2008).
Prior to the proliferation of GWAS, only a few MR studies had been
reported, and these typically used IVs that were well-​described, single
genetic predictors of exposures. As large-​scale GWAS revealed new
potential IVs for exposures and biomarkers of interest, the use of MR
methods has grown rapidly. As of October 2016, at least 27 MR stud-
ies reporting significant effects of various exposures and biomarkers
on cancer risk factors had been published (Boccia et al., 2009; Bonilla
et al., 2013, 2016; Brennan et al., 2009; Carreras-​Torres et al., 2016;
Day et al., 2015; Dixon et al., 2016; Gao et al., 2016; Guo et al., 2016;
Iles et  al., 2014; Khankari et  al., 2016a, 2016b; Lewis and Smith,
2005; Nead et al., 2015; Nimptsch et al., 2015; Ojha et al., 2016; Ong
et al., 2016; Painter et al., 2016b; Taylor et al., 2017; Thompson et al.,
2016; Thrift et al., 2015a, 2015b; Walsh et al., 2015, 2016; Wang et al.,
2011; Zhang B et al., 2015; Zhang C et al., 2015). These studies have
reported effects for age at onset of puberty, anthropometric traits, alco-
hol and coffee consumption, estradiol levels, polyunsaturated fatty acid
levels, vitamin D levels, and telomere length on various cancer types.
Methodological extensions of the MR method have also been
developed, including (1) the use of multiple genetic variants as multi-​
SNP IVs (Palmer et  al., 2012; Pierce et  al., 2011); (2)  two-​sample
approaches in which IV associations with the exposure and cancer risk
are measured in two independent data sets (Pierce and Burgess, 2013);
(3) the use of summarized (rather than individual-​level) data to obtain
MR estimates (Burgess et  al., 2013); and (4)  methods for detecting
violations of MR assumptions and reducing the impact of bias due to
violations (Bowden et al., 2015a, 2016).
MR has become a widely used methodology and has provided
important insights regarding the causality of risk factors for cancer
and many other disease phenotypes. “Hypothesis-​free” MR is a poten-
tial future direction involving mining of genotyping and phenotyping
data sets for evidence of causal relationships within biological net-
works without a priori specification of exposure or outcome (Evans
and Davey Smith, 2015). Relevant databases and methods are being
developed (http://​www.mrbase.org/​) (Voight, 2014). MR is also being
explored as a tool for informing drug discovery by its use in assessing
the probable efficacy of pursuing a target, investigating on-​and off-​
target drug effects, and to better target existing agents through drug
repurposing (Evans and Davey Smith, 2015). However, future progress
depends on the continued expansion and improvement of methodology
to address issues arising from potential violations of assumptions in
the selection of IVs such as pleiotropy (Bowden et al., 2015b; Burgess,
2015), and the advancement of high-​throughput omics technologies to
build comprehensive data sets of intermediate phenotypes for develop-
ment of better IVs.
FUTURE DIRECTIONS
Although the last 10  years have seen tremendous advances in our
knowledge of the genetic epidemiology of cancer, many important
questions remain open. To begin with, the known rare and common
risk variants represent only a part of the inherited genetic contribution
to cancer risk; more risk variants have yet to be discovered. Several
lines of evidence suggest this. First, meaningfully larger GWAS still
identify novel loci for most cancers. Second, the effect sizes for many
newly detected risk loci are small enough that luck played some role
in their discovery, implying that there are many more loci with simi-
larly small effects yet to be discovered. Finally, the known loci do not
account for observed familial clustering: GWAS-​identified SNPs can
explain 16% of the sibling relative risk of breast cancer, for example,
with known rare variants accounting for approximately another 16%
(Michailidou et al., 2015a). There are a number of reasons for this the
gap between the inherited genetic component due to known genetic
risk variants and that inferred from family studies, often referred to as
the “missing heritability” (Maher, 2008; Manolio et al., 2009).
Unknown common variants account for some of the “missing heri-
tability,” as do unknown rare variants. How much of the “missing heri-
tability” is due to undiscovered common risk variants and how much
is due to undiscovered rare variants is an open empirical question.
Current data are sparse and conflicting, largely due to the paucity of
large-​scale sequencing association studies of complex human diseases
and traits. A recent study of over 15,000 subjects with whole-​genome
and whole-​exome sequencing data (plus imputed genotypes on over
111,000 subjects with GWAS data) found that lower-​frequency vari-
ants do not have a major role in predisposition to type 2 diabetes
(Fuchsberger et al., 2016). On the other hand, targeted sequencing of
63 regions (comprising 12 Mb of sequence) in 9200 men suggested
that SNPs with MAFs of 0.1%–​1% “explain a substantial fraction of
prostate cancer risk in men of African ancestry.” However, the same
study found little evidence that rare variants substantially contributed
to risk in other ethnicities (Mancuso et  al., 2016). A  clear answer
regarding the relative contribution of rare variation to population-​level
variation in cancer risk will require very large samples to be sequenced
(on the order of more than 25,000 cases and a similar number of con-
trols; Zuk et al., 2014). Considering the substantial costs involved in
sequencing this number of samples, future discovery efforts should
take several complementary approaches, including additional GWAS
(especially for cancers and racial/​ethnic populations where GWAS
sample sizes have been relatively modest), sequencing of high-​risk
families (especially those known not to segregate a known risk muta-
tion), and large-​scale sequencing efforts.
Finally, for completeness, we note that some of the “missing herita-
bility” may be due to an apples-​to-​oranges comparison. The estimates
from GWAS and sequencing studies of the genetic contribution of
known, measured genetic variation to population variability in cancer
risk and shared familial cancer risk (i.e., estimates of hg2) typically
assume that variants interact additively; they do not include domi-
nance or epistatic (gene-​gene interaction) effects (Pharoah et al., 2002;
Risch, 1990; Yang et al., 2011). Estimates of heritability from family
studies can include both dominance and epistatic effects. Estimates
from twin studies, for example, include both (Falconer and Mackay,
1996; Zuk et  al., 2012). Moreover, family studies are susceptible to
bias from shared environment (Visscher et al., 2008). Thus, while pro-
viding some guidance as to the genetic architecture of cancer, herita-
bilities from family studies should not be taken as the final standard for
the success of current or future genetic discoveries.
Aside from the remaining unknown variants associated with cancer
risk, much remains to be learned about the genetic variants associated
with cancer survival and prognosis, response to treatment, the interac-
tions between genetic and environmental variation, and the biologic
mechanisms linking these risk-​associated loci to cancer etiology. We
discuss these areas in the next sections.
 67
Genetic Epidemiology of Cancer 67
Cancer Survival
Although it is well known that cancer risk has a heritable compo-
nent, little is known about the heritability of cancer progression and
ultimately cancer-​specific death. A  Swedish study (Lindstrom et  al.,
2007) of more than three million families, including one million cancer
cases, noted an increased risk for cancer-​specific death in children with
poor parental survival compared to those with good parental survival
for breast, colorectal, lung, and prostate cancer. In addition, a recent
study (Fejerman et  al., 2013)  in a Hispanic population showed that
individuals with higher Indigenous American ancestry had increased
risk of breast cancer–​specific mortality, and this association persisted
after adjusting for demographic factors.
Despite this, studies aiming at identifying specific genetic variants
associated with cancer survival have been conflicting. Recognizing the
heterogeneity in prognosis among cancer patients, many studies have
focused on specific subgroups, defined by either disease characteris-
tics or treatment. A GWAS of survival among 3494 colorectal cancer
cases identified SNPs at 6p12.1 to be associated with survival among
individuals with distant-​metastatic disease on a genome-​wide level
(HR = 1.8; 95% CI: 1.5, 2.2; p = 7.6 × 10–​10); however, these SNPs were
not significant among all cases (Phipps et al., 2016). SNPs at 5q23.2
and 6q21 were found to be associated with overall survival among
1537 diffuse large B-​cell lymphoma patients treated with immunoche-
motherapy (HR = 1.49; 95% CI: 1.29, 1.72; p = 3.53 × 10–​8), although
the risk estimates for disease-​specific survival were lower and did not
reach genome-​wide significance (Ghesquieres et al., 2015). For breast
cancer, variants on 11q24 (Guo et al., 2015) have been associated with
survival among 6881 cases with estrogen receptor negative (ER–​) dis-
ease (HR = 1.95; 95% CI = 1.55, 2.47; p = 1.91 × 10–​8).
All of these findings have not yet been replicated in independent stud-
ies. More evidence will be needed to confidently confirm them. Survival
GWAS for ovarian (Johnatty et al., 2015), prostate (Szulkin et al., 2015a),
lung (Wu X et al., 2013), and pancreatic (Wu et al., 2014) cancer have
all failed in returning genome-​wide significant findings. It is important
to note that GWAS of cancer survival are lagging cancer risk GWAS in
terms of sample sizes. In addition, they are struggling with additional
heterogeneity issues due to difference in treatment and disease stage. As
sample sizes become larger, we will be able to maintain adequate sta-
tistical power while stratifying patients according to treatment or tumor
characteristics; thus, novel loci for cancer survival are likely to emerge.
Pharmacogenetics and Treatment Response
Pharmacogenetics, the study of the relationship between genetics
and drug response, has shown that variants within drug-​metabolizing
genes can influence the rate at which the drug is converted to its metab-
olites, thus impacting its effectiveness or leading to unwanted side
effects. Most cancer genetic research regarding treatment response has
focused on somatic mutations. However, there is compelling evidence
that inherited genetics may influence the efficacy of cancer therapy and
management (Bell et al., 2015; Patel et al., 2013; Walko and McLeod,
2014). Currently, a handful of anticancer drugs have labels related to
specific germline genomic loci and outcomes (Pesenti et al., 2015).
As an example of the potential impact of germline variation, a recent
study determined that men with prostate cancer with germline (or
somatic) mutations in BRCA2 and other DNA repair genes were much
more likely to respond to a PARP inhibitor, olaparib, than those without
a DNA repair mutation (88% vs. 4% of patients) (Mateo et al., 2015).
In addition to impacting the response of drugs, SNPs may influence
the response to other types of cancer therapy, including radiation. The
field of radiogenomics focuses on the impact of genetic variants on
normal tissue radiosensitivity, which may result in decreases in quality
of life and disability (Kerns et al., 2014, 2015).
Gene–​Environment Interactions
“Gene–​environment interaction” is widely accepted to be ubiquitous in
the development of most cancers, in the broad sense that both “nature”
and “nurture” contribute to cancer initiation, growth, and prognosis.
Thus there is great interest in studying the joint effects of genetics and
environmental, lifestyle, and other non-​genetic exogenous and endog-
enous exposures using epidemiological data (Aschard et  al., 2012b;
Chatterjee and Mukherjee, 2009; Garcia-​Closas et  al., 2011; Hutter
et al., 2013; Kraft and Hunter, 2009; Mechanic et al., 2012). Such stud-
ies can address at least three goals. First, by accounting for the pos-
sibility that genetic effects may differ across exposure strata, studies
can leverage gene–​environment interaction to increase power to detect
loci that standard marginal genetic association tests (which average
genetic effects over exposure strata) fail to detect (Aschard et al., 2010,
2013; Dai et al., 2012; Gauderman et al., 2013; Hsu et al., 2012; Kraft
et  al., 2007; Lindstrom et  al., 2009; Pare et  al., 2010; Soave et  al.,
2015). Second, a better understanding of the joint effects of genotypes
and exposures can help identify individuals who might disproportion-
ately benefit from clinical interventions (or groups that might dispro-
portionately benefit from public health interventions) (Garcia-​Closas
et  al., 2013b; Maas et  al., 2016; Siemiatycki and Thomas, 1981).
Finally, understanding the pattern of disease risk across strata defined
by genotypes and exposures may provide some insight into the bio-
logical mechanisms through which genotypes and exposures influence
disease.
The study of gene–​environment interaction in epidemiological stud-
ies often focuses on statistical interaction, but it is important to note
that statistical interaction alone provides, at most, circumstantial sup-
port for any of these three goals (Kraft and Hunter, 2009; Siemiatycki
and Thomas, 1981; Thompson, 1991). Statistical interaction refers to
departures from additivity on a particular outcome scale. Changing
the outcome scale typically changes inference regarding the presence
or absence of statistical interaction. For example, in the top two pan-
els of Figure 5–​11, there is no interaction on the absolute risk scale,
which implies that there is an antagonistic interaction on the log odds
scale. Similarly, in the bottom panels, there is no interaction on the log
odds scale, which implies that there is a synergistic interaction on the
absolute risk scale. The interpretation of a statistical interaction thus
depends on the choice of outcome scale, and this scale should be cho-
sen with the research goals in mind.
In the context of locus discovery, the goal is not to identify statistical
interaction per se, but to maximize power to detect loci associated with
disease. This has led some to propose scale-​free joint tests of genetic
main effects and interactions, which are geared to detect markers that
are associated with disease in at least one exposure stratum (Aschard
et al., 2010, 2013; Kraft et al., 2007; Lindstrom et al., 2009; Pare et al.,
2010; Soave et al., 2015). Such tests are well powered across a wide
range of alternative scenarios, but may not be optimal to identify those
markers that interact with exposure but have modest marginal effects
(i.e., markers that a standard GWAS might fail to identify). Developing
tests that maximize power to detect statistical interactions (typically
departures from additivity on the log odds scale) is an active area of
research (Boonstra et al., 2016; Cornelis et al., 2012; Dai et al., 2012;
Gauderman et  al., 2013; Hsu et  al., 2012; Mukherjee et  al., 2012;
Thomas et al., 2012).
When the goal is to identify individuals or groups who might dis-
proportionately benefit from an intervention, the absolute risk scale
is the natural choice: departures from additivity in this case implies
that the change in disease risk due to a change in exposure depends on
individuals’ genotypes (see Figure 5–​11, panel [c]). Consequently, the
absence of interactions on the log-​odds scale (as is typically reported)
is potentially an interesting result, as it implies a supra-​additive inter-
action on the absolute risk scale.
Finally, there is no scale that would allow one to make universal
inferences about the underlying biological mechanisms through which
genotype and exposure influence disease; statistical interaction need
not imply biological interaction, and vice versa (Siemiatycki and
Thomas, 1981; Thompson, 1991). Ideally, in the setting where the
putative biological effects of genotype and exposure are known or sus-
pected, one could develop a falsifiable hypothesis about what the dis-
tribution of disease risks would look like across genotype-​by-​exposure
strata, and then test whether the observed data were consistent with
that hypothesis. But in the setting of a GWAS, where the biologic
68

68 Part I:  Basic Concepts

(a) (b)

0.5 0

Log odds of disease

Risk of disease
Carrier

Noncarrier

0 –3

Unexposed Exposed Unexposed Exposed

(c) (d)

0
0.5

Log odds of disease

Risk of disease

0 –3

Unexposed Exposed Unexposed Exposed

Figure 5–​11.  Two gene–​environment interaction scenarios for a binary disease, binary genotype, and binary exposure, and their representations on two
different scales. Panels (a) and (b) assume “no additive interaction” (i.e., no departure from an additive gene–​environment interaction model on the absolute
scale). Panel (a) shows this scenario on the absolute risk scale; panel (b) shows the same four disease probabilities on the log odds scale. Panels (c) and
(d) assume “no multiplicative interaction” (i.e., no departure from an additive gene–​environment interaction model on the log odds scale). Panel (c) shows
this scenario on the absolute risk scale, and panel (d) shows it on the log odds scale.

function of a tested SNP is typically unknown, it is very hard to infer a
SNP’s biologic function from the presence of statistical SNP–​exposure
interaction.
Empirical results on gene–​environment interactions in cancer have
been mixed. There are a handful of long-​established examples from
candidate gene studies involving variants known to alter the metabo-
lism of a carcinogen. These include a variant in NAT2 interacting with
smoking exposure to influence risk of bladder cancer (Garcia-​Closas
et al., 2005, 2013b; Rothman et al., 2007) and variants in ALDH and
ADH genes interacting with alcohol to influence risk of esophageal
squamous cell carcinoma (Brooks et al., 2009; Cui et al., 2009; Hashibe
et al., 2008; Wu et al., 2012). A review of the candidate gene literature
prior to 2013 found little compelling evidence for gene–​environment
interactions outside of these two examples, although modest sample
sizes, combined with gaps in the studied genes, exposures, and can-
cers, make these results difficult to generalize (Simonds et al., 2016).
Genome-​ wide screens for variants involved in gene–​ environment
interactions in cancer have been inconclusive. A number of possible
interactions have been identified, including several affecting risk of
colorectal cancer:  an interaction between a variant near CYP24A1
and hormone therapy affecting colorectal cancer risk (Garcia-​Albeniz
et  al., 2016)  and an interaction between a variant near MGST1 and
aspirin use (Nan et  al., 2015). Most of the suggestive interactions
from GWAS need to be replicated (Du et al., 2014; Figueiredo et al.,
2014; Figueroa et al., 2014; Garcia-​Albeniz et al., 2016; Gong et al.,
2016; Rudolph et al., 2013; Wu et al., 2012). Evidence for departures
from a multiplicative gene–​environment odds ratio model involving
GWAS-​identified risk variants has also been modest, either consider-
ing risk variants alone or aggregated in a genetic risk score (Campa
et al., 2011; Joshi et al., 2014; Kantor et al., 2014; Lindstrom et al.,
2011; Nickels et al., 2013; Pearce et al., 2013; Rudolph et al., 2016).
However, as noted earlier, absence of departures from additivity on
the log-​odds scale typically implies departures from additivity on
the absolute risk scale, and this has potential implications for risk-​
stratified public health and clinical interventions (Garcia-​Closas et al.,
2013b; Maas et al., 2016; Siemiatycki and Thomas, 1981). There are
a number of possible reasons for the relative paucity of identified
gene–​environment interactions in cancer, including the need for large
sample sizes to detect modest interaction effects, exposure measure-
ment error, lack of data on exposure during relevant time windows,
and limited range of exposure variability in the populations studied
to date (Hutter et al., 2013; Kraft and Aschard, 2015; Simonds et al.,
2016). Efforts to improve the power of gene–​environment interaction
studies in cancer have largely focused on increasing the sample size,
study diversity, and exposure measurement. A  better understanding
of the biologic mechanisms driving known population-​level associa-
tions may also help identify specific exposures likely to be involved in
gene–​environment interactions.
 69
Genetic Epidemiology of Cancer 69
Biological Mechanisms
Now that hundreds of risk alleles have been associated with cancer
risk, the current challenge is to determine the biological function of
these variants. The significant variants identified from GWAS may
not actually be the causal SNPs; it is likely that they are only cor-
related with the true causal SNP. In an attempt to identify the causal
variant, fine mapping of the region is performed (Darabi et al., 2015;
Edwards et  al., 2013; Ghoussaini et  al., 2016; Glubb et  al., 2015;
Meyer et al., 2013; Painter et al., 2016a). This can be accomplished
using publicly available resources such as the 1000 Genomes Project,
as well as by performing additional resequencing or dense genotyping
of the region. With these data, all SNPs in LD with the GWAS vari-
ant will be identified. Depending on the LD structure, this may result
in numerous plausible causal variants. The differences in LD struc-
ture across ethnic groups can potentially help to narrow the region
of interest (Franceschini et  al., 2016; Han et  al., 2015a; Lindstrom
et al., 2016; Liu et al., 2014; Wu Y et al., 2013). Additionally, detailed
annotation of the functional elements of the genome (enhancers, tran-
scription factor binding sites, etc.) is available through resources like
ENCODE (Encode Project Consortium, 2012; Schaub et al., 2012).
Tools such as PAINTOR (Kichaev et  al., 2014, 2016), HaploReg
(Ward and Kellis, 2016), and funciSNP (Coetzee et al., 2012; Hazelett
et al., 2014; Rhie et al., 2013) incorporate information on the strength
of the association and the potential function of the genomic location
in order to prioritize candidates within the identified list of possible
causal variants.
The next step is to characterize the function of the putative causal
variants (Freedman et al., 2011). Functional characterization of these
SNPs can involve many different types of studies and data. The major-
ity of significant GWAS loci are in non-​coding regions, so their func-
tion and the gene they impact are not generally obvious. However,
that many are located in potential gene regulatory regions helps to
guide functional studies. Many risk variants function as expression
Quantitative Trait Loci (eQTLs), loci that are associated with tran-
script abundance. eQTLs can be either located near the gene they
influence, or far from it (even on a different chromosome); however,
eQTLs near a gene typically have a larger effect than those that are
distant. An important consideration is that many eQTLs may be tissue
specific. The GTEx (Genotype-​Tissue Expression) project has created
a publicly available database of gene expression across numerous nor-
mal tissue types to address the issue of tissue specificity (http://​www.
gtexportal.org/​home/​) (The GTEx Consortium, 2015). However, gen-
eration of data for additional tissue and cell types may be necessary
depending on the cancer being studied. Another consideration is that
eQTLs may be context and timing specific, such that it is difficult to
obtain data from the relevant time period and environmental condi-
tions. Once a candidate gene is identified, more functional studies,
including in vitro cancer models to determine the gene’s impact on the
cells behavior, are warranted.
SUMMARY
Our knowledge of the inherited genetic contribution to cancer risk
has expanded tremendously over the last 10 years, from a handful of
very rare high-​risk mutations affecting a small proportion of the pop-
ulation to hundreds of modest-​effect alleles influencing risk across
the entire population. These advances have opened up many new
research questions, from basic biology—​understanding the mecha-
nisms through which genetic variation influences carcinogenesis and
progression—​to clinical and public health practice—​for example,
using genetic risk information for precision prevention, screening, or
treatment. At the same time, much remains to be learned about the
genetic architecture of cancer: much of the apparent inherited com-
ponent of risk remains unidentified, even for cancers that have been
studied in very large sample sizes, and the genetic contribution to can-
cer risk in non-​European populations remains understudied. Current
evidence is consistent with the hypothesis that a mixture of rare high-​
risk and common moderate-​risk alleles contributes to the unidentified
familial risk (“missing heritability”). This suggests that a range of
study designs is needed to discover new risk variants, including larger
GWAS (especially for non-​European ancestry populations and for
cancers where the current sample sizes are small) and population-​
and family-​based whole-​exome and whole-​genome sequencing stud-
ies. Methodological lessons from the last 10  years—​including the
importance of well-​powered studies, and appropriate consideration of
multiple testing or low priors—​will continue to be relevant. Although
current costs for whole-​exome and whole-​genome sequencing make
some study designs prohibitively expensive now, a combination of
clever use of existing data and alternate technologies (e.g., impu-
tation) and technological developments (cheaper sequencing) will
provide opportunities for future advances. The next 10 years should
bring quantitative and qualitative changes to our understanding of the
inherited genetic contribution to cancer risk, as we discover more risk
variants and better understand their biologic effects.
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 7
6 Application of Biomarkers in Cancer Epidemiology
ROEL VERMEULEN, DOUGLAS A. BELL, DEAN P. JONES, MONTSERRAT GARCIA-​CLOSAS,
AVRUM SPIRA, TERESA W. WANG, MARTYN T. SMITH, QING LAN,
AND NATHANIEL ROTHMAN
OVERVIEW
Advancements in OMICs (e.g., genomics, epigenomics, transcrip-
tomics, metabolomics, adductomics, proteomics) have enabled inves-
tigators to explore comprehensively the biological consequences of
exogenous and endogenous exposures, to detect (1) molecular sig-
natures of exposure, (2) early signs of adverse biological effects, and
(3) preclinical disease, and (4) to further classify subtypes of can-
cer at the molecular level. These new technologies have proven to
be invaluable for assembling a comprehensive molecular portrait of
human exposure, health, and disease. This includes hypothesis-​driven
biomarkers, as well as platforms that can comprehensively analyze
entire biologic processes and “compartments” agnostically, includ-
ing the measurement of small molecules (metabolomics), DNA
polymorphisms, and rarer inherited variants (genomics), methyla-
tion and microRNA (epigenomics), chromosome-​wide alterations,
mRNA (transcriptomics), proteins (proteomics), the microbiome
(microbiomics), and other biologic components within the human
body. Although the implementation of these technologies in cancer
epidemiology already has shown great promise, some challenges of
particular importance still need to be addressed to exploit the full
potential of these platforms. Non-​genetic OMICs markers vary over
time; therefore there is an urgent need for cohorts to collect and repeat
biological samples over time. In addition, due to the growing insights
that early-​life events have great importance for disease development
later in life, it is desirable to follow up cohort studies of children
and adolescents with biologic samples over their lifetime. As there
is growing evidence that many of the OMIC signals are tissue or
cell-​specific, more insights in transferability of OMIC signals across
organs, tissues, and cells are necessary. Lastly, the use of these high-​
dimensional platforms will result in vast amounts of interconnected
data. Therefore, procedures and methodologies to collect, manage,
and analyze such data will need to be generated.
INTRODUCTION
As noted in the third edition of Schottenfeld and Fraumeni’s Cancer
Epidemiology and Prevention, the prediction that biomarkers are
increasingly being incorporated into cancer epidemiology (Garcia-​
Closas et al., 2006) has truly materialized in the last decade. A search
in PubMed of the keywords “epidemiology,” “biomarkers,” and “can-
cer” provides us with a convincing picture of a steady increase in the
number of studies incorporating biomarkers in cancer epidemiology
research, with a sharp increase in the number of publications after
2010 (Figure 6–​1).
This trend follows quite well the technological advances that have
been made in array and sequence-​based OMICs analyses where the
number of markers being measured can be described by an exponential
function following closely Moore’s law (Figure 6–​2).
Since the publication of the third edition of Cancer Epidemiology
and Prevention, many of the OMICs technologies have been marked
by tremendous progress in the collection, analysis, and interpretation
of OMICs data. In addition, new OMICs technologies have emerged
(e.g., adductomics, microbiomics). In the previous edition of this
chapter we described (1) how biomarkers could be used in epidemio-
logical studies, (2) the importance of accurate biomarker characteriza-
tion, including knowledge about inter-​individual and intra-​individual
variability in biomarker response, and (3) how laboratory assay vari-
ability could impact the biomarker disease associations. These fun-
damentals, rooted in measurement error theory, still apply in the era
of large-​scale OMICs analyses, with the exception that for non-​fixed
biomarker endpoints we now need to assess the distribution of inter-​
individual, intra-​individual, and laboratory variability for hundreds to
thousands of signals before commencing a study. As such, the inter-
pretation of studies using high-​dimensional platforms should be done
with some care where positive findings may have meaning (i.e., if
replicated and biases can be excluded) but where null findings have
limited meaning. In the absence of knowing the intraclass correla-
tions coefficients (ICCs  =  intra-​individual variance /​total variance)
of these null findings, an interpretation of the findings cannot be given
and subsequent pathway analyses may be biased. (For a more detailed
discussion on the effect of measurement error on the interpretation of
molecular data, see Garcia-​Closas et al., 2006; International Agency
for Research on Cancer [IARC], 2011).
In the current update of the chapter we focus on describing these
new generations of high-​dimensional OMICs technologies and dis-
cuss their implementation in the analysis of non-​germline biomarkers
in healthy tissue in epidemiological studies, with a focus on etio-
logic studies. A  discussion of infectious, nutritional, immunologic,
germline, and somatic tumor markers is provided in Chapters  2–​4,
5, 19, 24, and 25, respectively, of the current textbook. Biomarkers
to assess other categories of exposures and lifestyle factors are
described in additional chapters. For a comprehensive review of con-
ceptual issues in the application of biomarkers in epidemiological
studies, a detailed discussion of technologies used to measure a wide
range of biomarkers, and their application in epidemiologic studies,
see the textbook Molecular Epidemiology: Principles and Practices
(IARC, 2011).
BIOMARKER CATEGORIES
Classically, biomarkers have been classified in discrete entities along
the pathway from exposure to disease. The National Research Council
in 1987 (Committee on Biological Markers of the National Research
Council, 1987) subdivided the process into markers of (1) exposure,
(2)  internal dose, (3)  biologically effective dose, (4)  early biologi-
cal effect, (5)  altered structure or function, and (6)  clinical disease;
each of these steps could be influenced by host susceptibility, includ-
ing genetic traits and effect modifiers (e.g., social economic status,
gender, or diet) (Figure 6–​3). This framework has been very useful
in the pre-​OMIC era, where many of the hypothesis-​driven markers
measured fit in these discrete steps with, for example, urinary metabo-
lites reflecting internal dose, DNA adducts biologically effective dose,
cultured peripheral lymphocyte chromosomal aberrations reflecting
early biological effects, and tumor mutations in specific genes reflect-
ing the disease. However, in the era of OMICs these distinctions
have become less clear, as many of these technologies may measure
more than one process. For example, metabolomics has been used
77
78

78 Part I:  Basic Concepts

1600

1400

1200

Number of publications
1000

800

600

400

200

0
1985 1990 1995 2000 2005 2010 2015 2020
Year

Figure 6–​1.  Number of publications based on the keywords “epidemiology,” “biomarkers,” and “cancer” in PubMed.

to measure both exogenous exposures and biological effects (Jones,
2016). Likewise, epigenetic changes have been linked to both exog-
enous exposures, early biological effects, and disease (Guida et  al.,
2015; Joehanes et al., 2016; Shenker et al., 2013). These new technolo-
gies therefore provide, on one hand, the unique opportunity to truly
measure the exposures and associated biological processes across the
continuum from exposure to disease; on the other hand, because of
the fact that they reflect potentially different steps of the multistage
process from exposure to disease, interpretations may not always be
straightforward, and questions concerning the specificity of the signals
will need to be answered. Of course the major scientific leap that has
been offered by OMICs technologies is the change from hypothesis-​
driven marker research to agnostic screening of hundreds to hundreds
of thousands of biological markers (Figure 6–​2). This now allows, as
in genomics, broad screening of biomarkers along the continuum from
exposure to disease. It furthermore allows the integration of signals at
different levels of biological regulation, providing a comprehensive
multidimensional picture of disease mechanisms. The use of OMICs
technologies to measure an exposure either directly or by its imprints
in the biological system has been termed exposomics and may enhance
exposure assessment (Vineis et  al., 2016; Wild, 2005, 2012)  and at
the same time provide mechanistic insights (Figure 6–​3). Other bio-
markers, often more downstream in the exposure–​disease continuum
and lacking identifiable exposure specificity, can provide mechanis-
tic insights and, potentially, have clinical applications (Figure 6–​3).
At the same time, with the availability of next generation sequenc-
ing data on whole exomes and whole genomes from a wide range of
tumors, and the application of new bioinformatic methods, a series
of mutational signatures have recently been identified that have been
linked to a number of exposures, including particularly striking and
consistent findings from certain components of tobacco smoking
(Alexandrov et al., 2016). This suggests that full characterization of

Development of OMIC technologies

10,00,00,000 10000000

100,00,000 1000000
Number of Analytes (other OMICs)

10,00,000 100000
KB per Day (Genomics)

100,000 10000

10,000 1000

1000 100

100 10

10 1

1 0.1
1996–2000 2001–2005 2006–2010 2011–2015 2016–2020

Genomics Epigenetics Metabolomics Adductomics Proteomics

Figure 6–​2.  Number of KB per day and analytes per day for the different OMICs platforms by 5-​year intervals.
 79
Application of Biomarkers in Cancer Epidemiology 79
Internal
Exposure
dose
Exposure Assessment
(Exposomics)
Genetic/other sources
of susceptibility
Figure 6–​3.  Defining a continuum of biomarker categories that reflect the carcinogenic process.
somatic alterations in tumors could provide important information for
at least some of the exposures that drive cancer risk. The use of mark-
ers to identify mechanisms of disease and for early detection is the
domain of mechanistic and clinical research. In exposomics, the inten-
sity, duration, persistence, and specificity of the exposure signal are
the most important characteristics of a successful exposure marker. In
the next section we discuss several of these new technologies and their
implementation in cancer epidemiology.
NEW BIOMARKER TECHNOLOGIES
Metabolomics
Metabolomics refers to the study of small molecules, typically with
molecular mass less than 2000 Dalton. This includes the molecular
fuels and building blocks for all macromolecular components, as
well as degradation and waste products generated by the body and
exogenous chemicals that can cause or protect against carcinogene-
sis, including non-​nutritive components of food, microbiome-​related
metabolites, drugs and related metabolites, and commercial and envi-
ronmental chemicals.
Contemporary metabolomics builds upon a strong history of ana-
lytical chemistry, which provides capabilities for the targeted analysis
of most metabolites and chemicals known to be relevant to cancer.
Recent studies have yielded promising leads (Armitage and Barbas,
2014) from targeted and non-​targeted analyses with mass spectrome-
try (MS), nuclear magnetic resonance (NMR) spectroscopy, and other
analytical approaches. Targeted methods are often used to test specific
hypotheses, while non-​targeted methods are used in an agnostic man-
ner to search for differences between groups or associations with other
variables. Both approaches are useful, but more powerful analytic
methods now enable the measurement of thousands of chemicals in
biologic samples, and some believe that tens of thousands will become
practical as human exposome research develops (Uppal et al., 2016).
Terminology can be confusing for metabolomics because some
methods provide a single signal derived from multiple chemicals,
while others give multiple signals from one chemical. Additionally,
some data are provided with absolute measures of abundance, while
others provide only relative quantification. In discussion of data, the
term metabolite is often used generically to refer to any small mol-
ecule in a living organism, regardless of origin. The term feature
or metabolic feature is used to refer to something measured, which
has insufficient characterization to determine whether it represents a
known chemical, a mixture of chemicals, or a product of a chemi-
cal generated during the assay (Miller and Jones, 2014). The Human
Metabolomics Database (HMDB), available at http://​www.hmdb.ca, is
an important resource for human metabolomics data; it contains infor-
mation on common metabolites and their concentrations in biologic
materials.
Only about 2000 metabolites are present in central human meta-
bolic pathways of the Kyoto Encyclopedia of Genes and Genomes
(KEGG), but the combined resources of KEGG, HMDB, Metlin, and
Early Altered
biological structure/ Disease
effects functions
Mechanistic/Clinical
others, contain more than 50,000 metabolites. The total number of
metabolites appears to be more than one million when including the
large number of lipids, complex carbohydrates, phytochemicals, and
environmental chemicals. Uncertainties in chemical identification and
quantification discussed earlier, along with limitations in databases
and knowledge bases, necessitate caution at every step in analysis and
interpretation. Additionally, because of the multiple and changing ana-
lytical platforms, extra effort is warranted in providing metadata for
sample collection, processing, and analysis, to facilitate evaluation of
reproducibility between studies.
High-​Resolution Metabolomics for Exogenous
and Endogenous Exposure Screening
Due to its large dynamic range, metabolomic measurements now cover
both exogenous (environmental, occupational, lifestyle) and endoge-
nous molecules. This allows metabolomics to be used to directly meas-
ure not only internal doses of exogenous and endogenous compounds,
but also the biological perturbations these exposures have on the bio-
logical system. An example of using metabolomics to measure the
internal dose of exogenous compounds can be found in Walker et al.
(2016), where, in a population of individuals occupationally exposed
to trichloroethylene (TCE), an industrial degreasing agent and envi-
ronmental contaminant, known and unknown TCE metabolites in
plasma were identified. Subsequently, these TCE metabolites were
linked to metabolites and biological measures indicative of immune-​
and nephrotoxicity, two known adverse-​outcome-​pathways of TCE.
This proof-​of-​principle study provides promise that metabolomics is
able to screen broadly for exogenous compounds and that interactions
of these compounds with adverse-​outcome-​pathways can be identified
(Figure 6–​4).
High-​Resolution Metabolomics for Cancer
Many putative biomarker candidates have been found to differ in
tissue-​specific cancer studies (Armitage and Barbas, 2014). These
include a diverse range of metabolic pathways, which could imply that
different tissue-​specific tumors have very different metabolic char-
acteristics and/​or that adaptive responses to cancer and cancer treat-
ments are heterogeneous. Some studies show that citric acid cycle,
glycolytic metabolites and ketone bodies differ, as expected from the
well-​known Warburg effect (Allegra et al., 2016). In addition, many
of the essential amino acids (phenylalanine, tryptophan, lysine, his-
tidine, isoleucine, leucine, valine, methionine, threonine) as well as
non-​essential amino acids (glutamine, glutamate, alanine, aspartate,
glycine, tyrosine, cysteine), differ for cancer at different sites. Amino
acid metabolites (4-​ hydroxyphenylacetic acid, homovanillic acid,
5-​hydroxyindoleacetic acid, hydroxyproline, isovaleric acid, tau-
rine) also differ, as do some nucleotides, purines (methyladenosine;
hypoxanthine, 8-​hydroxydeoxyguanosine), and pyrimidines (uridine,
methyluridine, 5-​hydroxymethyl-​2-​deoxyuridine). Additional meta-
bolic differences include formate, putrescine, bile acid metabolites,
and metabolites from a range of lipid pathways (free fatty acids, ultra
long-​chain fatty acids, oxidized fatty acids, acylcarnitines, phosphati-
dylcholines, sphingolipids, gangliosides, retinol). The information to
80

80 Part I:  Basic Concepts

Immune responsive biomarkers
TCE exposure biomarkers

Correlation coefficient

–0.7 0 0.6

Urinary TCE exposure biomarker

Urinary renal biomarker
Renal damage biomarkers Immunological markers
Unidentified halogenated m/z, by isotope pair
Identified metabolite

Figure 6–​4.  Network correlation analysis of molecular markers previously tested for association with TCE exposure and metabolic features detected
in this study. Only correlations with Spearman |r| ≥ 0.3 and p-​value ≤ 0.05 corresponding to identified metabolites or probable halogens were included.
Immune markers: CD4 = CD4+ T-​cell count; IgG = immunoglobulin G; IgM = immunoglobulin M; LY = lymphocyte cell count; mtDNA = mitochondrial DNA
turnover rate; sCD27 = soluble CD27; sCD30 = soluble CD30; WBC = white blood cell count. Nephrotoxicity markers: aGST = urinary α glutathione-​s-​transferase;
piGST = urinary pi glutathione-​s-​transferase; KIM1 = urinary kidney injury marker 1; NAG = urinary n-​acetyl-​beta-​glucosaminidase. TCE exposure markers: Conj.
TCEOH = urinary trichloroethanol glucuronide; Free TCEOH = urinary trichloroethanol; Tot TCEOH = sum of urinary trichloroethanol and trichloroethanol gluc-
uronide; TCA = urinary trichloroacetic acid. Source: Walker et al. (2016).

date suggests that metabolic responses to cancer and cancer treatment
are too complex to expect single metabolic biomarkers to approach the
utility of some genetic and proteomic markers.
Despite this, the cumulative findings provide a foundation for
improved experimental and analytical design and point to new stra­
tegies for biomarker development. The data show that differences
exist in most of the essential amino acids. Protein synthesis requires
essential amino acids for rapid cell growth, so the data indicate that
differences in circulating essential amino acid concentrations could
reveal characteristics of tumor vulnerability to anti-​metabolites that
disrupt essential amino acid transport or utilization. Essential amino
acid metabolism is directly linked to the mTOR pathway, known to
be responsive to growth factors, nutrients, energy and stress signals,
and essential signaling pathways, such as PI3K, MAPK and AMPK,
to control cell growth, proliferation, and survival. Inhibitors of mTOR
are under active investigation for tumor therapeutics, and the metabol-
omics data suggest that some of the essential amino acids may prove
to be useful biomarkers for therapeutic efficacy, as well as indicators
of useful targets to complement mTOR inhibitors with inhibitors of
essential amino acid utilization.
Differences in non-​essential amino acids may also provide useful
predictive biomarkers for the use of therapeutic adjuvants. Glutamine
is an anabolic amino acid linked to IGF-​1 signaling that inhibits apop-
tosis and supports tumor cell growth. Glutamate and aspartate are
mitochondrial energy substrates, but perhaps more important, nucle-
otide biosynthesis depends upon these amino acids. Non-​essential
amino acids also provide a sparing effect for glucose, which is needed
for NADPH supply for rapid cell growth. Cysteine is a precursor for
the antioxidant GSH, also known to support tumor resistance to cancer
therapeutics. Thus, like the essential amino acids, the non-​essential
amino acids could provide useful biomarkers for therapeutic efficacy,
as well as useful targets to complement therapeutics targeting IGF-​1-​
related signaling pathways.
Similar arguments can be made for mitochondria-​related metabo-
lites and other metabolites found to differ in cancer studies.
High-​Resolution Metabolomics for Cancer
Therapeutics
As precision medicine methods are developed, metabolomics is
assuming a central role because of the central role of metabolism
in bioenergetics, catabolism, and anabolism. Newer high-​resolution
methods are likely to play an increasingly important role because the
cost for analysis of > 10,000 metabolic features is less than that for
analysis of 300 metabolites by more conventional methods. A major
difference is the use of computational methods for data extraction
(Yu et al., 2013). With ultra-​high resolution MS, rigorously defined
chromatographic procedures, and replicate analyses of single sam-
ples, improved detection and reproducibility are obtained. With this
approach, unidentified features (ions) can be defined in terms of m/​z
(mass-​to-​charge ratio), retention time (seconds), and ion intensity.
For features that are present in a pooled reference sample, such
as NIST SRM1950 from the National Institute of Standards and
Technology, identity can be retrospectively assigned upon curation
of the pooled reference. Recent advances further establish a refer-
ence standardization protocol to quantify chemicals that are con-
firmed and quantified in a pooled reference analyzed concurrently
with unknown samples. In principle, this can be used for hundreds
to thousands of metabolites and includes most of the amino acids,
water-​soluble vitamins, and a broad spectrum of energy metabo-
lites, lipids, metabolic degradation products, and markers of organ
function.
 81

Application of Biomarkers in Cancer Epidemiology 81

Key issues for the use of high-​resolution metabolomics data for
epidemiology are similar to those faced for other OMICs technolo-
gies and include the need to protect against false discovery from large
numbers of statistical tests, the means to include unidentified measures
into analysis, and strategies to link multiple significant features into
common conceptual models. Large numbers of tests are often sum-
marized in terms of a metabolome-​wide association study (MWAS)
(Figure 6–​5(a)) in which the negative log p is plotted against the m/​z
or chromatographic retention time, analogous to genome-​wide associ-
ation study (GWAS).
In a standard workflow, selected features are used with a clustering
algorithm (e.g., hierarchical cluster analysis; HCA) or principal com-
ponent analysis (PCA) to determine how effectively individuals are
classified or separated by the selected features (Figure 6–​5(c)). Insight
into underlying disease etiology and therapeutic mechanisms can be
obtained from the metabolomics data using additional biostatistics,
bioinformatics, and pathway analysis tools (Figure 6–​5(d)).
As indicated earlier, an important advantage of high-​resolution
metabolomics is that measures are included for most metabolic
pathways, which is an advantage over the more targeted analyses
using platforms such as Biocrates ​or Brainshake. Thus, data are often
obtained with many apparently significant features, many of which
have not been curated and all of which could be true or could repre-
sent false discovery. Some aspects, such as multiple features derived
from one chemical, deviate from assumptions upon which statistical
methods are based. Thus, statistical tests and respective p values may
be better viewed as a way to prioritize features for more detailed
examination. With this in mind, one has a choice to select the top fea-
tures using either raw p value or false discovery rate (FDR) threshold
criteria. An advantage of the former is that all of these features pass
threshold criteria for significance (i.e., this list includes all features
that truly differ). The disadvantage is that there is certainty that many
of these have been detected by chance. To overcome this limitation,
one can use pathway enrichment to test for significant pathways. For

(a) MWAS of TB disease (b) Selected metabolites that differ

m/z 148.0594 m/z 399.2116 m/z 801.5767

9 Glutamate D-series resolvins αTrehalose-6-mycolate
6 20 20
8

Log (2) Intensity

7
0
6

5 0 0
– log P

–6 –4 –4
4
m/z 851.5953 m/z 237.0192 m/z 271.2319
Phosphatidylinositol Unidentified Unidentified
3 20 20 6
2
Log (2) Intensity

0
1

0
0
200

800

1400

2000

0
–1 –4 –16
HC TB HC TB HC TB
m/z

(c) 2-Way hierarchical cluster analysis

(d) KEGG Brite Classification

Raw Z Score
Color Key 5%
3%

–2 0 2
17% Commercial products

Control Environmental chemicals

1
Intermediatory metabolites
TB 47%
2 2% Microbial metabolites
3 Pharmaceuticals
m/z Clusters

4 Plant-derived metabolites

5 17%

6
7 9%
8

Figure 6–​5.  High-​resolution metabolomics workflow. (a) An MWAS was performed for pulmonary tuberculosis (TB) patients compared to uninfected
household controls. Respective broken lines, from bottom: raw p = 0.05; FDR = 0.2; FDR = 0.05. (b) Selected metabolites that differ in A are plotted using
box and whiskers plots. (c) Two-​way hierarchical cluster analysis of metabolites that differ in A shows that the metabolites separate the individuals and
that the metabolites are associated into clusters. (d) Use of the Kyoto Encyclopedia of Genes and Genomes (KEGG) Brite Classification of metabolom-
ics database matches gives a depiction of the types of chemicals that differ between patients and controls. FDR: false discovery rate. Source: Data are from
Frediani et al. (2014).
82
82 Part I:  Basic Concepts
instance, by testing all features significant at raw p < 0.05 for enrich-
ment of metabolites in specific pathways relative to that obtained by
a random selection of features from the total feature table, one can
identify pathways of interest. Mummichog (Li et al., 2013) is a pro-
gram designed to facilitate the use of high-​resolution data by using
all selected features to test for pathway enrichment without require-
ment for chemical identity prior to statistical analysis.
An alternative approach uses features that achieve a desired FDR
threshold along with MetabNet (Uppal et  al., 2015), a program that
tests for features that are significantly correlated with selected metabo-
lites. This approach is based upon the observation that the concentra-
tions of metabolites within a metabolic pathway are often correlated.
By selecting metabolites that are correlated with a feature that is sig-
nificant at an appropriate FDR threshold, pathway enrichment analysis
by Mummichog can provide evidence for important pathways, even for
unidentified features associated with disease. An example is provided
by a pentachlorofuran associated with age-​related macular degenera-
tion (Osborn et al., 2013). In principle, this provides means to detect
pathway associations of unidentified metabolites associated with can-
cer for further evaluation.
Integration of Metabolomics with Other
OMICs Platforms
As indicated earlier, metabolomics data can provide useful insight into
disease etiology, but evolving methods indicate that these data may
be even more useful in combination with phenotypic markers and/​or
genomics, transcriptomics, and other OMICs data. Two advantages are
evident from schema describing the functional genome and its interac-
tions with the environment (diet, microbiome, chemical exposures). First,
the metabolome includes metabolic products of the other components
of the functional genome. This means that metabolic associations with
genetic, epigenetic, transcription, or proteomic variation can be used
to infer functional relationships. Thus, corresponding metabolic asso-
ciations can provide insight into genome or transcriptome associations
with cancer. A second advantage is that the metabolome includes dietary,
microbiome-​related, and environmental chemicals. These metabolites
provide measures of exogenous influences relevant to cancer.
In summary, an accumulating literature demonstrates potential for
metabolomics to provide new cancer biomarkers. While well founded,
this interpretation also must be viewed within the reality of the com-
plexity of cancer. At the very best, metabolomics biomarkers could be
useful to define risk of cancer, to support early detection of cancer, to
improve ways to predict benefit and risk from specific treatment strat-
egies, and to provide means to follow treatment efficacy and disease
progression. At the very worst, however, failed biomarkers can mislead
in cancer prevention, cause misdiagnosis, contribute to cancer develop-
ment and progression, or misinform clinicians and patients concerning
treatment efficacy and disease progression. These realities force caution
and skepticism in the quest for metabolomics biomarkers for cancer.
Epigenetics
Epigenetics is the transmission of gene regulatory information from
parent cell to daughter cell (either germline or somatic) via modifi-
cations of cytosines in DNA or histones rather than DNA sequence
(Bernstein et al., 2007). Epigenomic studies examine this information,
be it DNA methylation or histone modification (chromatin state) pat-
terns, at a genome-​wide scale (Fazzari and Greally, 2004). As with
other biomarkers, epigenetic measurements have potential for detect-
ing signatures of exposure, early signs of cellular pathology, dis-
ease susceptibility, or preclinical disease (Feinberg and Fallin, 2015;
Joubert et al., 2012; Nelson et al., 2011; Reynolds et al., 2015). Rather
than comprehensively annotating many studies, we will outline gen-
eral concepts and principles for epigenetic studies in populations and
review several examples.
Transmission of Epigenetic Information
Normal development and differentiation of embryonic cells into tis-
sues involve dynamic, concerted genome-​wide changes of DNA meth-
ylation, chromatin state, and transcription, and the subsequent turning
on or off of expression of lineage-​determining transcription factors
(see Figure 6–​6 for a simplified depiction) (Bernstein et  al., 2007;
Gifford et al., 2013; Ziller et al., 2013).
New patterns are established by de novo methyltransferases and
histone-​modifying complexes, and once these are established, cell-​
type identity is preserved by epigenetic maintenance factors. Signals
from the environment (diet, metabolic stress, or exposure-​related) can
perturb these epigenetic patterns over a short period of time (Philibert
et al., 2012), such as during fetal development (Joubert et al., 2012,
2014; Marsit, 2015)  and the effects may be transient or persistent
(Richmond et  al., 2015; Tobi et  al., 2014; Wan et  al., 2012). Aging
drives epigenetic changes in blood and tissues (Horvath, 2013), and
these changes have been associated with mortality (Marioni et  al.,
2015). It has been proposed that environmentally caused epigenetic
changes may be an important mechanism connecting exposure to later
chronic disease risk (Barker and Clark, 1997; Heijmans et al., 2008;
Herceg et al., 2013; Tobi et al., 2014). In animal model systems there
is some evidence that epigenetic effects may persist across multiple
generations (Jirtle and Skinner, 2007; Rando and Verstrepen, 2007).
Tumor studies have demonstrated that tumor-​associated epigenetic
patterns, including epigenetic inactivation of tumor suppressor genes,
are transmitted as part of clonal growth and, along with somatic muta-
tions, are important determinants of the tumor transcriptome and phe-
notype (Christensen et al., 2011; Hansen et al., 2011; Landau et al.,
2014; McDonald et  al., 2011). In addition, characteristics of tumors
include a disorganized epigenetic state, loss of epigenetic lineage
identity, and stem cell-​like proliferative capacity (Hansen et al., 2011;
Jones and Baylin, 2007; Pujadas and Feinberg, 2012).
DNA Methylation, Chromatin State, and
Transcriptomics
Recent studies indicate that each of these interacting features have
genomic patterns that can be used to distinguish cell type, cell lineage,
and disease tissue (Bernstein et al., 2007; Bock et al., 2012; Schubeler,
2015; Thurman et  al., 2012; Ziller et  al., 2013), but each provides
different information and has advantages and disadvantages as a bio-
marker (including methodological). Transcriptome patterns (mRNA,
lncRNA, eRNA, miRNA) are highly informative as to current cell
state, but patterns may be transient and there are many situations when
it is difficult to obtain high-​quality RNA. The ENCODE and Roadmap
Epigenome projects have clearly demonstrated that specific histone
modifications (e.g., H3K4me3) are strongly correlated with transcrip-
tion (Ernst et  al., 2011), while other modifications (H3K27Ac) are
highly correlated with the DNA methylation status of gene regulatory
regions (Ziller et al., 2013). However, chromatin studies have primar-
ily focused on large scale multi-​tissue characterization (Kundaje et al.,
2015) or on mechanisms using model systems (Bernstein et al., 2007).
Techniques that provide more general genome-​wide chromatin state
information (like DNaseI-​sequencing or the transposase-​based ATAC-​
seq) have advanced rapidly and are being applied in larger and larger
studies. But these chromatin approaches are still technically challeng-
ing, relatively costly, and generally require the processing of freshly
isolated cells. Although the relationships are complex, we can assume
that persistent changes of chromatin state and the transcriptome are
likely to be accompanied by altered DNA methylation either within
the promoter, the gene body, or in associated enhancers (Schmidl
et al., 2009; Schubeler, 2015). In addition, the relative ease of use and
cost-​ effectiveness of measuring DNA methylation on microarrays
have rapidly expanded their potential application in population stud-
ies, to detect exposure-​related effects as well as disease susceptibility
(Michels et al., 2013).
Methods for  Measuring 5-​Methylcytosine.  Cytosines in
CpG dinucleotides are either methylated or not; however, the measure-
ment of methylation at a single CpG dinucleotide, or groups of CpGs,
is a continuous variable that is expressed as the ratio or percent of
methylated signal to unmethylated signal (e.g., 0.0–​1.0, or 0–​100%).
Measurement typically involves bisulfite treatment to convert unmeth-
ylated cytosines to uracils, and following amplification of the signal,
 83

Application of Biomarkers in Cancer Epidemiology 83

(a) (b)
Repressed Repressed
CpG Enhancer Promoter
No DNA methylation, chromatin, TF
5mC 5mC Transcription binding, and gene expression change
TSS with lineage commitment
5mCpGs
Gene exon
CpG
TF Binding Sites Promoter Pluripotent Stem Cell
Island

Progenitor Cell

Lineage Specific
Progenitor Cell
+ H3K27me3
DNMT HMT HDAC

TET HDM HAT

Terminally Differentiated Cells

Active Enhancer Active Promoter

eRNA (c) (d) (e)
TF TSS Transcription
5OHmCpG Pol2 Pol2 Exposure Exposure
DNA
Gene exon
Methylation
TF Binding Sites CpG Island Promoter Biomarker of
DNA Methylation Risk or
Biomarker of Preclinical
Pathology Disease
* * * # # # DNA
Pol2 Pol2
Methylation
# # Biomarker
H3K4me3
* H3K27ac
Disease Disease Disease
# H3K4me3

DNMT - DNA methyltransferase, TET - demethylase

HMT - Histone methyltransferase, HDM - Histone demethylase
HAT - Histone acetyltransferase, HDAC - Histone deacetylase

Figure 6–​6.  (a) Repressed enhancers and genes display high levels of DNA methylation, repressive histone modifications (H3K27me3), and no tran-
scription. Conversion to active state is accompanied by demethylation of the enhancer, transcription factor binding, activating histone modification
(H3K27ac, H3K4me3), and transcription. (b) Cell-​type lineage specification is accompanied by the repression and activation of lineage-​specific
genes, particularly transcription factors. (c) Exposure may drive methylation changes that are independent of the disease pathway. (d) Exposure-​
induced change in DNA methylation may represent an intermediate development of disease. (e) Altered DNA methylation in a tissue may be a marker
of susceptibility or an early sign of disease tissue.

these are detected as thymine using genotyping or sequencing meth-
ods. Most assays cannot distinguish 5-​methylcytosine from 5-​hydroxy
methylcytosine (a demethylation intermediate step). About 10% of
the 20 million or so CpGs in the genome are concentrated into CpG
“islands” (CGIs) that are associated with genes. Typically these CGIs
are unmethylated; however, fully methylated CGIs are often a feature
of repressed or silenced genes, and many CGIs become methylated
in differentiated tissues (Fazzari and Greally, 2004). Fully methylated
CpG sequences located in the > 500,000 retrotransposon repeat ele-
ments in the genome are also associated with the repression of expres-
sion of these elements. Global methylation techniques measure the
average level of methylation of all CpGs (or a subsample) across the
genome, and the methylation levels of CpG islands and repeat ele-
ments contribute greatly to measurements of global methylation level.
Important early studies of methylation found tumors to be hypometh-
ylated relative to normal tissue (reviewed in Jones and Baylin, 2007).
The concept that global methylation levels might predict risk has been
pursued in blood DNA, primarily using PCR-​based pyrosequencing
methods that examine CpG methylation in repetitive elements such as
Alu repeats and long interspersed nucleotide elements (LINE; Yang
et al., 2004), which sample the genome in hundreds of thousands of
locations. This approach can detect differences in methylation levels
among controls and cancer cases (Moore et al., 2008), but results from
these studies have not always been consistent (Brennan and Flanagan,
2012; Hsiung et al., 2007; Nelson et al., 2011) and the lack of speci-
ficity is problematic.
Methylation-​ specific polymerase chain reaction (Herman et  al.,
1996) and pyrosequencing (Colella et al., 2003) are both useful tech-
niques for quantifying methylation levels in a small target region.
There are numerous varieties of these approaches (Accomando et al.,
2012; Leng et al., 2012; Ma et al., 2015; Wan et al., 2012). The gold
standard for qualitative genome-​wide CpG analysis is whole genome
bisulfite sequencing (WGBS; Bernstein et al., 2007) to 30–​50 x depth
of coverage. While this technique has primarily been used to character-
ize differences among tumors or purified cell types, it is increasingly
being used to profile different individuals as the cost of sequencing
whole genomes comes down (Hansen et  al., 2011; Kundaje et  al.,
2015; Ziller et al., 2013). At this time, the technical variability and ana-
lytical reproducibility of whole genome sequencing methods have not
been evaluated. Reduced representation bisulfite sequencing (RRBS),
which can measure methylation at several million sites near CpG-​rich
regions, has recently been used effectively in a population study (Tobi
et al., 2014) with validation by PCR-​mass spectrometry. However, the
use of microarrays for reproducibly quantifying CpG methylation lev-
els, such as the 450K Human Methylation or 850K MethylationEPIC
arrays, has revolutionized epigenomic studies in populations, and the
84
84 Part I:  Basic Concepts
newer version provides additional informative CpGs located in gene
regulatory regions.
Epigenomics in  Population Studies. Study designs that
compare differences in DNA methylation between groups of unex-
posed and exposed individuals, or cases and controls, should follow
established GWAS recommendations involving appropriate sample
size, multiple comparisons, or FDR, controlling for population struc-
ture, gender, age, and other demographic variables. However, there
are a number of additional issues that must be considered, and these
have been reviewed in detail (Michels et al., 2013). It is known that
CpGs are the most polymorphic dinucleotides in the genome (Tomso
and Bell, 2003); thus any CpGs that overlap sequence polymorphisms
must be filtered out prior to analyses. Importantly, whereas genotype
will be invariant across tissues, methylation varies dramatically by
cell type and the choice of tissue sample for testing will greatly affect
downstream analysis and generalizability. Methylation arrays may be
subject to batch effects at each of these steps: DNA extraction, bisul-
fite treatment, amplification, and hybridization; therefore normaliza-
tion and batch correction should be applied. Numerous programs are
available for this (Aryee et al., 2014; Morris and Beck, 2015; Morris
et al., 2014; Teschendorff et al., 2013; Zhuang et al., 2012).
Heterogeneity of Cell Mixtures and Limit of Detection.
Whether DNA samples are obtained from a mixture of cells like blood,
or from purified cell types, detecting a methylation difference will
depend on the proportion of cells displaying the altered methylated
state. Thus, to have a stable measurement of unmethylated and methyl-
ated sequences, there must be a sufficient number of intact genomes in
the sample prior to any amplification step. Both technical variation and
limit of detection will be improved if the sample contains DNA from
20,000–​100,000 cells (~0.1–​0.7 μg). If whole blood DNA is analyzed,
DNA methylation changes may represent an expansion of a specific
cell type, a clone of immunologically stimulated cells, or groups of
cells from different lineages that share a similar response, but it may be
that only a specific lineage and small number of cells actually display
altered methylation. In any case, accounting for heterogeneity is nec-
essary to differentiate between methylation differences driven by cell
number or distribution changes, and those associated with the variable
of interest (Houseman et al., 2012, 2015; Jaffe and Irizarry, 2014; Liu
et al., 2013). However, if one knows that the etiology of the disease
involves a specific blood cell type that occurs at low frequency (such
as CD56+ natural killer cells), accounting for cell type heterogene-
ity in whole blood may not help in finding the signal, and it may be
important to enrich for the cell type of interest using flow sorting or
immunomagnetic beads.
Toxicant Exposure-​ Associated Changes in DNA
Methylation.  Studies in model organisms (Jirtle and Skinner,
2007) and human cells (Christensen et al., 2009; Joubert et al., 2012;
Langevin et al., 2011; Marsit, 2015) have clearly demonstrated that a
variety of exposures are associated with altered DNA methylation pat-
terns in non-​tumor cells. As cells respond and adapt to exposure condi-
tions, remodeling of methylation patterns across the genome occurs,
and in blood, specific immune cells may be affected. Exposure-​
induced changes in DNA methylation may represent a useful bio-
marker of exposure that is independent of toxicity or disease (Figure
6–​6(c)), or such change may be functionally intermediate in the dis-
ease process (Figure 6–​6(d)). Individuals displaying exposure-​induced
DNA methylation changes may be at higher risk for developing dis-
ease. The detection of DNA methylation changes as a biomarker of
tobacco smoke exposure has been highly successful, clearly identi-
fying individuals with low levels of exposure, such as in cord blood
(Joubert et al., 2012), and light smokers (Philibert et al., 2012), and
also those with previous exposure such as former smokers (Guida
et al., 2015; Joehanes et al., 2016; Lee et al., 2015; Shenker et al., 2013;
Wan et  al., 2012). Many of these tobacco smoke studies have com-
pared self-​reported smoking, or cotinine levels, with the methylation
changes at various loci (particularly the CpG in AHRR cg05575921),
and find methylation level at AHRR to be a robust biomarker with
regard to misclassification, dose-​response, and time since quitting
(Shenker et  al., 2013). However, as reported by Bauer et  al. (2015)
and Su et  al. (2016), some smoking-​associated differential methyl-
ated regions (DMRs) may be specific to a cell-​type lineage, and this
needs to be considered in the interpretation of results. With regard to
other environmental exposures, relatively few published studies have
both detailed quantitative measurements of exposure (Ruiz-​Hernandez
et al., 2015) and genome-​wide DNA methylation, but the number of
studies is increasing rapidly, particularly for arsenic (Argos et  al.,
2015; Kile et al., 2014; Koestler et al., 2013; Laine et al., 2015; Rojas
et al., 2015; Seow et al., 2014b) and mercury (Maccani et al., 2015).
A number of studies have examined the influence of maternal diet,
including folic acid, and famine on DNA methylation in offspring and
have linked these exposures with various outcomes such as birthweight
and metabolism (Kupers et al., 2015; Steegers-​Theunissen et al., 2009;
Tobi et al., 2014).
Disease Detection and Disease Association.  If changes in
DNA methylation occur in nascent diseased cells, then they may be
useful as an intermediate biological marker of pathology, preclinical
disease, or clinical disease (Figure 6–​6 (e)). The potential benefit of
early detection approaches is enormous, but clinical application will
depend greatly on cross-​validation and characterizing the nature of the
methylation difference. For example, it is important to determine if a
detected methylation effect represents a susceptibility that increases risk
of disease, a response to the presence of diseased cells, or the presence
of actual diseased cells (i.e., circulating tumor DNA). Belinsky and col-
laborators (Belinsky et al., 2005, 2007; Leng et al., 2015; Palmisano
et al., 2000) have developed assays that detect altered methylation sta-
tus of genes involved in lung tumorigenesis and have applied these to
sputum DNA to detect tumors prior to clinical diagnosis. Langevin
et al. identified methylation patterns in blood associated with various
solid tumors (Langevin et  al., 2014) and have recently reviewed the
potential use of epigenetic alterations, including DNA methylation, for
early detection, diagnosis, and assessing risk of lung cancer (Langevin
et al., 2015). Chan et al. (2013) applied bisulfite sequencing to DNA
isolated from plasma from a number of different cancer patients and
proposed this for early detection of cancers. Success of these methods
of early detection will depend very much on additional validation and
predictive accuracy relative to other clinical markers.
Using DNA methylation patterns to detect inherited or acquired
disease susceptibility has important study design requirements. As
pointed out recently (Garcia-​Closas et  al., 2013), prospectively col-
lected samples (preferably > 10 years prior to disease diagnosis) are
critical because the presence of incipient disease may affect the meas-
ured endpoints, in particular, altering immune cell-​type composition.
The rheumatoid arthritis study of Liu et al. (2013), which compares
whole blood DNA from prevalent cases to non-​diseased controls,
presents a striking example. Even after adjustment for gross leuko-
cyte cell-​type changes, more than 50,000 CpGs displayed differential
methylation at genome-​wide significance levels (p <1.2 × 10–​7) and
the authors attribute these changes to the consequences of rheumatoid
arthritis on the immune system.
Identifying specific CpG loci associated with cancer risk at genome-​
wide significance levels has proven difficult, but a number of reports
from prospective studies have described methylation patterns asso-
ciated with breast cancer (Brennan et  al., 2012; Severi et  al., 2014;
van Veldhoven et al., 2015; Xu et al., 2013). Van Veldhoven reported
on WGBS on pooled prediagnostic samples in one cohort and 450K
arrays in two others and found that decreased average methylation
across the genome was associated with risk, particularly in gene bod-
ies (van Veldhoven et  al., 2015). Severi et  al. compared averaged
methylation of functional promoters and regions outside promoters in
breast cancer cases and controls and found that higher methylation of
promoters was associated with increased risk, while higher methyla-
tion of non-​promoter CpGs was protective (Severi et  al., 2014). Xu
et al. reported on a set of 250 differentially methylated CpGs in breast
cancer (FDR Q < 0.05) and calculated prediction accuracy relative to
the Gail model (Xu et al., 2013). In a study looking at a CpGs near
 85
Application of Biomarkers in Cancer Epidemiology 85
2191 microRNAs, Cordero et al. identified a set of CpGs associated
with breast cancer in the EPIC study (Cordero et al., 2015).
The application of epigenetic analysis to population studies of expo-
sure, disease detection, and disease risk is increasing rapidly, and as
the science evolves along with the technology and analysis methods,
this approach is likely to produce important research discoveries and
useful biomarkers.
Transcriptomics
As previously mentioned, high throughput OMICs technologies are
invaluable for assembling a comprehensive molecular portrait of
human health and disease. This section will focus on transcriptomics,
or the study of total RNA in a cell or tissue (Willingham and Gingeras,
2006). In the previous edition of this chapter, transcriptomics was still
an emerging concept with promising yet limited applications. The
decade following its publication has been marked by tremendous prog-
ress in the collection, analysis, and interpretation of transcriptomic
data. Specifically, characterization of the human transcriptome across
a spectrum of chronic diseases has been instrumental for the identifica-
tion of clinical subtypes in cancer (Bhattacharjee et al., 2001; Golub
et  al., 1999), the development of diagnostic and prognostic markers
(Silvestri et al., 2015; van de Vijver et al., 2002), and the prioritization
of drug targets (Evans and Guy, 2004).
The application of transcriptomics in examining molecular changes
associated with established or potential disease risk factors is promis-
ing for a number of reasons. For one, an individual’s transcriptome
is highly dynamic and responsive to external stressors (Coughlin,
2014). An intermediate between genes and protein products, total
mRNA abundance in particular is regarded as a molecular phenotype
that provides a biologically relevant snapshot of cellular activity. The
measurement of changes in transcript abundance can provide critical
insight into the status of key biological mechanisms by which an expo-
sure might be exerting its effects. Rather than reflect the total amount
of exposure that comes into contact with host’s cells or target organ,
transcriptional profiling provides a proximal assessment of the host
response to an exposure’s biologically effective dose.
Transcriptomics can also influence the molecular underpinnings of
long-​term structural and functional alterations within different target
systems (Flavell and Greenberg, 2008). Furthermore, these molecular
profiles can be derived to account for inter-​individual variability in
processes such as metabolism and repair (Rogue et al., 2012). Since
the impact of environmental exposures can be different for each indi-
vidual due to a variety of genetic and non-​genetic factors, this is vital
for accurately relating exposures to health outcomes and disease risk
(Idaghdour and Awadalla, 2013). Accordingly, transcriptomic profil-
ing can constructively mediate the interplay between external expo-
sures and the physiologic host response.
Importantly, recent large-​scale genomic studies have demonstrated
that while the majority of the human genome is transcribed into RNA,
only a small fraction is accounted for by protein-​coding genes (Djebali
et  al., 2012). In contrast, a large proportion of transcripts belong to
the vast array of non-​coding RNAs (ncRNAs) (Cech and Steitz, 2014;
Iyer et  al., 2015). MicroRNAs (miRNAs), for instance, are a family
of small ncRNAs that can regulate the transcription, translation, or
degradation of mRNAs (He and Hannon, 2004); miRNA are com-
monly studied in conjunction with mRNA expression levels to pro-
vide biologic insight to regulatory networks and targeting mechanisms
(Devaraj and Natarajan, 2011). Relative to miRNAs, the study of other
ncRNAs (e.g., piRNAs, snoRNAs, lincRNAs) in the context of disease
etiology and screening has been limited, though their contribution to
gene regulation and the modulation of disease-​related phenotypes are
steadily being revealed (Esteller, 2011; Meseure et al., 2015).
To date, global transcriptional profiling studies have largely fea-
tured cDNA and oligonucleotide-​based microarray platforms, with
a shifting focus toward deep sequencing methodologies such as
RNA-​sequencing (Mutz et al., 2013; Woo et al., 2004). Studies have
examined the comparability and reproducibility of microarrays and
RNA-​sequencing results (Marioni et al., 2008; Zhao et al., 2014). As
sequencing technologies circumvent the traditional use of annotated
probe sets, its detection capabilities offer high dynamic ranges and
additional investigative opportunities such as the detection of novel
transcripts or isoforms (Garber et  al., 2011; Trapnell et  al., 2010;
Veneziano et  al., 2016; Wang et  al., 2009). Nevertheless, the ulti-
mate decision of selecting a profiling method should include multi-
ple considerations, including a study’s resources, design, and research
objectives.
We will highlight several studies that have employed transcrip-
tional profiling to capture the physiologic response to carcinogenic
exposures. A number of chemical compounds and environmental pol-
lutants have been shown to alter the transcriptional profiles of whole
blood as well as other tissues (Olsen et al., 2015; Rager et al., 2011;
van Leeuwen et al., 2006; Wang et al., 2005). Of note, tobacco smoke
is one of the few exposures to have been thoroughly examined using
gene expression profiling studies in human populations (Wild et al.,
2013). Several key findings in the space of cigarette use and lung
health have begun to underscore the promise of transcriptomics in
minimally invasively monitoring exposure–​ response relationships.
Specifically, whole genome profiling of histologically normal-​
appearing airway epithelial cells obtained from large and small air-
way brushings of current and former smokers have revealed distinct
mRNA patterns associated with tobacco use (Harvey et  al., 2007;
Spira et  al., 2004). Similar studies have shown that ncRNAs, such
as miRNAs, are also impacted by smoking and lung cancer (Beane
et  al., 2011; Perdomo et  al., 2011; Schembri et  al., 2009); miRNA
dysregulation, in particular, has been heavily implicated in the role of
lung disease development and progression (Angulo et al., 2012). In
addition, there is some evidence that exercise (Flowers et al., 2015)
and environmental exposures such as air pollution can alter miRNA
patterns (Vrijens et al., 2015). There is also some emerging evidence
that miRNA patterns in white blood cells may be related to future risk
of cancer development from prospective studies (Muti et al., 2014).
As an extension of this “field of injury,” gene expression differ-
ences in the airway epithelium of smokers can serve as a classifier
for the diagnostic evaluation of lung cancer (Silvestri et al., 2015;
Spira et al., 2007), as well as a guide for the clinical management
of chronic obstructive pulmonary disease (COPD) (Steiling et  al.,
2013). Moreover, transcriptomic profiling studies have pinpointed
concordant smoking-​induced changes in epithelial cells from the
bronchial epithelium and those obtained non-​invasively from the
buccal and nasal epithelium (Sridhar et  al., 2008; Zhang X et  al.,
2010). Thus, a growing body of evidence suggests that transcrip-
tionally profiling samples collected from the relatively accessible
epithelial cell lining of the nose and mouth can provide additional
opportunities to examine the host response to complex environmen-
tal exposures.
A framework of this environmental assessment paradigm was
recently applied in the household setting of indoor air pollution stud-
ies, wherein buccal epithelial brushings were used to non-​invasively
examine the host response among non-​smoking women exposed to
smoky (bituminous) and smokeless (anthracitic) coal (Wang et  al.,
2015). Specifically, whole genome microarray expression profiling
identified a signature of genes differentially expressed among female
residents who burned smoky coal in their residences of Fuyuan and
Xuanwei, China. Enrichment analysis, an analytic approach that can
be executed using an evolving compendium of computational methods
for identifying representative functional or biologic pathways in silico
(Huang da et al., 2009), indicated that this smoky coal signature was
enriched for pro-​inflammatory mediators as well as changes associated
with tobacco smoke exposure. These results provided biologic context
to epidemiologic investigations that previously reported an association
of smoky coal exposure with lung cancer risk (Barone-​Adesi et  al.,
2012; Downward et al., 2014; Lan et al., 2005; Mumford et al., 1987).
Notably, human peripheral blood is another source of relatively
accessible biological material whose transcriptomic utility should
not be overlooked. For instance, previous studies of publicly avail-
able gene expression data reveal that white blood cell (WBC) tran-
scriptomes can serve to a certain extent as surrogate biopsy material
to identify biomarkers for other organs (Liew et al., 2006; Mohr and
86
86 Part I:  Basic Concepts
Liew, 2007). The utility of WBC transcriptomes is further augmented
by the technical observation that human blood-​derived samples in
long-​term storage in biobanks generally have the potential to be ana-
lyzed using high-​throughput OMICs technologies; so long as the buffy
coats have been deep-​frozen within a few hours of blood collection,
RNA isolation from frozen buffy coats originally stored without RNA
preservatives can still be accomplished for transcriptomic profiling
(Hebels et  al., 2013). As such, there will be many opportunities for
conducting studies of the transcriptome and cancer risk in prospective
cohort studies. An example of such a study is the study on chronic
lymphocytic leukemia (CLL), where prediagnostic transcriptomic pro-
files were found to predict disease more than 10 years before diagnosis
(Chadeau-​Hyam et al., 2014).
In summary, the thoughtful application of transcriptomics can
provide physiologically relevant, molecular insights to complement
traditional exposure assessment strategies. Additionally, biomark-
ers generated by any given technology can be used in a number of
ways depending on the status (e.g., healthy or diseased) of the source
tissue. Continued integration of these methodologies into the canon
of molecular epidemiology can enable the public health community
to rapidly develop sensitive and specific markers of exposure, and to
more comprehensively evaluate the health consequences of exposure
interventions in environmental, occupational, or other targeted settings
among various populations.
Other OMICs Platforms
Microbiome
Studying the microbiome has recently gained much attention, in part
facilitated by the rapid advancements in sequencing (Zhernakova
et al., 2016). Humans carry in various parts of the body, such as the
gastrointestinal tract, lung, mouth, vagina, and skin, multitudes of
microorganisms. It is estimated that the human-​associated microbi-
ota consists of at least 40,000 bacterial strains in 1800 genera, which
collectively harbor at least 9.9  million non-​human genes (Walker,
2016). It is increasingly being recognized that microbiota have large
influences on biological processes and play a significant role in the
metabolism of exogenous compounds. While culture-​based tech-
niques are still relevant, the advent of sequence-​based analytical
techniques has made it possible to broadly explore interactions of
the microbiome with exposures and diseases; 16S (and 18S) rRNA is
the most commonly used universal marker gene method, exploiting
the fact that there are highly conserved regions of DNA sequence,
but also regions that are more variable and unique to certain micro-
bial groups or genera (Woese and Fox, 1977). Based on the S rRNA
analyses, data can be clustered into operational taxonomic units
(OTUs). Next-​generation sequencing allows a deeper investigation
in the microbiome by simultaneously sequencing many microbial
genomes (Fleischmann et  al., 1995). Next-​generation sequencing
also allows measurement of viruses, which are not covered in S
rRNA sequencing.
Given the influence that the microbiota has on innate immunity, it is
very plausible that the microbiome elicits an effect on both cancer risk
and host response to cancer therapy. An example of microbes influ-
encing colon cancer risk is Helicobacter hepaticus causing the exces-
sive release of nitric oxide from immune cells. (Thaiss et al., 2016).
Ahn et  al. (2013), in a case-​control study, investigated agnostically
the association between the gut microbiome and colorectal cancer and
described that cases had overall lower microbial community diversity.
In a small pilot study, Hosgood et al. described a potential influence
of indoor air pollution on the respiratory microbiome and lung cancer
risk (2014).
Although sequencing techniques have improved considerably, most
studies published to date are based on hospital-​based case-​control
studies, hampering separation of cause and effect. Many prospective
studies to date have not collected biological samples of the gut (i.e.,
feces), or respiratory tracts (e.g., buccal, nasal swabs) hampering eti-
ological research on the interaction between the microbiome and can-
cer. However, easy-​to-​use sampling techniques are being developed
currently to allow large-​scale sampling of the microbiome (Flores
et  al., 2015). This, together with ever-​ increasing next-​ generation
sequencing techniques, will allow in the near future the agnostic
screening of microbiota in different parts of the body, and the evalua-
tion of their interaction with environmental stressors and cancer risk.
Adductomics
DNA and protein adducts have been used for decades as biomark-
ers of exposure. They are especially useful for measuring exposure
to electrophiles or chemicals that are metabolically activated to elec-
trophiles. These electrophilic molecules are potentially toxic because
they react with nucleophilic sites in DNA and proteins to produce
mutations and post-​ translational modifications, respectively, and
their degradation and partitioning behaviors can contribute to reactive
toxicity (Grigoryan et al., 2016). While previous techniques focused
on measuring single DNA or protein adducts, current technology is
starting to allow for the measurement of the adductome, which can be
defined as the totality of adducts on a given nucleophilic target. The
term adductome was first used to describe all of the adducts on DNA
(Kanaly et al., 2006). However, because of their greater abundance and
residence times in human blood, adducts on the circulating proteins
hemoglobin (Hb) and human serum albumin (HSA) are preferable to
those of DNA for characterizing adductomes (Rappaport et al., 2012).
The nucleophilic hotspot represented by the only free sulfhydryl group
in HSA (HSA-​Cys(34)) offers particular advantages for adductomic
experiments. Although targeted adducts of HSA-​Cys(34) have been
monitored for decades, an unbiased method has only recently been
reported for visualizing the HSA-​ Cys(34) adductome. Cys34, the
only free thiol in HSA, is a nucleophilic hotspot that accounts for
about 80% of the antioxidant capacity of serum. Different analytical
methods have been proposed to measure the adductome, for example,
triple-​
quadrupole mass spectrometry (TQMS) with selected reac-
tion monitoring (SRM) and LC-​high-​resolution-​mass-​spectrometry
(Grigoryan et al., 2016). Although some proof of principle has been
described by showing interactions between exogenous exposures (i.e.,
smoking), lifestyle, and anthropometric measures, the value in cancer
epidemiology still needs to be established.
Proteomics
Proteomics measures all proteins and peptides. As many biologi-
cal functions are transmitted through proteins, proteomics can yield
valuable insights into disease biology. Proteomic technologies have
been developing from two-​dimensional electrophoreses, enabling the
analyses of a few tenths of proteins to thousands of proteins using
liquid chromatography–​MS (LC–​MS) techniques. LC–​MS is a power-
ful technique that it is oriented toward the identification of proteins in
complex mixtures (Horvatovich et  al., 2010). Several LC-​MS tech-
niques can be distinguished, varying from digestion of proteins to pep-
tides and direct LC-​MS analyses to quantitative proteomics techniques
using isobaric tags for relative and absolute quantitation (iTRAQ),
stable isotope labeling by amino acids in cell culture (SILAC), and
the use of aptamers in the systematic evolution of ligands by exponen-
tial enrichment (SELEX) (Priyadharshini and Teran, 2016). For the
detection of low-​abundant proteins, targeted protein microarrays with
well-​characterized molecules with specific activity, such as antibodies,
peptide-​MHC complexes, or lectins, are used as immobilized probes
(Jain, 2016).
Several studies have incorporated proteomic approaches to iden-
tify novel proteins for disease screening, such as for cancers of the
bladder (Frantzi et al., 2016), pancreas (Pan et al., 2015), liver (Tsai
et al., 2015), lung (Shiels et al., 2013), and ovary (Trabert et al., 2014).
However, only few of these have been conducted in prospective stud-
ies. Two prospective studies using targeted immune microarrays have
found predictive protein markers for lung and ovarian cancer (Shiels
et al., 2013; Trabert et al., 2014). These studies hold promise for pro-
teomics, especially if LC-​MS platforms mature to be able to have
direct quantification and measure low-​abundance proteins, to provide
pictures of the protein networks involved in the pathophysiology of
cancer, providing opportunities for early screening and novel treat-
ment options.
 87
Application of Biomarkers in Cancer Epidemiology 87
Chromosomal Alterations, Aberrations,
and Mutations
The assessment of chromosomal alterations in healthy tissue has been
extensively reviewed (Shuga et  al., 2011). There are many reports
linking chromosomal aberrations and micronuclei in peripheral blood
lymphocytes to various exogenous exposures, and some of these
events have been associated with future risk of cancer (Bonassi et al.,
2008, 2013; Murgia et al., 2008; Shuga et al., 2011). New approaches
to measuring chromosome damage are available, such as array-​based
cytogenetics and single cell sequencing (Shuga et  al., 2013). For
example, GWAS data generated from the analysis of peripheral white
blood cell DNA can be used to detect large structural genetic mosa-
icism in human autosomes and partial or complete loss of chromo-
somes X and Y. It has been shown that these events increase with age,
but their association with risk of cancer has not yet been demonstrated
(Machiela et  al., 2015b, 2016b; Zhou et  al., 2016). Another type of
chromosomal characteristic that can be measured in peripheral white
blood cell DNA is chromosomal telomere length. Longer white blood
cell telomere length phenotype was associated with increased risk of
several cancers in prospective cohort studies, including non-​Hodgkin
lymphoma (NHL; Hosnijeh et  al., 2014; Lan et  al., 2009)  and lung
cancer (Seow et al., 2014a). Further, a genetic risk score of telomere-​
length-​associated genetic variants obtained from GWAS data was used
to predict longer telomere length and was associated with risk of NHL,
especially chronic lymphocytic leukemia, and lung cancer in a study of
non-​smoking females in Asia (Machiela et al., 2015a, 2016a).
INCORPORATION OF BIOMARKERS
IN EPIDEMIOLOGIC STUDIES
Cross-​Sectional Studies with Biomarker Endpoints
Cross-​sectional or longitudinal designs on healthy subjects exposed to
particular exogenous or endogenous agents can be used to investigate
factors associated with biomarkers, which are treated as the outcome
variable. These studies focus on exposure and intermediate endpoint
biomarkers and often evaluate modifiers of the exposure–​endpoint
relationship. Issues in the validation of studies of intermediate end-
points were discussed previously (Garcia-​Closas et al., 2006).
Cross-​sectional studies collect biomarker and exposure informa-
tion at a single point in time. Cross-​sectional studies are often used to
answer questions such as whether a given population has been exposed
to a particular compound, the level of exposure, the range of the expo-
sure, and the external and internal determinants of the exposure. The
National Health and Nutrition Examination Survey (NHANES) con-
ducted since 1999 biannually in the United States provides the most
comprehensive cross-​sectional survey to date in which over 400 infec-
tious, biochemical, physiological, and environmental variables are
measured in large samples of the general population, allowing detailed
analyses of the exposure and biomarker distribution, its determinants,
and interrelations (Patel and Manrai, 2015).
Cross-​sectional studies can evaluate intermediate biologic effects
from a wide range of exposures in the diet and environment, as well
as from lifestyle factors such as obesity and reproductive status. For
instance, cytogenetic markers, including chromosomal aberrations
and micronuclei, have been used as intermediate endpoints in cross-​
sectional studies to demonstrate DNA-​damaging effects derived from
environmental and dietary exposures (Bonassi et  al., 2005). This
design can provide mechanistic insight into well-​established expo-
sure–​disease relations and to supplement suggestive but inconclusive
evidence of the carcinogenicity of an exposure. For example, cross-​
sectional molecular epidemiology studies of formaldehyde and tri-
chloroethylene provided insights into the ability of these chemicals
to cause hematologic, immunologic, and/​or nephrotoxic alterations
(Lan et al., 2010, 2015; Vermeulen et al., 2012; Zhang L et al., 2010).
In addition, effects from comparable studies of the same endpoints
across multiple types of exposures, including those that are established
carcinogens, can also complement studies of cancer as an endpoint
by comparing and contrasting underlying mechanisms of action (e.g.,
comparison of hematological effects of benzene, TCE, and formalde-
hyde (Bassig et al., 2016), and comparison of transcriptomic effects of
exposure to indoor combustion of coal with tobacco smoking (Wang
et  al., 2015). Furthermore, such studies can evaluate whether there
are early biologic perturbations caused by new exposures or recent
changes in lifestyle factors that have not been present long enough to
have been evaluated for their association with cancer (Rothman et al.,
1995). For instance, due to the increasing use of nanoparticles in both
research and manufacturing operations, the assessment of preclinical
indicators of disease, such as biomarkers of pulmonary inflammation,
is important for identifying potential adverse health effects in asymp-
tomatic individuals at an early stage (Schulte et al., 2008; Vlaanderen
et al., 2017).
Longitudinal designs collect repeated biomarker and exposure infor-
mation from the same individuals at different points in time. These
studies can be used to assess intra-​individual variation in exposure
levels, which are critical to the application and interpretation of expo-
sure biomarkers in prospective cohort studies, and to directly compare
changes in exposure to changes in biomarkers within the same indi-
viduals. For instance, longitudinal study designs have demonstrated
that changes in diet are directly related to changes in hemoglobin
adducts of acrylamide (Vikstrom et al., 2012). Additionally, longitu-
dinal studies can be used to determine the effectiveness of interven-
tion studies by studying the changes in exposure and/​or intermediate
endpoints. For example, changes in mammographic breast density
12–​18 months after starting Tamoxifem therapy have been shown to
be predictive of the response to this drug in preventing breast cancer
(Cuzick et al., 2011).
A distinct advantage of the cross-​sectional study is that detailed and
accurate information can be collected on current exposure patterns,
potential confounders, and effect modifiers. This can enable the evalu-
ation of the extent to which a wide range of exogenous and endog-
enous exposures leave either short-​term or longer-​term “imprints” on
biomarker endpoints, and the degree of specificity of such associa-
tions. As noted previously, the long-​term relationship between tobacco
smoking and specific methylation patterns (Joehanes et al., 2016) pro-
vides an example of how an exposure signature may be discerned
using an OMIC technology. The ability to identify specific exposure
signatures is likely to aid exposure assessment in future nested case-​
control studies.
Selection of an appropriate unexposed group can be challenging in
a cross-​sectional study. Apart from coming from the same base popu-
lation as the exposed group, efficiency is increased by some level of
matching based on age, sex, ethnicity, socioeconomic status, and per-
haps smoking, as these studies are often relatively small. For biomark-
ers with large inter-​individual variation among unexposed individuals,
an alternative study design in which subjects are used as their own ref-
erent and followed from the start of the exposure up to a certain length
of exposure (or vice versa) might be more efficient for biomarker end-
points with short half-​lives. An example of such a study is a study
among farmers exposed to pesticides, with intermediate endpoints that
were spaced across an entire growing season (Vermeulen et al., 2005).
By having both repeated samples over time among exposed farmers
and controls, group and individual differences over time can be ana-
lyzed simultaneously using an instrumental variable approach. Such
an approach leverages both the inter-​and intra-​individual differences
in exposures between groups and within individuals overtime (Lerro
et al., 2016).
The explosion of OMICs technologies is providing unprecedented
opportunities to comprehensively assess all endogenous and exogenous
exposures during an individual’s lifetime, or what has been referred
to as the exposome (Rappaport, 2012; Rappaport et  al., 2014; Wild,
2005, 2012). In this context, cross-​sectional and longitudinal studies
are critical to characterize the determinants of these biomarkers in the
population. For instance, studies of the impact of blood collection fac-
tors (such as fasting time, season, and time of the day) on OMICs mea-
surements are critical for the design and interpretation of studies and
disease risk (Hebels et al., 2013; Townsend et al., 2016). Longitudinal
studies of biomarkers such as DNA methylation to evaluate the tempo-
ral variation in repeated specimens from the same individual are also
8
88 Part I:  Basic Concepts
critical, particularly when subsequent studies with disease risk as the
outcome only have biological specimens collected at a single point in
time for each individual (Flanagan et al., 2015).
Case-​Control and Case-​Series Studies
The advantages and disadvantages of case-​control and cohort study
designs have been discussed in detail elsewhere (Caporaso et  al.,
1999; Clayton and McKeigue, 2001; Langholz et al., 1999; Rothman
and Greenland, 1998; Wacholder et al., 2002b), and we have previ-
ously compared these designs in detail with regard to the collection
and use of biologic samples for studies of cancer etiology (Garcia-​
Closas et al., 2006). We summarize several key issues here. Important
advantages of case-​control studies compared to prospective cohort
studies are their ability to enroll large numbers of cancer cases quickly
and the potential to study uncommon tumors that do not occur in large
enough numbers in cohort studies. Because only one disease is eval-
uated, questionnaires can be used for a more detailed and focused
exposure assessment than in cohort studies, which address multiple
outcomes.
However, because case-​control studies collect exposure information
and biologic specimens after diagnosis and sometimes after treatment
of the disease, they are vulnerable to differential misclassification and
to uncertainties in the temporal relation between the cancer devel-
opment and the biomarker under study. The influence of the disease
process and treatment on biomarkers of interest is often unknown.
Although this is not a concern for genetic susceptibility markers that
do not change over time, it can be an important problem for other
types of biomarkers, including epigenetic, transcriptomic, proteomic,
metabolomic and microbiomic markers (see section on prospective
cohort studies later in this chapter).
The hospital-​based case-​control design has been popular in molecu-
lar epidemiology because it facilitates subject enrollment and intense
collection and processing of biologic specimens. Personal contact with
the study participants by doctors, nurses, or interviewers is made easy,
which usually results in higher participation rates for interviews and
collection of biologic specimens (Morton et al., 2006). In addition, the
easier access to health professionals and laboratories allows collection
of different types and larger quantities of biologic specimens and more
elaborate processing protocols, such as cryopreservation of lympho-
cytes. Because study subjects generally are geographically less spread
out than those in population-​based or cohort studies, rapid shipment of
specimens to central laboratories for more extensive processing proto-
cols is facilitated. In addition, because cases are usually diagnosed in
fewer hospitals than population-​based studies, the collection of tumor
samples for molecular pathology studies (Sherman et al., 2010) is also
facilitated. Furthermore, it is easier to enroll cases before surgery and
establish collaborations with pathology departments at the hospital(s)
for more intense, specialized tissue collections (e.g., freshly fro-
zen tissue, alcohol-​fixed tissue). Another advantage of the hospital-​
based design is the easier follow-​up of the patients to determine their
response to treatment and their survival. Follow-​up of cases can be
extremely valuable in molecular epidemiology studies, as many of the
biomarkers under study (e.g., tumor characteristics, genetic polymor-
phisms) may be especially relevant for clinical outcomes in addition
to cancer etiology (Berrington de Gonzalez and Morton, 2012; Elena
et al., 2013; Ransohoff, 2013).
There are established criteria for selecting controls in hospital-​based
studies to estimate the disease association of a single factor without
bias, but the criteria for assessing associations between more than one
factor (e.g., gene–​environment interactions) are less clear. Wacholder
et al. discussed the appropriate exclusion criteria in control selection
for estimating main and subgroup effects as well as additive and mul-
tiplicative gene–​environment interactions (Wacholder et  al., 2002a).
Other study design and analytical considerations in the study of inter-
actions include sample size considerations and the impact of measure-
ment error (Garcia-​Closas et al., 2011).
One of the main challenges of population-​based case-​control stud-
ies has been obtaining high participation, especially when participation
involves collecting biologic specimens. Collection of biologic materi-
als using non-​invasive approaches (e.g., collecting genomic DNA from
buccal cells) (Hansen et  al., 2007)  might help increase participation
rates. Lack of participation biases the study results when the reason
for non-​participation is directly or indirectly related to the factors
under study. Because this condition is often difficult to prove, espe-
cially when many factors are under study, high participation rates
become the only means to ensure comparability of participants and
non-​participants. When participation rates are lower than desirable, it
is important to seek some basic risk factor information, and biospeci-
mens when possible, from non-​participants to identify differences
between participants and non-​participants (Mezei and Kheifets, 2006).
In the case–​case, case series, or case-​only design, only subjects
with the disease of interest and no controls are enrolled in the study.
This design has been proposed to evaluate etiologic heterogeneity
using tumor markers (Begg and Zhang, 1994; Sherman et al., 2010).
The degree of etiologic heterogeneity can be quantified by the ratio
of the relative risk for the association of exposure on marker-​positive
tumors to the relative risk for marker-​negative tumors. This parameter
is equivalent to the odds ratio for the association between exposure
and tumor marker in the cases. However, case-​only studies are limited
to an estimation of the ratio of the relative risks and cannot be used
to obtain estimates of the relative risk for developing different tumor
types. It should be noted that the relative risk from a case-​only design
underestimates the relative risk derived in a case-​control design when
the exposure of interest is associated with more than one tumor type
in the study.
The case-​only study has also been proposed as a valid design to
evaluate multiplicative gene–​ gene (Yang et  al., 1999)  and gene–​
environment (Khoury and Flanders, 1996) interactions. However, this
design has important limitations; most notably, it cannot be used to
obtain estimates of risk for disease or additive interactions, is suscep-
tible to misinterpretation of the interaction parameter (Schmidt and
Schaid, 1999), and is highly dependent on the assumption of inde-
pendence between the exposure and the genotype under study (Albert
et  al., 2001). Because of these limitations, case-​control designs are
preferable to designs using only cases.
Prospective Cohort Studies
Establishing a cohort study is initially extremely costly and time-​
consuming; however, in the long run it becomes more cost-​efficient
because it can study multiple disease endpoints and provides a well-​
defined population that can be easily sampled for efficiency (Potter,
1997). Biologic specimens are collected before disease diagnosis and,
ideally, before the beginning of the disease process. Therefore, it is
well suited to study biomarkers that are directly or indirectly affected
by the disease process (Hunter, 1997).
As in case-​control studies, the collection of biospecimens to mea-
sure biomarkers in cohort studies may adversely affect participation
rates. Cohort studies can avoid selection biases by collecting ques-
tionnaires and biological samples at baseline or before disease onset,
provided that specimens remain available for each participant and
follow-​up is complete. However, subjects with biological specimens
collected after the cohort has been formed might have different charac-
teristics from the rest of the cohort. Increasingly, concerns over privacy
have also affected the willingness of participants to take part in some
research studies.
With adequate infrastructure, cohort studies can be used to collect
prospective serial biological specimens to evaluate how changes in bio-
markers over time relate to disease risk. However, many large cohort
studies have only been able to collect a single biologic sample at one
point in time. Although this is not a concern for DNA-​based assays of
inherited susceptibility markers, it poses some limitations for several
other categories of markers, particularly for exposure biomarkers that
have relatively short half-​lives in the presence of exposures that vary
substantially from day to day. Notably, advances in OMICs technolo-
gies are providing unprecedented opportunities to integrate informa-
tion from a wide range of endogenous and exogenous exposures,
 89
Application of Biomarkers in Cancer Epidemiology 89
through analyses of the epigenome (Mill and Heijmans, 2013), adduc-
tome, transciptome, proteome, metabolome, and microbiome. Because
of the changing nature of the exposome, longitudinal cohort studies
with repeated biological specimens processed and stored using appro-
priate protocols are essential to study their relationship with disease
risk. In addition, tools that allow integration of the large amounts of
data, including pattern recognition and visualization tools, are required
to analyze increasingly complex and large data sets. Careful consider-
ation of the principles of study design (Spitz and Bondy, 2010) will
still be critical to fulfill the promise of the growing number of X-​wide
association studies (Bock, 2012; Chadeau-​Hyam et al., 2010; Foxman
and Martin, 2015; Garcia-​Closas et al., 2013; Hanage, 2014; Homuth
et al., 2015; Michels et al., 2013). Finally, observational cohort studies
with serial collections that also collected clinical data can be highly
valuable to identify and validate early detection biomarkers (Schully
et al., 2015).
Given that most members of a cohort do not develop cancer, nested
case-​ control and less commonly case-​ cohort studies are used to
improve efficiency (Wacholder, 1991). With these designs, only sam-
ples from cases and a random subset of non-​cases are analyzed, reduc-
ing the laboratory requirements and cost considerably. The nested
case-​control design includes all cases identified in the cohort up to a
particular point in time and a random sample of subjects free of dis-
ease at the time of the case diagnosis. On the other hand, a case-​cohort
design includes a random sample of the cohort population at the onset
of the study and all cases identified in the cohort up to a particular
point in time. Increasing the case to control ratio to two or three con-
trols per case can easily increase the efficiency of nested case-​control
studies. The case-​cohort design is simpler and allows evaluation of
several disease endpoints; however, because in case-​cohort studies the
same disease-​free subjects are repeatedly used as “controls” for dif-
ferent disease endpoints, it is difficult to perform assays on matched
samples from diseased and disease-​free subjects; thus, depletion of
samples from the disease-​free group may be an issue. These study
designs have been compared with respect to other biomarker-​related
issues that arise in study implementation, such as batch effect, length
of storage, and freeze-​thaw cycles (Rundle et al., 2005).
The number of subjects enrolled in existing (e.g., http://​epi.grants.
cancer.gov/​Consortia/​cohort.html; UK Biobank:  http://​www.bbmri-​
lpc-​biobanks.eu/​cohorts.html; China Kadoorie Biobank: https://​www.
asiacohort.org), ongoing (Precision Medicine Initiative), and planned
prospective cohort studies among adults will most likely approach or
exceed 10 million people within the next 5 or so years. These studies
will provide an unprecedented opportunity to apply a wide range of
hypothesis-​driven biomarkers and OMIC platforms on large numbers
of patients for both common and less common cancers, allow the study
of even relatively uncommon tumors with pooling across cohorts, and
enable replication and extension of findings. The vast majority of these
cohorts are located in North America, Europe, Asia, and Australia, and
these cohorts provide important opportunities for replication within
and across these populations. At the same time, there remain impor-
tant opportunities to study the etiology of diseases present in South
America and Africa.
Cohort studies often have limited ability to collect tumor samples
from large numbers of subjects and to follow up cases for the purpose
of carrying out survival studies. New cohort studies based on large
institutions such as integrated health providers could enable access
to tumor samples and easier follow-​up of cases to study treatment
response and survival. New prospective cohort studies can take advan-
tage of increasingly available electronic medical records, technologi-
cal advances in the collection and analysis of biological specimens,
wearables, and Big Data management platforms and analytics. The
collection of biologic samples in newer large prospective cohort stud-
ies has stimulated the testing, evolution, and optimization of biologi-
cal sample collection and storage as well as biorepository technology
(Hubel et al., 2011; UK Biobank; Vaught, 2016). In addition, improved
infrastructure should facilitate repeated biospecimen collections over
time (e.g. blood, urine, buccal and stool samples), and allow special
collection or processing of biologic samples that might be needed
for the optimum application of new and emerging technologies. The
establishment of new cohorts and biobanks such as UK Biobank,
China Kadoorie Biobank, German National Cohort (2014), Cancer
Prevention Study 3 (Cancer Prevention Study 3), and the National
Institutes of Health’s Precision Medicine Initiative are steps toward
these goals.
Incorporation of Biomarker Information
in Risk-​Prediction Models
Genome-​wide association studies (GWAS) have uncovered hundreds
of common single nucleotide polymorphisms (SNPs) related to sus-
ceptibility to common diseases. In addition, targeted, exome, and
whole genome DNA sequencing studies, performed in increasingly
large study populations, are extending the search for susceptibility
markers to uncommon variants. This work is leading to the emergence
of gene-​panel and whole-​genome tests to assess polygenic disease
risk, which is likely to increase in the future. Information on genetic
and other biomarkers of risk can be integrated with information on
environmental factors in risk prediction models (Garcia-​Closas et al.,
2014). Thus, continuous development and evaluation of risk models
incorporating increasing knowledge on risk factors will be required
(Chatterjee et  al., 2016). Prospective cohort studies play a key role
both in the discovery of new biomarkers, as well as in the evaluation
of the ability of improved models to provide accurate estimates of the
probability of developing disease in the future.
CONCLUSIONS
There has been a confluence of events that, when taken together, will
provide unprecedented opportunities to extend our knowledge about
the environmental and genetic forces that drive cancer risk (Smith
et al., 2011).
These include the enhancement of the ability to measure external
exposures through improved questionnaires linked to databases of
environmental, occupational, nutritional, and other exposures and the
development of advanced technology that has produced a wide range
of wearable devices capable of measuring a diverse array of exposure
and lifestyle characteristics such as environmental exposures, physical
activity, and sleep quality (DeBord et  al., 2016). Second, as noted,
there has been an exponential increase in the type and quantity of
molecules that can be measured and identified in biologic samples
that have been collected, processed, and stored appropriately. These
include hypothesis-​driven biomarkers as well as platforms that can
comprehensively analyze entire biologic processes and “compart-
ments” agnostically, including the measurement of small molecules
(metabolomics), DNA polymorphisms and rarer inherited variants
(genomics), methylation and miRNA (epigenomics), chromosome-​
wide alterations, mRNA (transcriptomics), proteins (proteomics), the
microbiome, and other biologic components within the human body.
These advancements, and their continuing evolution, will enable
investigators to comprehensively study the biological consequences
of exogenous and endogenous exposures, to detect (1) molecular sig-
natures of exposure, (2) early signs of adverse biological effects, and
(3) preclinical disease, and (4) to identify clinical subtypes in cancer.
Finally, there will soon be 10 million or more adult subjects enrolled in
prospective cohort studies on several continents that have collected and
stored one or more types of biological samples. These three forces will
be combined in unprecedented ways to provide profound new insights
into cancer etiology and at the same time provide myriad opportunities
for translational research and applications that have great potential to
reduce the burden of disease through primary prevention, including
public health guidelines, standards, and regulations, as well as second-
ary and tertiary prevention, including the emerging concept of preci-
sion medicine (Collins and Varmus, 2015).
Some challenges of particular importance include the need for
cohorts to collect repeat biological samples over time; the desirability
of following up cohort studies of children and adolescents with bio-
logic samples over their lifetime; and the need to be able to collect,
manage, and analyze in meaningful ways the vast amount of data that
90
90 Part I:  Basic Concepts
future studies will generate. Cohorts that are able to collect repeat bio-
logical samples, especially blood, as well as pre-​neoplastic tissue sam-
ples when possible, will be especially well positioned to apply new
and emerging technologies to study non-​fixed biological endpoints
that show substantial intra-​individual variation over time, reflecting
random fluctuation, secular trends, and early disease processes. The
ability to derive individual trajectories of the disease processes would
be a major step toward precision medicine that allows targeted pri-
mary and secondary prevention programs. In addition, a comprehen-
sive life-​course approach to studying the etiology of cancer and other
chronic diseases would add considerably to these efforts, and could be
accomplished in part if prospective cohort studies of children and ado-
lescents could be followed up into adulthood and beyond. Finally, the
huge data generated from the application of multiple OMICs platforms
to each subject are providing an unprecedented challenge to integrate
and interpret the resulting data in a meaningful way. There are many
ongoing attempts to come to grips with the tsunami of data we will
be facing over the coming years, and new methods, including more
explicit integration of mechanistic evidence and biology, will no doubt
be developed over time to study the wealth of information these stud-
ies will generate (Bhuvaneshwar et al., 2016; Kristensen et al., 2014).
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 97
7 Causal Inference in Cancer Epidemiology
STEVEN N. GOODMAN AND JONATHAN M. SAMET
OVERVIEW
Judgments about causality are central to the development of interven-
tions intended to prevent or reduce exposure to risk factors that cause
cancer. Because causation is not directly observable in medicine, sci-
entists and philosophers have had to develop sets of constructs and
heuristics that define “cause” operationally. Just as the Henle-Koch
criteria are used to confirm that a specific microorganism causes an
infectious disease, a parallel framework has been developed to evaluate
whether associations observed in epidemiologic studies of non-com-
municable diseases represent causation, rather than spurious correla-
tions or chance. The criteria in this framework, often attributed to the
British medical statistician Sir Austin Bradford Hill or to the 1964
Report of the US Surgeon General on tobacco, include consistency,
strength of association, specificity, temporality, coherence/plausibility/
analogy, biological gradient, and experiment. This chapter reviews
these criteria in depth and considers the challenges of applying them
to population research on cancer. It discusses the concepts of causation
in the context of the multistage nature of cancer, the “counterfactual”
notion of causation, the component cause model for understanding dis-
eases with multiple causes, and the “weight of the evidence” approach
for integrating information from multiple lines of research. It also
describes the increasing power of mechanistic information to reveal
the processes of carcinogenesis at the molecular level. It posits that
mechanistic information, such as the discovery of molecular “signa-
tures” of specific exposures, will continue to grow in importance as
one of the “twin pillars” of causal inference, and will in some cases
reduce our reliance on empirical, population-based data.
INTRODUCTION
The prevention of disease has long been based implicitly on taking
action on the assumption that a disease is caused by a factor that can
be controlled. Early examples include the experimental evidence gen-
erated by Lind, showing that consumption of oranges and lemons
prevented scurvy, and Snow’s observations on cholera occurrence in
London, showing a disease pattern consistent with water-​borne trans-
mission (Johnson, 2007; Rosen, 1993). In these examples, preventive
steps followed: After Lind’s experiment, the diets of the British navy
were supplemented with citrus fruits; and after Snow’s observational
study, steps were taken to ensure that the source of water was changed
in the affected areas of London. Over the ensuing centuries, infec-
tious agents were causally linked to specific diseases, and preven-
tion was accomplished by interrupting transmission and by vaccines.
During the twentieth century, public health was threatened by parallel
epidemics of several chronic diseases, including cancer; and as the
causal agents were identified, a broad range of preventive strategies
was implemented. Underlying these actions was the determination that
a causal relationship existed between some agent and disease risk.
The concept of causation has long had a central and pivotal role in
the application of epidemiologic evidence for controlling cancer. The
designation of a risk factor as “causal” has been the starting point for
initiating cancer prevention programs based on reducing exposure to
the risk factor. Although the concept of causation itself remains a mat-
ter of continuing discussion among philosophers and others, use of the
term in public health implies that the evidence supporting causality
of association has reached a critical threshold of certainty and that a
reduction of exposure can be expected to be followed by reduced dis-
ease occurrence. Over the last 50 years, identification of the external
causes of cancer has been the primary focus of most epidemiologic
research on cancer; only relatively recently has attention shifted toward
identifying inherited and acquired genetic determinants of susceptibil-
ity, metabolic factors that affect risk, intermediate markers of the early
stages of carcinogenesis, and evaluation of preventive interventions.
There are numerous examples in which the identification of a cause
of cancer has led to intervention and reduction of disease occurrence.
Tobacco use and cancer of the lung is a notable example for its histori-
cal precedence and for the framework applied to the scientific evidence
as the causality of the association was evaluated (US Department of
Health, Education and Welfare, 1964; White, 1990). A broad range
of causal risk factors has been linked to diverse forms of cancer.
These include infectious agents (e.g., human papillomavirus and cer-
vical cancer), physical agents (e.g., ionizing radiation and leukemia
and solid tumors), inhaled agents (e.g., tobacco smoke or radon and
lung cancer), pharmaceutical agents and hormones (e.g., diethylstil-
bestrol and adenocarcinoma of the vagina), food contaminants (e.g.,
aflatoxin and liver cancer), workplace exposures (e.g., asbestos and
mesothelioma), behavioral exposures (e.g., alcohol consumption and
liver cancer), and inherited genetic mutations (e.g., Li-​Fraumeni syn-
drome and cancer of multiple sites). These and other factors have been
judged to be causal only after the accumulation of sufficient evidence
that, in most instances, represents multiple lines of research including
epidemiologic studies, clinical research, laboratory experiments and
preventive interventions that have reduced risk.
This chapter provides an overview of causal inference with a focus
on the interpretation of epidemiologic data on cancer risk. It begins
with an introduction to the centuries-​old discussion on cause and
causation and next considers the epidemiologic concept of causation,
setting the discussion in the context of current understanding of car-
cinogenesis as a multistep process. The criteria for causation, often
attributed to the Britis medical statistician Sir Austin Bradford Hill
(1965) or to the 1964 Report of the US Surgeon General on tobacco
(US Department of Health, Education and Welfare, 1964), have pro-
vided a framework for the evaluation of evidence in judging the cau-
sality of associations.
These criteria are addressed in depth, and their application is illus-
trated with the example of tobacco smoking, both active and passive, in
relation to lung cancer. The chapter concludes with a consideration of
emerging issues concerned with causation, including the interpretation
of data coming from the new “-​omics” (e.g., genomics, epigenomics,
metabolomics, exposomics, and proteomics), the expanding technolo-
gies of contemporary “molecular epidemiology,” and new approaches
to modeling epidemiological data and evaluating causation.
CONCEPTS OF CAUSATION
At its foundation, “cause” is not knowable with certainty. This fact under-
lies much of the methodologic and conceptual confusion that often swirls
around claims of causation based on scientific evidence. The fundamental
intuition underlying the causal concept is that event A somehow produces
another event, B. However, the “production” of B is not observable. The
philosopher Bryan Magee summarized this conundrum eloquently.
97
98
98 Part I:  Basic Concepts
It seems to be impossible for us to form any conception of an
ordered world at all without the idea of there being causal con-
nections between events. But when we pursue this idea seriously
we find that causal connection is not anything we ever actually
observe, nor ever can observe. We may say that Event A causes
Event B, but when we examine the situation we find that what we
actually observed is Event A  followed by Event B.  There is not
some third entity between them, a casual link, which we also
observe… . So we have this indispensable notion of cause at the
very heart of our conception of the world, and of our understanding
of our own experience, which we find ourselves quite unable to
validate by observation or experience… . It actually purports to tell
us how specific material events are related to each other in the real
world, yet it is not derived from, nor can it be validated by, observa-
tion of that world. This is deeply mysterious. (Magee, 2001)
The fact that causation is not directly observable means that sci-
entists and philosophers have had to develop a set of constructs and
heuristics by which to define a “cause” operationally. These constructs
typically have two components:  a predictive or associational one,
determined empirically from variations in the probability of disease
occurrence, and an explanatory one, based on a proposed underlying
mechanism. All causal claims rest on these twin pillars; an association
with no plausible mechanistic basis is typically not accepted as causal,
and a proposed mechanism, however well founded, cannot be accepted
as the basis for a causal claim without empirical demonstration that
the outcome occurs more often in the presence of the purported cause
than in its absence. However, these components need not contribute
equally, and various causal claims may rest on quite different balances
of contributions of empirical and mechanistic information.
Underlying any operational definition of causality must be an onto-
logic one: that is, how a cause is defined in principle. A particularly use-
ful, widely accepted definition in both philosophy and epidemiology is
the “counterfactual” notion of causation. This concept had its origins at
least as far back as the English philosopher David Hume (1711–​1776)
(Hume, 1739). During the twentieth century, this concept was further
developed and applied by statisticians, philosophers, and epidemiolo-
gists (Bunge, 1959; Glass et  al., 2013; Greenland, 1990; Greenland
et al., 1999; Hernán and Robins, 2016; Lewis, 1973; Neyman, 1990;
Pearl, 2000; Robins, 1986; 1987; Rubin, 1974). The counterfactual
definition holds that something is a cause of a given outcome if, when
the same individual is observed with and without a purported cause and
without changing any other characteristic of that individual, a different
outcome would be observed; for example, the counterfactual state for
a smoker is the same individual never having smoked. The state that
cannot be observed is called the counterfactual state: literally, counter
to the observed facts. The impossibility of observing the counterfactual
state is what makes all causal claims subject to uncertainty.
In practice, the risk caused by most exposures is not so extreme that
it can be observed in every individual. Rather, the definition is probabi-
listic, meaning that the outcome is more likely to occur in the presence
of the cause than in its absence. Health research rarely deals with causes
that inevitably produce certain outcomes, or with outcomes that never
occur absent specific causes. For example, smokers do not always get
lung cancer, and never-​smokers do develop this malignancy. Therefore,
the counterfactual definition must be expanded to encompass the notion
of a probabilistic rather than deterministic outcome. The formal defini-
tion of a cause in population studies requires that a factor X be associ-
ated with a difference in the likelihood (probability) of an outcome. For
example, if X may take on two different values, y or z:
Condition 1: observed association
Pr(outcome | X = y) ≠ Pr(outcome | X = z)
Properly designed studies provide a scientific basis for inferring
what the outcome of the counterfactual state would be and permit the
related uncertainty to be quantified. In a laboratory, scientists are able
to predict the outcome in this counterfactual state, generally with a
high degree of confidence, by repeating an experimental procedure
with every factor tightly controlled, varying only the factor of interest.
In observational studies of humans, however, researchers must try to
infer what the outcome would be in a counterfactual state by study-
ing another group of persons who, at least on average, are substan-
tively different from the exposed group in only one variable:  the
exposure under study. The outcome of this second group is used to
represent what would have occurred in the original group if it were
observed with an exposure different from that which actually existed
(Greenland, 1990). For example, in the case of smoking and disease,
this comparison is between disease risk in smokers and nonsmokers.
Simply observing a difference in the probability of an outcome
between two groups that differ on X is not sufficient evidence for cau-
sation because it does not distinguish between causation and spurious
or indirect association, produced by “confounders,” or ancillary causes.
The notion of “causation” requires that the cause somehow actively
“produce” its effect, which is captured operationally by the requirement
that active manipulation of the cause should produce a change in the
probability of the outcome. For example, if one saw that students with
poor visual acuity typically sat closer to the front of a classroom, one
would not call the seating arrangement a “cause” of their poor eyesight
unless it could be shown that seating them farther back improved it. The
notation that captures this idea is one that introduces an operator, not
part of traditional statistical notation “Set (X = x),” which corresponds
to actively setting a risk factor X equal to some value x, rather than
simply observing that the factor is equal to x. Thus, the counterfactual
notion of probabilistic causation for a risk factor X requires condition 2.
Condition 2: no confounding
Pr[outcome | set(X = x)] = Pr(outcome | X = x)
If we put together condition 1 (that there is an observed association
between cause and effect) with condition 2 (that there is no other extra-
neous cause responsible for the observed effect), we have the coun-
terfactual condition for probabilistic causation, expressed as follows.
Condition 1 + Condition 2 = Causality condition
Pr[outcome | set(X = y)] ≠ Pr[outcome | set(X = z)]
This condition states that if the probability of an outcome changes
when risk factor X is actively changed from z to y, then X is regarded
as a cause of the outcome.
In the randomized controlled trial, a risk factor is actively manipu-
lated. Understanding the role of randomization can deepen insights
into the interpretation of nonrandomized designs used in observational
studies. Randomization has two critical consequences:  (1)  it makes
exposure to a proposed causal factor independent of potentially con-
founding factors; and (2) it provides a known probability distribution
for the potential outcomes in each group under a given mathematical
hypothesis (i.e., the null) (Greenland, 1990). Randomization does not
necessarily free the inference from an individual randomized study
from unmeasured confounding (it does so only on average, assum-
ing proper randomization). Randomization does imply that measures
of uncertainty about causal estimates from randomized studies have
an experimental foundation. In the absence of randomization, uncer-
tainty about causal effects depends in part on the confidence that all
substantive confounding has been eliminated or controlled by either
the study design or the analysis. The level of confidence is ultimately
based on scientific judgment and consequently is subject to uncertainty
and questioning.
One way to increase that confidence is to repeat the study. Similar
results in a series of randomized studies make it increasingly unlikely
that unmeasured confounding is accounting for the findings, as the
process of randomization makes the mathematical probability of such
confounding progressively smaller as the sample size or number of
studies increase. In observational studies, however, increasing the num-
ber of studies reduces the random component of uncertainty, but does
not necessarily eliminate systematic bias from confounding. Without
randomization, there is no mathematical basis for assuming that an
imbalance of unknown confounders decreases with an increase in the
number of studies. However, if observational studies are repeated in
different settings with different persons, different eligibility criteria,
 9
Causal Inference in Cancer Epidemiology 99
and/​or different exposure opportunities, each of which might eliminate
another source of confounding from consideration, the confidence that
unmeasured confounders are not producing the findings is increased.
There are no fixed guidelines on how many studies need to be done,
how diverse they need to be, and how relevant they are to the question
at hand to guarantee the benefits of consistency. These are matters of
scientific judgment; explicit criteria cannot be offered.
In the scientific community, including epidemiologists, there is a
general move to support efforts that will enhance the reproducibility
of results (Begley and Ioannidis, 2015; Peng, 2011). The approaches
include active sharing of data and analytical models, including the
code used for the models. The finding of reproducible results in analy-
ses of pooled data does not exclude bias arising from participant selec-
tion and confounding, but it does minimize false leads from chance,
from biases that individual investigators may introduce in analyzing
and reporting data and from outright errors.
Confidence that unmeasured confounding is not producing the
observed results is further increased by understanding the biologic
process by which the exposure might affect the outcome. This under-
standing allows better identification and measurement of relevant con-
founders, making it less likely that unmeasured factors are of concern.
Biologic understanding can also serve as the basis for a judgment
that the observed difference in outcome frequency could be produced
only by an implausible degree of imbalance in the confounding factor
between exposed and unexposed groups. Thus, causal inference based
on observational studies typically requires more replication and stronger
biologic evidence to support plausibility and to exclude confounding
than is needed for inferring causation from randomized studies. The new
“-​omics” technologies expand the opportunities to combine mechanistic
and probabilistic evidence as the basis for causal inference.
COMPONENT CAUSE MODEL
Causes defined in the manner described in the preceding can be
viewed as working together in many ways. Rothman (1976) proposed
a useful framework for considering multiple-​cause diseases that has
ready extension to the causation of cancer, as most cancers have sev-
eral causes. Rothman proposed that a disease may have several suf-
ficient causes, each accounting for some proportion of the cases in the
population, and that each cause may have several components (Figure
7–1) (Rothman, 1976). In this model, all of the components of any
single causal complex must be present for disease to develop. In this
example, causal complexes I and II would be incomplete if either A or
B were not present. Factor A (but not B) is also a necessary component
of sufficient cause III. Because factor A must be present in all of the
causal complexes, it is a necessary cause of the disease. It is not a suffi-
cient cause of the disease, however, since other factors must be present
to complete any one of the causal complexes.
Rothman’s model is useful for considering causation of the diverse
forms of cancer, particularly for the majority of cancers for which both
inherited (genetic) and acquired (environmental) risk factors typically
play a role in a multistage process that transforms a normal cell into a
malignant cell. There may be multiple ways to complete this sequence
of changes, involving the actions of different complexes of factors,
analogous to composite causes I, II, and III in Figure 7–1. A particular
exposure, such as factor A, is considered causal if it contributes to at
Sufficient Sufficient Sufficient
Cause Cause Cause
I II III
E D H G J I
A C A F A F
B B C parasite.
Figure 7–1.  Conceptual schemes for the causes of a hypothetical disease.
least one of these causal complexes. Individual cases result from hav-
ing the full complement of components for one or more of the causal
composites. We know, for example, that cigarette smoking is a power-
ful cause of lung cancer that accounts for approximately 90% of cases
in most countries. In the example shown in Figure 7–1, smoking would
correspond to factor B, which contributes to causal complexes I and
II but not III. Smoking is not a necessary cause of lung cancer, since
approximately 5%–​10% of cases in the United States occur in never-​
smokers (Samet et  al., 2009). Nor is smoking by itself a sufficient
cause of lung cancer, since not all long-​term heavy smokers develop
the disease. Figure 7–1 indicates the need for additional cofactors,
such as genes that influence carcinogen metabolism, DNA repair, and
the programmed cell death of genetically damaged cells, to complete
causal complexes I and II.
Rothman’s model has significant implications for considering the
burden of cancer attributable to a particular risk factor and when
assigning priorities to specific preventive interventions. For example, a
single exposure can contribute to multiple component pathways (e.g.,
A and B in causes I and II), implying that the cases associated with
these causes might be prevented by eliminating exposure to either A or
B. This is useful when ranking the priority of various interventions,
even though it may appear confusing that the sum of the attributable
fraction estimates exceeds 100%. The overlap in causation should not
be misinterpreted because of the expectation that the total burden of
preventable cancers associated with all of the various causal factors
should add up to 100% (Schottenfeld et al., 2013).
CRITERIA FOR CAUSALITY
Epidemiologists and other health researchers have needed pragmatic
definitions of causation to support the translation of evidence from
etiologic research into preventive and curative interventions (Olsen,
2003; Susser, 1973). The epidemiologic literature has consequently
placed great emphasis on identifying criteria by which evidence is
evaluated to determine if a factor can be considered to cause disease.
These criteria are necessarily different for chronic diseases such as
cancer, which have multiple causes, heterogeneous clinical features,
and a much longer induction period than those used for infectious dis-
orders caused by specific microorganisms.
In biomedical research, the first criteria came following the dis-
covery of bacteria during the nineteenth century. A method was then
needed for judging if an organism caused a particular disease. The
criteria originally put forward for making this judgment are gener-
ally attributed to Robert Koch and his mentor Jacob Henle, although
Koch also acknowledged Eugene Klebs. Evans (1993) provided a full
accounting of the elaboration of these criteria, now referred to as the
Henle-​Koch postulates (Box 7–1). The criteria proved valuable for
linking infectious agents to infectious diseases, which often have spe-
cific clinical features and unique, specific causal agents (e.g., pulmo-
nary tuberculosis and Mycobacterium tuberculosis).
The criteria used for infectious diseases proved unsuitable, however,
for inferring the causation of cancer and other chronic diseases, which
became the dominant causes of death in high-​and middle-​income
countries throughout the twentieth century. Unlike many infectious
diseases, these diseases were commonly associated with multiple fac-
tors, and many cases could not be clearly linked to any risk factors.
The limitations of the Henle-​Koch postulates were recognized during
Box 7–1.  HENLE-​K OCH POSTULATES
1. The parasite occurs in every case of the disease in question and
under circumstances that can account for the pathologic changes
and clinical course of the disease.
2. It occurs in no other disease as a fortuitous and nonpathogenic
3. After being fully isolated from the body and repeatedly grown
in pure culture, it can induce the disease anew.
10
100 Part I:  Basic Concepts
Box 7–2.   SIR AUSTIN BRADFORD HILL’S CAUSAL
CRITERIA: ASPECTS OF ASSOCIATION TO BE
CONSIDERED BEFORE DECIDING ON CAUSATION
Strength
Consistency
Specificity
Temporality
Biologic gradient
Plausibility
Coherence
Experiment
Analogy
the first wave of epidemiologic studies on chronic diseases in the mid-​
twentieth century. In 1959, Yerushalmy and Palmer proposed criteria
for evaluating the etiology of chronic diseases that acknowledged the
need for evidence of increased risk in exposed persons and for hand-
ling the lack of specificity compared to infectious diseases. Lilienfeld
(1959) and Sartwell (1960), discussing the article, added the consider-
ation of dose–​response, the strength of the association, its consistency,
and its biologic plausibility.
The most widely cited criteria in epidemiology and public health were
set forth by Sir Austin Bradford Hill in 1965 (Box 7–2) (Hill, 1965). Five
of the nine criteria he listed were also put forward in the 1964 Surgeon
General’s report (US Department of Health, Education and Welfare,
1964)  as the criteria for causal judgment:  consistency, strength, speci-
ficity, temporality, and coherence of an observed association. Recently,
these criteria were attributed to Reuel Stallones, an epidemiologist and
consultant to the Advisory Committee that authored the 1964 report
(Stallones, 2015). Hill also listed biologic gradient (dose–​response),
plausibility, experiment (or natural experiment), and analogy. Many of
these criteria had been cited in earlier epidemiologic writings (Lilienfeld,
1959; Sartwell, 1960; Yerushalmy and Palmer, 1959); and Susser and
others have refined them extensively by exploring their justification, mer-
its, and interpretations (Kaufman and Poole, 2000; Susser, 1973, 1977).
Hill (1965) clearly stated that these criteria were not intended to
serve as a checklist.
Here are then nine different viewpoints from all of which we
should study association before we cry causation. What I do not
believe … is that we can usefully lay down some hard-​and-​fast
rules of evidence that must be obeyed before we accept cause
and effect. None of my nine viewpoints can bring indisputable
evidence for or against the cause-​and-​effect hypothesis, and none
can be required as a sine qua non. What they can do, with greater
or less strength, is to help us to make up our minds on the funda-
mental question—​is there any other way of explaining the facts
before us, is there any other answer equally, or more, likely than
cause and effect? (Hill, 1965)
All of these criteria pertained to the evaluation of statistical associa-
tions observed in one or more study; if no association was observed,
the criteria are not relevant. Hill explained how if a given criterion
were satisfied, it strengthened a causal claim. Each of these nine cri-
teria served one of two purposes: as evidence against competing non-
causal explanations, or as positive support for causal ones. Noncausal
explanations for associations include chance; residual or unmeasured
confounding; model mis-​specification; selection bias; errors in mea-
surement of exposure, confounders, or outcome; and issues regarding
missing data (which can also include missing studies, such as publica-
tion bias). The criteria are discussed in the following.
Consistency
The consistency criterion refers to the persistent finding of an associa-
tion between exposure and outcome in multiple studies of adequate
power and carried out by different investigators in studies involving
different persons, places, circumstances, and times. Consistency can
have two implications for causal inference. First, consistent findings
reduce the likelihood of chance associations; if the results from several
studies are combined, this also improves the precision of the estimates.
Second, consistency makes it less likely that unmeasured confounding
accounts for the observed association. Such confounding would have
to persist across diverse populations, conditions of exposures, and
measurement methods. Confounding is still possible if the exposure
of interest were strongly and universally tied to an alternative cause, as
was claimed in the form of the “constitutional hypothesis” put forward
in the early days of the smoking-​disease debate (US Department of
Health, Education and Welfare, 1964). This hypothesis theorized that
there was a constitutional (i.e., genetic) factor that made people more
likely to smoke and, independent of smoking, to develop cancer. No
such factor has ever been identified. Nevertheless, it is true that con-
sistency serves mainly to exclude the possibility that the association is
produced by an ancillary factor that differs across studies, but this does
not eliminate the possibility that an extraneous factor could affect all
or most of the studies (Rothman and Greenland, 1998).
Consistency does not include the qualitative strength of such stud-
ies, which Susser subsumed under his subsidiary concept of “surviv-
ability,” relating to the rigor and severity of tests of association (1991).
Strength of Association
Strength of association includes two dimensions: the magnitude of the
association and its statistical strength. An association strong in both
aspects makes the alternative explanations of chance and confounding
unlikely. The larger the measured association, the less likely it is that
an unmeasured or poorly controlled confounder could account for it
completely. Associations that have a small magnitude or weak statisti-
cal strength are more likely to reflect artifactual correlations caused by
chance, a modest degree of bias, or unmeasured weak confounding.
However, the magnitude of association is reflective of underlying bio-
logic processes and should be consistent with understanding the role
of the risk factor in these processes. Either a strong or a weak effect
might be considered plausible, based on knowledge of the underlying
processes.
In the example of active smoking and lung cancer, the relative risks
listed in the first Surgeon General’s Report (US Department of Health,
Education and Welfare, 1964)  were notably elevated in men, reach-
ing as high as 10 or more. At that time, other causes of lung cancer,
particularly occupational agents, had been identified. Exposure to
occupational carcinogens would have been much lower in the general
population than in occupational subgroups, making these implausible
as potential confounders in the general population.
Passive smoking, by contrast, has a far smaller effect on lung cancer
risk. Based on studies that compared persons with greater and lesser
exposures (e.g., never-​smoking women married to smokers vs. those
married to never-​smokers), the 1986 report of the US Surgeon General
(US Department of Health and Human Services, 1986)  concluded
that passive smoking caused lung cancer. The magnitude of the effect
was much smaller than for active smoking in most studies, as would
be anticipated, but within a plausible range. The relative risk associ-
ated with marriage to a smoker has been estimated to be around 1.2 in
various meta-​analyses (International Agency for Research on Cancer,
2004; US Department of Health and Human Services, 2006).
Specificity
Specificity has been interpreted to mean that an exposure causes only
one (or few) diseases, or that a disease has only one cause. There are
some cancers caused principally by a single type of exposure, for exam-
ple, mesothelioma from asbestos exposure and angiosarcoma from
exposure to vinyl chloride monomer. These are exceptions, however.
The requirement for specificity was originally derived from the Henle-​
Koch postulates for infectious causes of disease (Susser, 1991) and is
seldom relevant to chronic diseases. When specificity with respect to
outcomes exists, it can strengthen a causal claim, but its absence does
 10
Causal Inference in Cancer Epidemiology 101
not weaken other evidence (Sartwell, 1960). For example, most can-
cers are known to have multifactorial etiologies; many cancer-​causing
agents can cause several types of cancer, and these agents can also
have noncancerous effects.
When considering specificity in relation to the smoking–​lung can-
cer association, the 1964 Surgeon General’s report (US Department
of Health, Education and Welfare, 1964) provides a rich discussion of
this criterion. The committee recognized the linkage between speci-
ficity and the strength of association and understood the symmetrical
relationship between the two. In the most extreme instance, a particu-
lar exposure always results in a specific disease, and the disease always
results from the exposure. The committee acknowledged that smoking
did not match that example, since it does not always result in lung
cancer and lung cancer has other causes. However, the report noted the
extremely high relative risk for lung cancer in smokers and the high
attributable risk, and concluded that the association between smoking
and lung cancer had “a high degree of specificity.”
There is, however, another interpretation of specificity that can be
critical to the design and interpretation of observational studies. This
is that, in a given study, some outcomes are highly unlikely to be caus-
ally related to the exposure, based on a priori knowledge. These can be
used as internal “negative controls” to detect broad nonspecific associ-
ations. The absence of observed associations between these outcomes
and the exposure of interest provides some assurance that the observed
associations are meaningful (Schuemie et al., 2014).
Temporality
Temporality requires that exposure to a cause precede its purported
effect. Temporality is the sine qua non of causality, since a causal
exposure must be present before it can affect risk. Rothman and oth-
ers emphasize that temporality is the only criterion that must be ful-
filled for an association to be considered causal (Rothman, 1986; Glass
et al., 2013). Any question about a temporal sequence seriously weak-
ens a causal claim. However, establishing temporal precedence does
not by itself establish strong evidence for causality.
Coherence, Plausibility, and Analogy
Although the original definitions of coherence, plausibility, and anal-
ogy were subtly different, in practice they have been treated essentially
as one idea: that a proposed causal relation should not violate known
scientific principles, and that it be consistent with experimentally
demonstrated biologic mechanisms and other relevant data, such as
observed patterns of disease (Rothman and Greenland, 1998). In addi-
tion, if biologic understanding can be used to set aside explanations
other than a causal association, it offers further support for causality.
Together, these criteria can serve to both support a causal claim (by
supporting the proposed mechanism) and refute it (by showing that the
proposed mechanism is unlikely).
Biological understanding evolves continuously as scientific
advances make possible ever deeper exploration of disease pathogen-
esis. For example, in 1964 the Surgeon General’s committee found the
causal association of smoking with lung cancer to be biologically plau-
sible based on knowledge of the presence of carcinogens in tobacco
smoke and animal experiments. More than 50  years later, this asso-
ciation remains biologically plausible, but that determination rests not
only on the earlier evidence but on subsequent discoveries regarding
the genetic and molecular basis of carcinogenesis, which provide a
level of understanding that could not have been anticipated in 1964. In
fact, the 2010 report of the Surgeon General on tobacco was devoted
to the topic of the mechanisms by which smoking causes disease (US
Department of Health and Human Services, 2010).
Biologic Gradient (Dose–​Response)
The finding of a graded increase in risk in relation to increasing expo-
sure to the possible cause provides strong positive support in favor
of a causal hypothesis. This is not just because such an observation
is predicted by many cause-​and-​effect models and biologic processes
but, more importantly, because it makes most noncausal explanations
highly unlikely. If some factor other than that of interest explains the
observed gradient, the unmeasured factor must change in the same
manner as the exposure of interest. Except for confounders that are
closely related to a causal factor, it is extremely difficult for such a
pattern to be created by virtually any of the noncausal explanations for
the association. The finding of a dose–​response relation has long been
a mainstay of causal arguments in smoking investigations; virtually all
health outcomes causally linked to smoking have shown an increase in
risk and/​or severity with an increase in the lifetime smoking history.
This criterion is not based on any specific shape of the dose–​response
relation.
Experiment
The criterion “experiment” refers to situations where natural condi-
tions might plausibly imitate conditions of a randomized experiment
in an otherwise observational setting, producing a “natural experi-
ment” whose results might have the force of a true experiment. An
experiment is typically a situation in which the scientist manipulates
the exposure in a manner independent of the subject’s characteristics.
Sometimes nature produces similar conditions. The reduced risk after
smoking cessation serves as one such situation that approximates an
experiment, although it is conceivable that unmeasured causal fac-
tors associated with health are more frequent among those who stop
smoking than among those who continue. The causal interpretation is
further strengthened if risk continues to decline among former smok-
ers with increasing time since quitting. Similar to the dose–​response
criteria, observations of risk reduction after quitting smoking have the
dual effects of making most noncausal explanations unlikely and sup-
porting the biologic model that underlies the causal claim.
APPLYING THE CAUSAL CRITERIA
The process of inferring causation from observational data involves
more than simply lining up the evidence as it relates to each criterion,
although there is evidence that epidemiologists tend to use the evi-
dence in neither a consistent nor comprehensive manner (Weed and
Gorelic, 1996). Judgments about the strength of individual studies,
the appropriateness of design and analysis, adequacy of the sample
size, and rigor in excluding confounding must then be assessed in light
of other lines of evidence. Epidemiologic evidence alone is generally
not regarded as sufficient for establishing causality (Last et al., 2001).
In the example of tobacco smoke, the epidemiologic data must be
integrated with evidence from experimental, toxicological, and clini-
cal studies in a multidisciplinary process. A  weight-​of-​the-​evidence
approach is then used to assess how well an observed association ful-
fills the causal criteria. It is ultimately a matter of judgment whether
the collective the evidence is sufficient to exclude alternative explana-
tions. The 1964 Surgeon General’s report still stands as one of the fin-
est examples of the power of applying these criteria systematically and
comprehensively. Starting with the criterion for consistency, the com-
mittee noted that all 29 retrospective studies (i.e., case-​control) and 7
prospective studies (i.e., cohort) at the time reported highly significant
smoking–​lung cancer relations. They further noted that all of the stud-
ies comparing long-​term smokers to nonsmokers showed high relative
risks for lung cancer (~10). Dose–​response effects were also observed
in every prospective study and in all retrospective studies where it
could be calculated. The temporal sequence was reported to be not
absolutely certain, but seemed highly unlikely to be in the direction of
lung cancer causing smoking, as cancer typically appears many years
or decades after the onset of smoking. With regard to coherence of the
association with known facts, the studies noted the ecologic increase in
lung cancer rates with increased smoking in the population; the gender
differential in lung cancer, which at the time was consistent with lon-
ger term smoking by men; the urban-​rural difference, which air pollu-
tion could not completely explain; socioeconomic differentials in lung
cancer, for which smoking seemed to be the strongest explanation;
102
102 Part I:  Basic Concepts
and the topography of cancers within the respiratory tract in relation
to the type of smoking. The studies also cited the known reduction
in risk among former smokers, with greater risk reductions correlated
with more time spent not smoking. These observations, in combination
with histopathological evidence, basic biologic observations, and an
in-​depth discussion of each competing non-​smoking-​related explana-
tion (e.g., occupation, constitutional hypothesis, infections, environ-
mental factors such as pollution) produced a case for causation that
proved irrefutable.
The 1986 Report of the Surgeon General (US Department of Health
and Human Services, 1986)  concluded that passive smoking causes
lung cancer, a conclusion that has proven to be momentous in its impli-
cations. This report also based its evaluation of the evidence on the
causal criteria. A  clear distinction was made between the evidence
regarding active smoking and that expected from the much lower
doses of carcinogens arising from passive smoking. Biologic plausibil-
ity was emphasized, including the substantial evidence on lung cancer
risk in active smokers. This causal conclusion has been reaffirmed in
all subsequent reports (International Agency for Research on Cancer,
2004; Samet and Wang, 2000; US Department of Health and Human
Services, 2006, 2014).
EMERGING ISSUES IN CAUSAL INFERENCE
AND CANCER
Perhaps the most challenging and exciting issue facing all scientific
disciplines in cancer is the prospect of more fully understanding the
processes of carcinogenesis at the molecular level. Great advances
have been made that have implications for understanding etiology,
early diagnosis, and treatment. The paradigm of “precision oncology”
is being vigorously promoted with the goal of highly individualized
therapy based on the tumor’s genome. Underlying this paradigm shift
is the proposition that increasingly in-​depth sequencing of germ-​line
and tumor DNA, along with other data, will provide genetic and epi-
genetic “signatures” that indicate the causal pathways and tumor char-
acteristics that should be targeted for individual patients.
With the opening of the cancer “black box,” however, comes greater
recognition of the extraordinary complexity of carcinogenesis at the
molecular level (Smith et al., 2015). This is apparent in many ways.
Not only are the effects of external exposures modified by metabolic
pathways, but environmental factors also can modify gene expression
(e.g., through DNA methylation) (Brien et al., 2016; Mortensen and
Euling, 2013), interact with each other and with genetic factors in myr-
iad ways, and perhaps most intriguingly, behavioral patterns can be
influenced by inherited genetic susceptibility, as has been documented
for nicotine, alcohol, and drug addiction (Morozova et al., 2014; US
Department of Health and Human Services, 2010). This complexity
poses significant challenges for population-​based risk assessments
and causal inference because it raises, more acutely than with con-
ventional risk factors, questions about which genes lie in the causal
pathway (those that do should not be considered covariates), which
genes or biomarkers are necessary for the effects or function of oth-
ers (i.e., there may be many biologically based high-​level interaction
terms), whether an observed association represents a direct or indirect
effect on causation, and whether it is meaningful to talk about binary
exposure–​outcome or gene–​outcome relations when the components
of these complex networks either cannot be changed individually or
cannot be changed at all (Taioli and Garte, 2002).
It is interesting to consider the implications of this level of complex-
ity for causal inference in cancer. Obviously, we now better understand
the biologic basis of action of long-​established carcinogens, such as
smoking, chemotherapy, and various chemical agents. Mechanistic
explanations that relate particular exposures to specific types of cancer
increase confidence that an observed association between the exposure
and the incidence of that cancer is justifiably labeled “causal.” Such
mechanistic understanding may also advance the possibility of early
detection and preventive interventions. Molecular “signatures” of spe-
cific exposures (e.g., p53 CpG hotspots) (Greenblatt et al., 1994) are
identifying the relevant effects of certain exposures more precisely. It
seems possible that such approaches may soon be able to document
causal connections between a subset of exposures and disease at the
individual level. If such signatures are eventually established with suf-
ficient confidence, the societal implications would be profound, as
responsibility for causation in individuals could be assigned.
One challenge that results from these developments is that our
technical ability to perform mass screening using high throughput,
genomic, and proteomic technologies has far outstripped our ability
to understand what we find. The functions of many genes, genetic
alterations, and gene products are not yet understood. The enormous
quantities of data related to exposure and susceptibility increasingly
overwhelm our traditional approaches to data analysis and interpreta-
tion. Epidemiologists have long faced the problem of data overload,
but never on this scale. Millions of potential markers are now measured
and analyzed in all combinations, sometimes in only tens or hundreds
of subjects. Undoubtedly, future research will generate even larger
and richer data sets from full genome sequencing and “exposomics.”
Consequently, the potential for false-​positive associations caused by
multiplicity (“data dredging”) will continue to increase (Begley, 2013;
Begley and Ioannidis, 2015).
Issues concerning measurement must also be considered in this rush
toward exploring new potential causes of cancer (Little et al., 2002).
Many of the techniques and assays used to identify metabolic prod-
ucts, genes, and gene products are still relatively new and are not yet
fully standardized. Understanding the reliability and validity of these
techniques is an arduous process that often does not receive sufficient
attention, yet it is critical for distinguishing likely spurious claims
from those that are well grounded.
Our existing frameworks for causal inference will certainly continue
to evolve with future advances in understanding the basic mecha-
nisms of carcinogenesis and the ever-​widening array of biomarkers
that reflect internal exposures, metabolic pathways, and pre-​malignant
events. New criteria will be needed to determine whether a proposed
mechanistic pathway is actually an important contributor to risk
(Goodman and Gerson, 2013). This inferential problem is recognized,
and adaptations of the Hill guidelines have been proposed (Goodman
and Gerson, 2013). Epidemiologists also have some new tools for
facilitating causal inference. Directed acyclic graphs (DAGs) have
utility for sharply specifying underlying causal, mechanistic pathways
(Greenland et al., 1999). Over the last two decades, causal modeling
approaches have advanced that are based around a causal framework
and that improve estimation of causal effects in comparison with ear-
lier approaches (Petersen and van der Laan, 2014). Marginal structural
models are widely used for this purpose.
We are increasingly able to identify subpopulations of individu-
als who may experience different degrees of risk or benefit from a
particular exposure or interventions. This heterogeneity of risk may
result from inherited or somatic alterations that affect the absorption,
metabolism, or cellular effect of an agent or the host’s susceptibility
to the exposure or intervention (Links et al., 1995; National Research
Council et al., 2012). The smaller size of these subpopulations poses
its own set of challenges to epidemiologic approaches to risk assess-
ment: the finer the risk stratification, the more difficult it is to measure
variations in risk using epidemiologic methods and to assess whether
associations are causal (Moore et al., 2003; Slattery, 2002).
As we come closer to understanding cancer on the molecular level,
many have raised the possibility of individual risk prediction, guided
by molecular data (Hussain et al., 2001; National Research Council,
2011; Terry, 2015). This supposition underlines the concepts of what
are currently termed “precision medicine” or “precision prevention”
(National Research Council, 2011; Terry, 2015). Some commentators
have suggested that mechanistic understanding may ultimately render
population studies irrelevant. However, it is instructive to consider the
case of infectious diseases. Understanding the basic mechanisms of
infectious disease has not eliminated the need to study disease patterns
and causal factors on a population level, and the same will likely be
true for cancer (Nevins et al., 2003). There are many reasons to believe
that cohort studies will be as important in the future as they are now,
albeit perhaps focused on different kinds of questions. To understand
a mechanism after a cancer occurs is not the same as predicting it at
 103
Causal Inference in Cancer Epidemiology 103
some early stage of the process when the disease can be prevented.
Prediction will necessarily be less than 100% accurate, and defining
optimal groups for screening and early intervention will still require
population-​based data. Risk groups must be defined using far fewer
factors than we know are operating at the molecular level, the latter
being almost unique for an individual.
The molecular revolution in cancer may ultimately force a merg-
ing of two “schools” of determining causation: the probabilistic, risk-​
based model that the Hill criteria addressed and the more mechanistic,
deterministic models used for infectious disease, for which the Henle-​
Koch criteria were devised (Fredricks and Relman, 1996). It is interest-
ing that the Henle-​Koch criteria have proven to be inadequate, even for
understanding viral carcinogenesis. These criteria were based on the
nineteenth-​century understanding of bacterial disease causation and
are poorly suited for viral disease mechanisms or outcomes. Efforts
to refashion the Henle-​Koch criteria for the new era of molecular
medicine (Fredricks and Relman, 1996; Vineis and Porta, 1996) have
shown that it is extraordinarily difficult to outline a set of experimental
conditions that apply to all known pathogens—​not to mention new
pathogens with different mechanisms—​in order to provide a universal
framework for all new infectious diseases.
In the case of viral carcinogenesis, the situation is even more com-
plex because the final disease is only partly a direct manifestation of an
infectious process. Numerous viral agents have been linked to cancer
with what is designated “sufficient” evidence of carcinogenicity (see
Chapter 24 in this volume). In some cases, such as Epstein-​Barr virus
and human papillomavirus, the virus integrates directly into the host
DNA. The immunosuppression caused by human immunodeficiency
virus (HIV) increases the pathogenicity of other viruses such as HPV
and HTLV1. Other microbial organisms, such as hepatitis B and C
viruses, bacterial infection with helicobacter pylori, and protozoal
infections such as schistosomiasis and liver flukes, create a continu-
ing cycle of cell necrosis and repair that is associated with increased
cancer risk in the affected tissues. Thus, there is no single molecular
finding that definitively implicates an infectious organism as a cause
of cancer. The variety and complexity of mechanisms by which infec-
tious organisms increase cancer risk seem to defy a set of causal crite-
ria based on any specific mechanism.
Multiplicity, Transparency, and Reproducible
Research
There has been increasing acknowledgment and concern about the
validity of claims from biomedical research in general, and obser-
vational research in particular (Begley and Ioannidis, 2015; Collins
and Tabak, 2014). Problems in cancer research have been identified at
almost all levels, from identification of therapeutic targets (Prinz et al.,
2011)  to alleged carcinogenic effects of common foods (Schoenfeld
and Ioannidis, 2013) to genetic risk factors for cancer (Ioannidis and
Khoury, 2011) and findings of modest cancer risk factors from stan-
dard case control or cohort studies (Tai et al., 2014).
There are many sources of these problems, but one of the most
common is that of multiplicity, which is particularly pernicious when
hidden. Problems with multiplicity occur when multiple exposures or
risk factors are considered, multiple outcomes are assessed, multiple
models fit or analyses are implemented, and multiple experiments are
conducted. When statistical significance is a determinant of whether or
where a paper is submitted, which papers are published, which models
are reported, which exposures, experiments, or outcomes are reported,
and which analyses are presented, we in effect produce a potent scien-
tific false-​positive machine with results highly unlikely to reproduce.
Moreover, media publicity about the findings is often based on novelty,
rather than on reproducibility or scientific credibility.
The solutions to this problem are diverse (Begley, 2013; Begley
and Ioannidis, 2015), ranging from raising the statistical standards of
evidence (Johnson, 2013) to complete disclosure of all analyses con-
ducted, data sharing (Doshi et al., 2013), pre-​registration of observa-
tional studies, and modification of institutional incentive structures
that reward the quality of papers published rather than the quantity
or publicity generated. While such concerns are not framed in causal
language, if an observed correlation is highly likely to have been
observed by chance, the question of cause is moot. Standards for the
conduct and reporting of virtually all biomedical research are evolving
to enhance the validity of statistical and causal inference.
CONCLUSION
It seems unlikely that the need for population-​based risk estimates and
causal inference will disappear from cancer research, just as it has not in
infectious disease. However, we are entering an era in which the relative
strength of the “twin pillars” of causal inference—​knowledge derived
from empirical, population-​based patterns and that based on understand-
ing of biologic mechanisms in individuals—​will tilt farther toward the
mechanistic end, requiring less proof from populations and more from
the laboratory. Despite this, the public health importance of the findings
will continue to be based on the prevalence of exposure and magnitude
of risk. One challenge for causal inference in the future will be how best
to integrate these various forms of evidence and how to assemble groups
with the sufficient interdisciplinary expertise to assess them.
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 105

II
THE MAGNITUDE OF CANCER
 107
8 Patterns of Cancer Incidence, Mortality, and Survival
AHMEDIN JEMAL, D. MAXWELL PARKIN, AND FREDDIE BRAY
OVERVIEW
The global burden of cancer is expected to increase from 14.1  mil-
lion newly diagnosed cases and 8.2 million cancer deaths in 2012 to
22 million cases and 13 million deaths in 2030. This increase, based on
projected population aging and growth, will disproportionately affect
low-​and middle-​income countries (LMICs), where large numbers of
young adults are now surviving to older ages, when cancer becomes
common. The future cancer burden is likely to be even higher than
predicted from demographic changes alone, because of the ongoing
adoption of Westernized patterns of diet, physical inactivity, delayed
reproduction, and cigarette smoking. The incidence of cancers tra-
ditionally associated with Western behavioral, environmental, and
cultural factors (breast, colorectum, lung, and prostate) are increas-
ing in LMICs, whereas cancers caused at least partly by infectious
agents (stomach, liver, uterine cervix) are decreasing. The timing and
pace of this epidemiologic transition varies by region; however, many
LMICs continue to bear a large burden of infection-​related cancers.
Furthermore, survival after a diagnosis of cancer tends to be consider-
ably lower in LMICs because of late stage of diagnosis and a lack of,
or limited availability of, standard treatments.
In high-​income countries, the incidence rates of the most common
cancers are either stabilizing at a high level or decreasing, depending
on the underlying risk factors and the extent to which early detection
and screening approaches are utilized. The over-​diagnosis of certain
tumors adds to the cancer burden in affluent countries, yet mortality
rates are decreasing for many sites due to a combination of prevention
and improved treatment.
Population-​based cancer registries (PBCRs) are central to cancer
surveillance and control. These registries now cover over 95% of the
population in North America, but less than 10% of the populations
of South America and Africa. There is an urgent need to expand the
coverage and improve the quality of cancer registration and death cer-
tification in LMICs. Equally, there is a need to attract and train young
investigators in the uses of surveillance data for cancer control.
INTRODUCTION
Population-​based cancer registries (PBCRs) provide information on
newly diagnosed cancer cases, deaths, and survival in geographically
well-​defined populations (Parkin, 2008). Because the target popula-
tion is defined by place of residence rather than the location of treat-
ment, PBCRs avoid the potential for referral biases that affect clinical
series and, to some extent, hospital-​based registries (Ries and Devesa,
2006). The first PBCRs were established in North America in 1935
(Connecticut Department of Public Health [CDPH], 2016), and in
Nordic countries in the 1940s and 1950s (Wagner, 1985). Since then, a
network of registries, the International Association of Cancer Registries
(IACR; http://​www.iacr.com.fr) has developed as a professional orga-
nization with over 500 members worldwide. At present, 291 registries
in 68 countries provide high-​quality data, as evaluated and compiled in
the most recent volume of Cancer Incidence in Five Continents (CI5;
http://​ci5.iarc.fr). Depending on their resources, PBCRs monitor can-
cer occurrence by anatomic site, histologic subtype, stage at diagnosis,
and survival. In high-​income countries the data can be linked to other
administrative databases, thereby broadening the scope of research to
encompass access to cancer care, quality of care, quality of life, and
cost of care (Glaser et al., 2005; Hiatt et al., 2015; Howe et al., 2003;
Wingo et al., 2005).
Over the last 20  years, PBCRs have become the cornerstone of
cancer surveillance and control (Shin et al., 2007). Surveillance data
are used to monitor trends, guide resource allocation, forecast future
needs (Bray and Moller, 2006; Hiatt and Rimer, 1999; Storm, 1996),
and evaluate the impact of preventive and curative interventions
(Parkin, 2008).
This chapter describes international patterns of cancer incidence,
mortality, and survival as estimated by GLOBOCAN 2012, a com-
prehensive profile of the risks and burden from cancer in 184 coun-
tries for the year 2012 (http://​globocan.iarc.fr). It describes temporal
trends in cancer incidence based on the CI5 series (Ferlay et al., 2013)
and mortality data from the World Health Organization (WHO). We
begin by discussing several basic concepts in cancer surveillance, par-
ticularly the distinction between risk (the average probability of being
diagnosed with or dying from cancer in a designated time period), and
burden (the total number of newly diagnosed cases, cancer deaths,
prevalent cases, and/​or economic costs in the population). Other terms
are defined as they appear in the text. The methods used to develop
GLOBOCAN 2012 are described only briefly here, since they are
documented extensively elsewhere (Ferlay et al., 2015). Unlike the
chapters on cancer surveillance in previous editions of this text (Parkin
and Bray, 2006; Ries and Devesa, 2006), we do not discuss cancer
surveillance in the United States separately from the global picture,
nor do we present detailed information on individual cancer sites. Site-​
specific information can be found in Part IV of this text, “Cancers
by Tissue of Origin.” Detailed statistical data for the United States
are widely available online from major cancer research organizations
(Centers for Disease Control and Prevention [CDC], 2016; National
Cancer Institute [NCI], 2016; the American Cancer Society [ACS],
2016), and are updated more frequently than is possible in this text.
GENERAL CONCEPTS
Distinction Between Risk and Disease Burden
As noted in the preceding, risk represents the average probability that
individuals in a population will be diagnosed with or die from some
specified form of cancer during a defined time interval. Conceptually,
risk is probabilistic; it can be defined only in a group of people, not
a single individual. The average annual risk of developing or dying
from cancer can be approximated as an incidence or mortality rate per
100,000 people per year for adult cancers, and per million per year for
childhood cancers. While the average risk in a population is inevitably
higher or lower than that of nearly all individuals, the incidence and
mortality rates can be standardized or stratified by age to allow valid
comparisons between populations that differ in size or age structure.
The rates are calculated by dividing the number of events in a given
year by the number of people at risk. The methods of standardizing or
otherwise controlling for the age of the population are described at the
end of this chapter.
Unlike risk, disease burden represents the absolute numbers (or
counts) of incident cases, deaths, cancer survivors, and economic
costs in a population, regardless of its size or age composition. The
107
108
108 Part II: The Magnitude of Cancer
number of incident cases and deaths correspond to the numerator in
calculations of incidence and mortality rates. These absolute numbers
provide a partial indication of the human costs of cancer in the popula-
tion. They do not represent risks and should not be used to estimate
risk in different populations or time periods. The American Cancer
Society (ACS) publishes estimates of the number of newly diagnosed
cancer cases and deaths anticipated in the current year in the United
States (Siegel et al., 2016). These represent estimates rather than actual
counts, since the data for the current year do not become available at
the national level until several years later. The ACS estimates are pro-
jections, based on statistical modeling of the observed number of cases
and deaths in previous years (Chen et al., 2012; Zhu et al., 2012). For
2016, the ACS estimated that about 1.7 million new cancer cases and
almost 600,000 cancer deaths would occur in the United States (Siegel
et al., 2016).
Cancer Survival and Prevalence
The terms used to describe cancer survival and prevalence are in cer-
tain respects more ambiguous than incidence and mortality rates, since
it is often unclear whether a cancer has been cured or is merely in
remission. The NCI program of Surveillance, Epidemiology and End
Results (SEER) in the United States uses several measures of preva-
lence. Limited duration prevalence signifies the proportion of people
alive at a designated date diagnosed with cancer within a specified
time period in the past (e.g., 5, 10, or 15  years). This chapter uses
the definition adopted by the International Agency for Research on
Cancer (IARC) in GLOBOCAN, with 5-​year prevalence estimating
the number of cancer patients diagnosed with the disease within the
last 5 years and alive in 2012. Complete prevalence describes the pro-
portion of people alive who were ever diagnosed with cancer, regard-
less of when this occurred (SEER, 2015).
GLOBOCAN 2012 does not use the term relative survival, although
this is mentioned in many chapters of this book. Relative survival sig-
nifies the ratio between the proportion of cancer patients who have
survived for a specified time period after diagnosis, divided by the
percentage of survivors of the same age who have not been diagnosed
with cancer. This term is often referred to erroneously as a rate.
Factors That Affect Cancer Risk and Burden
Population Aging
Attained age is a strong risk factor for cancer. The overall incidence
rate from cancer more than doubles with each 10-​year increase in
attained age. Consequently, the number of people affected by, or dying
from, cancer (disease burden) increases as the population ages. The
influence of the age distribution of the population on incidence (and
mortality) rates must be taken into account when comparing risk in
two or more populations (see discussion of methodologic issues later
in this chapter). In general, age-​standardized and age-​specific rates are
independent of the age structure and size of the population, whereas
the burden increases with population aging and growth. Growth and
aging of populations have an especially large effect on the future
cancer burden in economically developing countries, because of the
large population of young adults who are now surviving into older age
groups where cancer becomes common.
Risk Factors
Changes in the prevalence of risk factors that increase or decrease
tumorigenesis directly affect both the risk and disease burden from
cancer. Many risk factors are associated with economic develop-
ment, as discussed in the following subsection. People who live in
low-​income countries have greater exposure to oncogenic infections
such as Helicobacter pylori, hepatitis B virus (HBV), untreated human
immunodeficiency virus (HIV), parasitic disorders, and so on (see
Chapter  24), but less exposure to factors associated with economic
development (manufactured cigarettes, excessive caloric intake, physi-
cal inactivity, and delayed reproduction). In consequence, the types of
cancer occurring may change with economic development. The so-​
called epidemiologic transition involves an increase in the incidence
rate of cancers traditionally associated with Western lifestyles (breast,
colorectum, lung, and prostate), and a decrease in cancers caused
by infectious agents (stomach, liver, uterine cervix), and usually an
increase in the all-​cancer incidence rate. The transition occurs at a dif-
ferent pace in different countries, reflecting local differences in culture
and the physical and social environment.
Economic Development
Economic and social development has complex effects on the risks
and burden from cancer. Improvements in sanitation, nutrition, vacci-
nation, and treatment can all reduce the occurrence of cancers caused
by infectious agents (stomach, liver, uterine cervix, Kaposi sarcoma),
as mentioned earlier. Economic development can also prevent severe
nutritional deficiencies, which likely contribute to the incidence of
certain cancers, such as squamous cell carcinoma of the esophagus
in Asia and Africa (Schneider et al., 2007). Exposure to occupational
and environmental pollutants, such as asbestos, arsenic, and indoor
air pollution, at first increase and then decrease with economic and
social development (Bray et al., 2015b). Some forms of early detec-
tion reduce the incidence and mortality rates from specific cancer sites.
Treatment improves survival. These benefits can be offset, however,
by urbanization and increased exposure to Westernized patterns of
diet, physical inactivity, delayed reproduction, and cigarette smoking.
Like occupational exposures, cigarette smoking first increases with
economic development, but then decreases with social development.
Over-​diagnosis inflates the incidence rate of screening-​detected cancer
of the prostate, breast, and thyroid, among others.
Screening
The effects of screening on cancer risk and burden are equally com-
plex (see Chapter 63). Screening for certain cancers (e.g., cervical and
colorectal) decreases both incidence and death rates by detecting and
leading to the removal of premalignant lesions and early stage can-
cers. These tests reduce both risk and burden. In contrast, screening for
breast cancer and lung cancer decreases mortality from these cancers,
but at the cost of increasing other aspects of burden (e.g., incidence
and unnecessary treatment). Screening for prostate cancer provides
marginal benefits in terms of a reduction in mortality for men at aver-
age risk, but dramatically increases incidence and overestimates sur-
vival. The distorting effects of prostate cancer screening on incidence
and mortality rates are discussed later in the chapter. The effects of
screening with prostate specific antigen (PSA) on relative survival is
equally large, since periodic screening advances the time of diagnosis
while differentially detecting indolent tumors rather than cancers that
grow rapidly. This creates the appearance that screening has improved
survival, even when it has not (Chapter 63). When routine PSA screen-
ing was first introduced in the United States and was recommended
for all men over age 50 years, the 5-​year relative survival for prostate
cancer increased from 68% (for those diagnosed in the mid-​1970s), to
nearly 100% (for those diagnosed in 2004–​2010) (Siegel et al., 2013).
The decrease in the mortality rate was considerably smaller (Welch
and Albertsen, 2009; Welch and Black, 2010).
Over-​diagnosis
Over-​diagnosis refers to the detection of small and/​or indolent cancers
during screening or diagnostic evaluation that otherwise would not
have become clinically evident during the patient’s lifetime (Parkin
and Moss, 2000). This tends to affect cancers that may remain indolent
or latent for long periods of time (e.g., prostate, thyroid, some breast
cancers, kidney, lung, and melanoma) (Cook et  al., 2009; Fontana
et al., 1991; Welch and Black, 2010) and, because it is a consequence
of population screening, is more of a problem in high-​income coun-
tries than in LMICs. It has been estimated that over-​diagnosis from
screening may account for as many as 40% of newly diagnosed pros-
tate cancer cases and 10%–​30% of incident breast cancer cases in the
United States and several other Western countries (Bleyer and Welch,
2012; Etzioni et  al., 2002; Loeb et  al., 2014; Vickers et  al., 2014).
Over-​diagnosis can affect trends in mortality rates as well as incidence,
 109
Patterns of Cancer Incidence, Mortality, and Survival 109
due to attribution bias (Feuer et  al., 1999). The main problem with
over-​diagnosis, however, is the increasing number of people who are
diagnosed with cancer and who may receive unnecessary treatment
(Vaccarella et al., 2016).
Under-​diagnosis
Under-​diagnosis of cancer occurs more often in LMICs than in afflu-
ent countries. Under-​ diagnosis occurs because of limited medical
resources and infrastructure, lack of awareness (education), and bar-
riers to care. It is more of a problem for cancers that require sophisti-
cated diagnostic tests (e.g., pancreas and ovary) than for sites that are
more easily diagnosed.
Methodologic Issues
Age Adjustment
As the incidence and death rates of many forms of cancer increase
exponentially with attained age, it is necessary to standardize or strat-
ify rates according to age groups when comparing populations with
different age structures. The approach used most commonly in sur-
veillance data is direct age standardization. Age-​standardized rates
summarize the average rates in two or more populations by weighting
each age group to the age distribution of a standard population. This is
essentially the hypothetical rate that would prevail if all of the popula-
tions being compared had the same age distribution as the standard
population. The actual structure of the standard is of no consequence
for comparative purposes (Bray et al., 2002), but of course the same
standard population must be used for all of the populations being com-
pared. Nevertheless, different organizations and countries use different
standard populations when reporting incidence and mortality rates. In
order to allow comparisons between different populations, and over
time, IARC continues to use the World Standard (Doll and Cook,
1967) to compare international rates. In the United States, health agen-
cies have historically used the national age distribution as the standard,
but have shifted this in more recent years as the population has aged
(Klein and Schoenborn, 2001). In most public and private health agen-
cies in the United States, the national age distribution in 1940 was used
until 1970; it then shifted to the 1970 distribution until 1980; the 1980
distribution until 1999, and the 2000 US population thereafter (Klein
and Schoenborn, 2001).
An alternative measure that does not require choice of an arbi-
trary or varying standard is the cumulative rate (or risk) of develop-
ing (or dying from) cancer by a selected upper age limit (e.g., 65, 75,
85) (Day, 1992).
Enumeration Errors
Errors in enumerating cases, deaths, and/​or the population at risk can
also bias measurements of cancer risk and burden. This can occur for
several reasons. Incomplete ascertainment or changes in tumor clas-
sification can bias numerator data. Inconsistent approaches to the
classification of multiple primary tumors can be especially problem-
atic (Chapter 60). In the United States, delayed reporting of recently
diagnosed cases causes an undercount of cancers diagnosed in non-​
hospital settings during the previous 1–​3  years (Clegg et  al., 2002).
For example, leukemia is underestimated by about 14% in the most
recent years, and prostate cancer by about 4% (NCI, 2015). Changes in
a population between census counts due to migration or other factors
can cause estimates based on interpolation to over-​or underestimate
the population at risk (Ward et al., 2005).
Migrant Studies
Classic studies have measured the risk of specific types of cancer
among migrants who move from a high-​to low-​risk country, or vice
versa, and have compared this to the risk in their country of origin and
in the host country (Haenszel, 1961). Within one or two generations,
the risk of colorectal, stomach, or breast cancer among immigrants
approaches that of the host country. The differences in risk following
migration parallel the changes that occur within countries undergoing
economic development. In both settings, the changes in risk are pre-
sumed to reflect change in “environmental” (i.e., acquired) exposure,
rather than in inherited genetic susceptibility (Bray and Parkin, 2014).
Although migrant studies can be biased by selection for factors that
enable migration (“healthy migrant effect”) or by differences in the
completeness of cancer detection between the country of origin and
the host country (Parkin and Khlat, 1996), they provide important evi-
dence that factors other than inherited genes strongly affect cancer risk
in human populations.
GLOBAL CANCER PATTERNS, 2012
This section discusses global and regional patterns of cancer incidence,
mortality, and survival, based on the estimates of GLOBOCAN 2012
(http://​globocan.iarc.fr) and longitudinal data from Cancer Incidence
in Five Continents (http://​ci5.iarc.fr/​). It also considers cancer risk and
burden in relation to Human Development Index (HDI) designations
for 172 countries. The methods used to make the GLOBOCAN 2012
estimates are described briefly at the end of the chapter.
Human Development Index (HDI)
The Human Development Index (HDI) is as a composite measure of
economic and social development, based on life expectancy, educa-
tion, and gross domestic product per head (http://​hdr.undp.org/​en/​con-
tent/​human-​development-​index-​hdi). A map of countries in relation to
quartiles of HDI (Figure 8–​1) shows the geographic distribution of
this index in 2012. Most low HDI countries were concentrated in sub-​
Saharan Africa. Medium-​HDI countries spanned much of Asia, includ-
ing China and India, and parts of Africa and Latin America. High HDI
countries predominated in Eastern Europe, the former Soviet Union,
northern Africa, Mexico, and northern South America. Very high HDI
countries included Japan, Australia, Argentina, Chile, several Gulf
States, and countries in Western Europe and North America.
Geographic Distribution of Cancer Burden
All Sites Combined
Our analyses of all cancer sites combined exclude non-​melanoma skin
cancer. Figure 8–​2 shows the global distribution of the cancer bur-
den by geographic region for all anatomic sites combined in 2012.
Asia accounted for nearly half (48.0%) of the 14.1 million newly diag-
nosed cases in that year, and more than half (55%) of the 8.2 million
cancer deaths. Asia contributed a smaller proportion of cancer cases
and deaths than might be expected, given that it comprises 60% of
the global population. Moreover, Asia accounted for only 40% of all
prevalent cases, reflecting the generally poor survival and case mix
of cancer patients in middle-​and low-​resource countries. In contrast,
Europe, which accounts for only 10% of the world population, con-
tributed 24% of incident cases, 21% of cancer deaths, and 28% of
prevalent cases.
Specific Anatomic Sites
In analyses of men and women combined, a relatively small number
of anatomic sites accounted for more than half of the total number of
incident cases, cancer deaths, and prevalent survivors in 2012 (Figure
8–​3). Lung and colorectal cancer were among the four most common
sites for all three measures. Lung cancer ranked first for incidence and
mortality, but fourth for prevalence. Breast cancer ranked first for prev-
alence, second for incidence, but fifth for mortality.
Five Most Common Cancer Sites by Gender
Figures 8–​4 and 8–​5 show the five most common cancer sites in men
and women separately in terms of incident cases, cancer deaths, and
prevalent cases (IARC, 2016). These rankings are not stratified by HDI
level. In men, cancers of the lung, prostate, and stomach rank among
10

110 Part II: The Magnitude of Cancer

Human Development Index

Low HDI
Medium HDI
High HDI
Very High HDI

No data Not applicable

The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever
on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities,
or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines
for which there may not yet be full agreement.

Figure 8–​1.  Countries according to Human Development Index (HDI), 2012. Source: World Health Organization (WHO).

the top five sites for incident and prevalent cases and cancer deaths.
In women, cancers of the breast, colorectum, and uterine cervix are
consistently among the most common. For all three measures, the five
most common sites account for more than half of the total. In terms of
prevalence, thyroid cancer ranked among the five most common can-
cers in women, reflecting over-​diagnosis from screening and the low
fatality rate of screen-​detected thyroid cancers.
Geographic Distribution of Cancer Risk
Striking geographic differences have long been observed in the
incidence and mortality rates of certain types of cancer (Muir,
1996; Parkin and Bray, 2006; Ries and Devesa, 2006). As early
as 1915, Hoffman reported a 10-​fold difference in the death rate
from breast cancer between Japanese and British women (Hoffman,
1915; Muir, 1996). The regional differences in incidence rates
exceed 25-​fold for cancers of the esophagus, nasopharynx, and
prostate (IARC, 2016), and approach 10-​fold for cancers of the
breast, colorectum, lung, and liver. These differences are larg-
est when examining smaller areas within the WHO regions. For
example, Burkitt lymphoma in children is rare, except in endemic
malarial regions of equatorial Africa (Chapter 40). Nasopharyngeal
cancer is rare throughout most of the world, but is very common in
the high-​risk regions of southern China and parts of East and South
Africa (Chapter 26).

Incidence Mortality Prevalence (5 years)

Africa
Africa 5.5%
6.0% North North America
Africa America 16.3%
North 7.2% 8.4%
America Latin America &
Latin America &
12.7% the Carribean
the Carribean Latin America
7.4%
7.8% & the Carribean
8.1%
Asia Europe Asia
Asia 21.4%
48.0% Europe 54.9% 40.5%
24.4%
Oceania Europe
0.7% 28.2%

Oceania
1.1%

Oceania
1.4%

14.1 million 8.2 million 32.5 million

New cases Deaths Persons

Figure 8–​2.  Regional distribution of newly diagnosed cancer cases, deaths, and survivors worldwide, 2012. Source: GLOBOCAN (2012).
 1

Incidence Mortality Prevalence (5 years)

Breast
Lung 19.2%
13.0% Other
Lung 31.0%
Other Breast Other 19.4%
35.3% 11.9% 32.0% Liver Prostate
9.1% 12.1%
Colorectum
9.7%
Cervix uteri 3.2% Stomach
Prostate 3.7% 8.8%
Bladder 3.1% Pancreas 4.0% Colorectum Thyroid Colorectum
Prostate
Esophagus 3.2% 7.9% Esophagus Breast 8.5% 3.7% 10.9%
4.9% 6.4%
Cervix uteri 3.7% Liver Stomach Corpus uteri Lung
5.6% 6.8% 4.1%
Cervix 5.8%
Bladder uteri
4.1% 4.8%
Stomach
5.8%

14.1 million 8.2 million 32.5 million

New cases New cases Persons

Figure 8–​3.  Percentage contribution to commonly diagnosed cancer cases and deaths and prevalent cases worldwide, 2012. Source: IARC.

Prevalence
Incidence Mortality (5 years)

Lung
Lung Prostate

Prostate 40.3%
42.4% Liver 40.5%
57.6% Colorectum
59.5%
59.7%
Colorectum Stomach Lung
Stomach Colorectum Stomach
Liver Prostate Bladder

7.4 million 4.7 million 15.3 million

New cases Deaths Persons

Figure 8–​4.  Five most common cancer sites worldwide in men. Source: IARC.

Prevalence
Incidence Mortality (5 years)

Breast
Breast
Breast

Lung 32.9%
44.2% 47.8%
Colorectum 55.8% 52.2% 67.1%

Colorectum Colorectum
Lung
Cervix uteri
Cervix uteri
Cervix uteri Corpus uteri
Stomach Thyroid
Stomach

6.7 million 3.5 million 17.2 million

New cases Deaths Persons

Figure 8–​5.  Five most common cancer sites worldwide in women. Source: IARC.

12
112 Part II: The Magnitude of Cancer
The large international differences in cancer risk, and changes in
risk among migrants who move from one country to another, have led
to estimates of the preventability of cancer. The landmark study by
Doll and Peto in 1981 estimated that approximately 80% of cancer
deaths in the United States were preventable “in principle” (Doll and
Peto, 1981). This is supported by the large temporal changes in the
incidence of specific cancer sites occurring within countries.
Cancer Risk and Burden by Level of HDI
Whereas the annual risk (per 100,000) of being diagnosed with cancer
is about 80% higher in countries designated as high/​very high HDI
(240.6) than in low/​medium HDI countries (135.8), the latter account
for more than half of all cases globally. This reflects the large constit-
uent populations of low and medium HDI countries, which in 2012
included China and India. The burden from cancer is higher and is
increasing more rapidly in LMICs than in high-​and very-​high-​income
countries. Figure 8–​6 shows the anticipated shift in the cancer bur-
den from developed to developing countries. From 2012 to 2035,
the proportion of all cancers accounted for by LMICs is projected to
increase from 57% to 65% (IARC, 2016). The future cancer burden
is likely to be even larger than predicted from demographic changes
alone, because the incidence rates of cancers that are high in Western
countries and traditionally associated with factors linked to lifestyle
and environment within these countries (breast, colorectal, prostate,
lung) are increasing rapidly in many LMICs, as discussed later in the
chapter.
The cumulative risk of cancer between ages 0–​74  years is lowest
in low HDI countries in Western Africa (9.8%) and Middle Africa
(10.9%) and in medium HDI countries in South Central Asia (10.7%),
and highest in very high-​income countries such as Australia and New
Zealand (30.7%), North America (30.9%), Western Europe (29.1%),
and Northern Europe (27.6%) (IARC, 2016).
Cancer Mortality Risk and Burden by Level of HDI
There was less variation in overall cancer mortality rates than in inci-
dence rates in relation to HDI level. When expressed as cumulative
risk of death from cancer by age 74, the probabilities in GLOBOCAN
2012 were 9.0% in economically developed countries and 8.1% in
developing countries. The generally poor survival of patients with can-
cer in LMICs partially offsets their lower incidence rates.
For prevalent cases, countries designated as high or very high HDI
account for the majority of cases of cancers of the breast, prostate,
colorectum, urinary bladder, uterus, thyroid and kidney, as discussed
later. Exceptions to this were cancers of the uterine cervix (which
were more common in low and medium than in high or very high HDI
Estimated Cases Projected Cases
(millions)
2012 2025 2035
57%
61% 65%
14.1 19.3 24.0
Developed regions
Developing regions
Figure 8–​6.  Shift in cancer burden from developed to developing c­ ountries.
Source: GLOBOCAN (2012).
countries), and lung and stomach cancer, for which the number of
prevalent cases was similar.
Temporal Trends in Site-​Specific Cancer Risk
by Level of HDI
Figures 8–​7 through 8–​10 show the temporal trends in incidence and
mortality rates for four cancer sites in relation to the level of HDI.
Decreasing incidence and mortality rates are observed for cancers
of the stomach (Figure 8–​7) and uterine cervix in most populations
(Figure 8–​8), whereas increasing rates are widely observed for cancers
of the breast (Figure 8–​9) and colorectum (Figure 8–​10).
Relation of 15 Cancer Sites to Level of HDI
The relationships between the incidence and death rates from specific
cancer sites and the level of HDI are also evident cross-​sectionally
in GLOBOCAN 2012 (Figure 8–​ 11). This figure shows the age-​
standardized incidence rates of the 15 most common types of cancer
worldwide in men (10 sites) and women (12 sites) in relation to the
level of HDI. The data from China and India are shown separately
from other medium HDI countries because of their massive popula-
tions (1.35 and 1.25 billion inhabitants, respectively). Incidence rates
rise with increasing HDI for lung, prostate, and colorectal cancer in
men and for breast and colorectal cancer in women. The relationships
between HDI and the incidence of other cancer sites are inconsist-
ent. Figure 8–​11 also illustrates that the incidence rate of lung cancer
in 2012 among Chinese women was as high as that in high and very
high HDI countries, despite the low prevalence of cigarette smoking.
Factors that affect lung cancer risk in Chinese women are discussed
later in the chapter. The incidence rate of lung cancer among Chinese
men was about four times higher than that among men in India, and
was higher than that of any of the HDI groupings.
Stomach Cancer.  A decrease in non-​gastric cardia cancer inci-
dence and mortality rates has occurred in nearly all countries in the
last 30 years (Figure 8–​7). The rate of decrease has been remarka-
bly similar in men and women, in high-​risk countries such as Japan
and low-​risk countries such as Denmark (Ferlay et  al., 2013), and
across a wide range of HDI levels. The decrease has been observed
in mortality rates in the United States since 1930 (Paik et al., 2001).
The age-​standardized incidence rate has decreased by more than
80% in parts of the United States since 1950 (Siegel et  al., 2016).
The reasons for the decreasing rates are not known conclusively,
but are postulated to involve improvements in sanitation, hygiene,
food preservation, and antibiotics (Howson et al., 1986). The fortu-
itous decrease in gastric cancer parallels temporal decreases in the
prevalence of Helicobacter pylori, the principal cause of non-​cardia
stomach cancer (Chapter 31), and coincides with the global spread
of refrigeration that made curing and salting foods obsolete in most
parts of the world. The decrease in gastric cancer that occurs within
countries undergoing economic development parallels the decrease
observed among migrants who move from high-​risk areas such as
Japan to lower risk areas such as the United States (Locke and King,
1980). Nevertheless, gastric cancer remains a common cancer site
globally, ranking among the top four incident cancers among men,
and fifth among women.
Cervical Cancer. Although less common than stomach cancer,
cancer of the uterine cervix remains the most commonly diagnosed
cancer among women in 39 of the poorest countries, and the leading
cause of cancer death among women in 19 countries in sub-​Saharan
Africa. The incidence and death rates are decreasing in most countries
(Figure 8–​8), but the incidence rates remain approximately twice as
high and the mortality rates three times higher in countries designated
low/​medium HDI than in those designated high/​very high HDI. The
decreases in higher-​income countries largely parallel the introduction
of effective screening programs, and have occurred despite high preva-
lence of persistent human papillomavirus (HPV) infection (Vaccarella
et al., 2014). The decreases in some lower income countries are thought
 13

Patterns of Cancer Incidence, Mortality, and Survival 113

Low/Medium HDI High/Very high HDI
80 80

60 60

50 50
Japan*
Age-standardized (world) incidence rate per 100,000, males

Age-standardized (world) incidence rate per 100,000, males

40 40

30 30
China
25 Colombia*
25

20 Japan 20
China* Denmark
France Colombia
15 15
Philippines*

Australia
10 10
India* USA*:
USA*: France* Black
Uganda* White
7 Thailand* 7
Australia
USA:
5 Black 5
Philippines Denmark
4 4

3 3

USA:
White
2 2

1980 1990 2000 2010 1980 1990 2000 2010

Year

Incidence Mortality

Figure 8–​7.  Trends in stomach cancer incidence and mortality rates for select countries, 1975–​2012. Source: IARC.

to result from improved genital hygiene (Dhillon et al., 2011), delayed
exposure to HPV, and some limited implementation of screening.
Female Breast Cancer.  Breast cancer is the most common cancer
among women worldwide. It is also the most common cause of cancer
death among women in less developed regions and the second most
common cause of cancer death (after lung cancer) in women in more
developed regions. Figure 8–​9 shows the temporal trends in incidence
and mortality rates from breast cancer in relation to HDI. The incidence
rates are increasing in most countries, but have reached a plateau in some
high/​very high HDI countries, where mortality rates are now decreasing.
The incidence rates still vary by a factor of nearly four across the world
regions. Cumulative risk between ages 0–​74 years in 2012 was highest in
North America (10%) and other high-​income countries (Western Europe,
Canada, and Australia). Cumulative risk was lowest in Central Africa and
East Asia (2.7%). The variation in mortality rates across world regions
was less than the variation in incidence rates, since it reflects differences
in treatment as well as underlying occurrence. The cumulative risk of
breast cancer death before age 75 in 2012 was lowest in East Asia (0.6%)
and highest in West Africa (2.1%).
in those designated as low/​medium HDI. In general, the incidence
rates in countries with high-​quality population-​based cancer regis-
tries increase with rising levels of HDI (Bray et al., 2012; Center and
Jemal, 2011). However, a downturn in incidence rates has occurred in
the United States (in both whites and blacks) and France, and a level-
ing off in Australia. The downturn in the United States is attributed
to the increased uptake of screening and the detection and removal of
premalignant colorectal lesions (Siegel et al., 2014). The stabilization
or decrease in incidence rates in younger birth cohorts in high-​income
countries is thought to reflect changes in dietary and activity patterns
in recent decades.
Mortality rates from colorectal cancer are substantially lower than
incidence rates. The mortality rates are increasing in low/​medium
HDI countries, but decreasing in all high/​very high HDI countries
except for Japan (Figure 8–​10). The increase in incidence rates began
later and has been larger in Japan than in other affluent countries. For
example, the incidence rate (per 100,000) of colorectal cancer among
men in the Myagi prefecture in Japan increased from 19.7 in 1979 to
61.6 in 2005, surpassing that of other high/​very high HDI countries
(Center et al., 2009).

Colorectal Cancer. Colorectal cancer is the third most com- Lung Cancer.  The geographic and temporal patterns of lung cancer
mon cancer in men and the second most common cancer in women. are discussed in Chapter 28. In absolute terms, the variations in lung
Regional incidence rates vary by a factor of 10 in both sexes. cancer risk during the last century have been larger than for any other
Figure 8–​10 shows the increase in incidence rates in most countries anatomic site. In 2012, lung cancer was the most frequently diagnosed
worldwide, with higher rates in high/​very high HDI countries than neoplasm among men in 38 countries and the leading cause of cancer
14

114 Part II: The Magnitude of Cancer

Low/Medium HDI High/Very high HDI

50 50
Uganda*
40 40
35
Age-standardized (world) incidence rate per 100,000, females

30

Age-standardized (world) incidence rate per 100,000, females

30
25 25
Thailand*
20 Colombia* 20
Philippines*
Japan*
15 India* 15

Australia Denmark
10 10
USA: Colombia
White
7 France* 7
6 USA:
China* 6
Black
5 5

4 Denmark 4
Philippines

3 USA*: 3
China Black
Japan
2 2
USA*:
1.5 Australia White 1.5
France

1 1
1980 1990 2000 2010 1980 1990 2000 2010
Year
Incidence Mortality

Figure 8–​8.  Trends in cervical cancer incidence and mortality rates for select countries, 1975–​2012. Source: IARC.

death in 91 countries (Figures 8–​12 and 8–​13). The incidence and
mortality rates were highest among men in Eastern Europe and much
of Asia, including China and Indonesia. Among women, lung cancer
was the most commonly diagnosed cancer only in China, but was the
leading fatal cancer in 25 countries, predominantly in North America,
Northern Europe, Australia and New Zealand, and China (Figures
8–​14 and 8–​15). More than half of all cases occur in economically
developing countries where smoking remains common, especially
among men.
Except among women in China, lung cancer rates overwhelm-
ingly reflect lifetime and recent cigarette smoking. Smoking cessation
among men in high-​income countries is causing a substantial reduc-
tion in lung cancer incidence and mortality rates, although the rates
continue to increase or are only now reaching a plateau among women
in these countries. In China, only 2% of women are current smok-
ers, and many former smokers used pipes rather than cigarettes. The
high lung cancer rates among Chinese women are largely the result of
indoor air pollution from cooking and heating with unventilated stoves
that have historically used coal (Chapter 28).
Site-​Specific Cancer Burden by Level of HDI
Figure 8–​16 shows the estimated number of incident cases, deaths,
and prevalent cancers in 2012 for the 10 most common cancer sites
in relation to two categories of HDI. High/​very high HDI countries
accounted for more than half of all incident cases of cancers of the
lung, breast, colorectum, prostate, urinary bladder, and non-​Hodgkin
lymphoma, notwithstanding the much smaller populations in these
countries. Low/​medium HDI countries accounted for the majority of
cancers of the stomach, liver, uterine cervix, and esophagus.
In terms of cancer deaths, the low/​medium HDI countries accounted
for more fatal cancers of the lung, liver, stomach, esophagus, and uter-
ine cervix than the high/​very high HDI countries. The latter accounted
for more deaths from cancers of the colorectum, pancreas, and pros-
tate. These two groups were approximately equal for deaths from can-
cers of the breast and leukemia. In terms of prevalent cases, high/​very
high HDI countries accounted for the majority of cancers of the breast,
prostate, and colorectum, by far the most prevalent types of cancer.
Survival Patterns
As indicated in Figure 8–​16, the number of cancer patients surviv-
ing 5 years after diagnosis (prevalent cases) is higher in high/​very
high HDI countries than in low/​medium HDI countries. Prevalence
is affected by the true underlying incidence rate and clinical behavior
of the cancer and by the availability and effectiveness of treatment.
Survival has lengthened for cancers of the breast and prostate and
colorectum in high-​and very-​high-​income countries (Allemani et al.,
2015). For breast and prostate cancer, this is due to an earlier average
 15

Patterns of Cancer Incidence, Mortality, and Survival 115

Low/Medium HDI High/Very high HDI
France* Denmark
100 100
USA*:
80 White USA*: 80
Black

Age-standardized (world) incidence rate per 100,000, females

Age-standardized (world) incidence rate per 100,000, females

60 Philippines* 60
Australia
50 Colombia* 50
China* Japan*
40 40

30 30
Thailand* Denmark
25 India* 25

Uganda* USA:
20 Black 20

France
Australia
15 Philippines 15
USA:
White
12 12

10 Colombia 10
Japan
8 8
7 7

6 China 6

5 5

1980 1990 2000 2010 1980 1990 2000 2010

Year

Incidence Mortality

Figure 8–​9.  Trends in female breast cancer incidence and mortality rates for select countries, 1975–​2012. Source: IARC.

stage at diagnosis and greater availability of effective treatments in In North Africa and West Asia, lung cancer predominates among
affluent countries. Survival from breast, prostate, and thyroid can- men, but colorectal cancer is increasing in the Gulf States, and liver
cer, however, are artificially inflated in high/​very high HDI countries cancer and non-​Hodgkin lymphoma are major cancers elsewhere
because of the early diagnosis of non-​aggressive cancers detected by (Figure 8–​19). Among women, breast cancer ranks first in incidence
screening. Figures 8–​2 through 8–​5 show the distribution of prevalent throughout the region (Figure 8–​20). In Central and South America,
cases by WHO region and anatomic site. prostate cancer is the leading cause of cancer death among men
(Figure 8–​21), although lung and stomach cancer predominate in
some countries. Among women, breast cancer is the most common
Regional Patterns incident cancer regionally, although cervical cancer still ranks first
Figures 8–​17 through 8–​30 depict regional patterns of cancer inci- in low-​income countries in Central America, as well as in Peru and
dence, mortality, and survival among men and women in seven WHO Bolivia in South America (Figure 8–​22). In North America, lung
geographic regions. There are many distinctive features. Sub-​Saharan cancer is the leading fatal cancer in both men and women (Figures
Africa is the only region in which men have high death rates as well 8–​23 and 8–​24, respectively). South Asia includes a large area
as high incidence rates of prostate cancer (Figure 8–​17). This contrasts where incident cancers of the lip and oral cavity predominate in men
with the patterns in North America and Europe, where prostate cancer (Figure 8–​25), whereas breast cancer is the predominant incident
incidence rates are high, partly due to screening practices, while mor- cancer in women (Figure 8–​26). In East and Southeast Asia, lung
tality rates are relatively low. Even within sub-​Saharan Africa, prostate cancer is the most common site for incidence and mortality in men,
cancer mortality rates vary by 8-​fold, with higher death rates in Central and breast cancer in women (Figures 8–​27 and 8–​28, respectively).
and East Africa. Kaposi sarcoma is common is Southeast Africa due to Mongolia has the highest liver cancer incidence rate in the world
untreated HIV infection. Cervical cancer is the leading cause of can- in both sexes, due to the high prevalence of chronic infection with
cer death among women in large areas of sub-​Saharan Africa (Figure hepatitis B and/​or C viruses (Chimed et al., 2017). Thyroid cancer is
8–​18). The lifetime risk of cervical cancer is 6%–​8% in Malawi, commonly diagnosed in Korea due to screening for this cancer with
Mozambique, and Zimbabwe. Cervical and breast cancers account for ultrasound. The patterns in Europe are generally similar to those in
over half of all female incident cancers in sub-​Saharan Africa. North America for men (Figure 8–​29) and women (Figure 8–​30).
16

116 Part II: The Magnitude of Cancer

Low/Medium HDI High/Very high HDI
50 50
Australia

40 France* USA*: 40
Black
35 China* Denmark 35
Age-standardized (world) incidence rate per 100,000, males

Age-standardized (world) incidence rate per 100,000, males

30 Japan* USA*: 30
Philippines*
White
25 25
Denmark

20 20
Australia

USA:
15 Black 15
Thailand*
France

Japan Colombia*
USA:
10 White 10
China

Uganda*
India*
7 7
Colombia

5 5
Philippines

4 4

3 3

1980 1990 2000 2010 1980 1990 2000 2010

Year

Incidence Mortality

Figure 8–​10.  Trends in colorectal cancer incidence and mortality rates for select countries, 1975–​2012. Source: IARC.

Breast cancer is the leading cancer among women in the region in
terms of incidence and mortality; the highest breast cancer rates are
observed in a number of Northern and Western European countries
(Figure 8–​30).
Demographic Patterns
Cancer registries collect individual-​level information on core demo-
graphic characteristics on all cases. These data include date of birth,
gender, race/​ethnicity, age at diagnosis, and place of residence. This
demographic information allows study of cancer risk in individuals
according to these characteristics, thereby avoiding the well-​known
limitations of “ecologic” studies, which rely on exposure information
on the population, rather than individual cases. Historically, epidemi-
ologists have drawn landmark insights from the demographic informa-
tion, particularly on the relationships between cancer incidence and
attained age.
Relationships with Age
The incidence and mortality rates of many types of cancer increase
exponentially with age during adulthood, except in the oldest age
groups. The relationships between attained age and the age-​specific
incidence rates of various types of cancer are illustrated in Figure
8–​31. The age-​related increases in risk are approximately exponen-
tial for most solid tumors in adults below age 80 years, as evidenced
by cancers of the gastrointestinal and respiratory tracts and bladder
cancer.
Armitage and Doll and others studied the mathematical relation-
ship between attained age and the mortality rate from various solid
tumors (Armitage and Doll, 1954). They observed a linear relation-
ship between the log of the age-​specific death rates for certain types
of cancer and the log of attained age. From this, they hypothesized
that carcinogenesis was a multistage process that required six or
more discrete events for the development of certain solid tumors.
Their hypothesis was advanced 10  years before elucidation of the
structure of DNA, and over 30  years before the identification of
the first oncogenes and tumor suppression genes. Molecular biolo-
gists have since identified many of the actual genetic and epigenetic
events. These accumulate in tumor tissue over time and dysregu-
late normal cellular control over replication, survival, and growth
(see Chapter 2) (Armitage and Doll, 2004; Hornsby et al., 2007; Wu
et al., 2016).
The shape of the relationship between attained age and the age-​
specific incidence rates can also reflect physiologic changes during
life. Clemmesen observed that the age-​specific incidence rate of breast
cancer was not a smooth continuous curve (Clemmesen, 1948). Rather,
incidence rates increase rapidly between menarche and menopause,
followed by a “point of inflection” and a more gradual increase after
menopause. This observation (ascribed to the author as Clemmesen’s
hook) led him to theorize that there were two different pathways for
 17

Incidence, Men Mortality, Men

Low HDI Low HDI

Medium HDI Medium HDI
High HDI High HDI
Very high HDI Very high HDI
China China
India India

0 50 100 150 200 0 50 100 150 200

Age-standardized rate (W) per 100,000

Lung Stomach Liver Esophagus Pancreas

Prostate Colorectum Bladder Other pharynx Lip, oral cavity

Incidence, Women Mortality, Women

Low HDI Low HDI

Medium HDI Medium HDI
High HDI High HDI
Very high HDI Very high HDI
China China
India India

0 50 100 150 200 0 50 100 150 200

Age-standardized rate (W) per 100,000

Breast Cervix uteri Liver Ovary Stomach Pancreas

Colorectum Lung Corpus uteri Thyroid Esophagus Lip, oral cavity

Figure 8–​11.  Age-​standardized cancer incidence and mortality rates for specific cancer sites in relation to the level of Human Development Index (HDI).
Source: World Health Organization (WHO).

Prostate (87) Kaposi sarcoma (6)

Lung (38) Lip, oral cavity (5)

Liver (20) Leukaemia (2)

Stomach (12) Non-Hodgkin lymphoma (2)

Colorectum (11) Esophagus (1)

No data Not applicable

The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning
the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent
approximate border lines for which there may not yet be full agreement.

Figure 8–​12.  Most commonly diagnosed cancer among men by country, 2012. The parentheses following the cancer type represents the number of coun-
tries in which that cancer is the most commonly diagnosed among men. Source: World Health Organization (WHO).
18

118 Part II: The Magnitude of Cancer

Lung (91) Leukaemia (4)

Prostate (42) Esophagus (2)
Liver (23) Colorectum (1)
Stomach (13) Lip, oral cavity (1)
Kaposi sarcoma (6) Non-Hodgkin lymphoma (1)
No data Not applicable

The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning
the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent
approximate border lines for which there may not yet be full agreement.

Figure 8–​13.  The leading cause of cancer death among men by country, 2012. The parentheses following the cancer type represents the number of coun-
tries in which that cancer is the leading cause of death among men. Source: World Health Organization (WHO).

pre-​and postmenopausal breast cancer, and that hormonal changes
associated with menopause modify the relationship with age (Hakama,
1969; Hill et  al., 1983). Other distinctive age relationships are
observed with cancer of the cervix (Chapter 48), Hodgkin lymphoma
(Chapter  39), kidney cancer (Chapter  51), and all of the childhood
cancers (Chapter 59). These can reflect age-​related changes in the tim-
ing of exposure, susceptibility to the exposure, and/​or the number of
discrete events related to carcinogenesis.
Birth Cohort and Period Patterns in Age-​Specific
Incidence Rates
The relationships between age and cancer incidence rates can vary
because of differences in the timing and intensity of exposure and
because of changes in tumor detection (Bray, 2016). Consequently,
the age-​related patterns are neither static nor universal. Figures 8–​32
and 8–​33 show temporal changes in the age-​specific incidence rates of
lung and prostate cancer, respectively, in US men. The rise and fall of

Breast (140)

Cervix uteri (39)

Liver (2)

Lung (2)

Thyroid (1)

No data

Not applicable

The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning
the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent
approximate border lines for which there may not yet be full agreement.

Figure 8–​14.  Most commonly diagnosed cancer among women by country, 2012. The parentheses following the cancer type represents the number of
countries in which that cancer is the most commonly diagnosed among women. Source: World Health Organization (WHO).
 19

Breast (103)

Cervix uteri (45)

Lung (25)

Stomach (5)

Liver (3)

Colorectum (2)

Esophagus (1)

No data

Not applicable

The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization
concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps
represent approximate border lines for which there may not yet be full agreement.

Figure 8–​15.  The leading cause of cancer death among women by country, 2012. The parentheses following the cancer type represents the number of
countries in which that cancer is the leading cause of death among women. Source: World Health Organization (WHO).

World cancer incidence

1034
1000 947
927897 913
New cases in 2012 (Thousands)

750
641
554 582 High/Very High HDI
500 447 Low/Medium HDI
397 368
331 310
243
250 200
164 160
124 120 143

0
ng

st

te

a
i

r
er
ve

de
gu
ac

om
ea

tu

ta
Lu

ut
Li

ad
om

ha
ec

os
Br

ph
x

Bl
or

Pr

op
vi
St

m
er
ol

Es

ly
C
C

in
gk
od
–H
on
N

World cancer mortality World cancer prevalence (5 years)

4103
816 4000
773
750 3489
Persons in 2012 (Thousands)
Deaths in 2012 (Thousands)

3000
563 2586
500 462 2152
418
2000
265 297
261 275
250 257 227 1100
204 199 958 1009 1017
183 1000
128138
793 781757 765 845 689
103 103 103 538 451 361
66 434 303 218
0 0
g

as

te

ia
er
st
ve

Pr st

te

ng

er

y
gu
n

ac

er

er
m
tu

ta

ne
ac

oi
ea

re
Lu

ut

ea

ta

tu

d
Li

Lu

ut

ut
om

ha

ae
ec

os

yr
ad
nc

om

d
os

ec
Br

Br

Th

Ki
x

s
or

op

Pr

vi

uk

Bl
St

Pa

or

vi

pu
St
er
ol

Le
Es

er
ol

or
C
C

C
C

Figure 8–​16.  Number of cancer cases and deaths for top 10 cancers according to Human Development Index (HDI), worldwide, 2012. Source: World
Health Organization (WHO).
120

120 Part II: The Magnitude of Cancer

Prevalence
Incidence Mortality (5 years)

Prostate Prostate
Prostate

46.6%
49.4% 49.4%
Liver Liver
50.6% 50.6%
Kaposi 53.4%
Kaposi sarcoma Kaposi sarcoma sarcoma
Non-Hodgkin Colorectum
Esophagus
lymphoma Lip, oral cavity
Non-Hodgkin
Colorectum lymphoma Non-Hodgkin lymphoma

256,000 201,000
453,000
New cases Deaths
Persons

Prostate
Uganda
Burundi
Congo, Democratic Republic of
Congo, Republic of
Kenya
Madagascar
South African Republic
Tanzania
Angola
Nigeria
South Sudan
Central African Republic
Rwanda
Equatorial Guinea
Cameroon
Guinea
Zimbabwe
Sierra Leone
Zimbla
Comoros
Benin
Liberia
Chad
Nambia
Senegal
Somalia
Mauritius
Mortality Mauritania
Guinea-Bissau
Prostate (19) Burkina Faso
Cote d Ivoire
Liver (14) Gabon
France, La Reunion
Kaposi sarcoma (6) Mali
Togo
Lung (3) Niger
Swaziland
Leukemia (2) Malawi
Cape Verde
Non-Hodgkin lymphoma (1) Mozambique
Ghana
Esophagus (1) Djibouti Eastern Africa
Eritrea
Lesotho Middle Africa
Stomach (12) Botswana Southern Africa
No data Ethiopia Western Africa
The Gambia
Not applicable
0 0.5 1 1.5 2 2.5 3 3.5 4 4.5
Mortality cumulative risk, male, 0–74 years (%)

The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization
concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps
represent approximate border lines for which there may not yet be full agreement.

Figure 8–​17.  The cancer burden in sub-​Saharan Africa, males, 2012. The parentheses following the cancer type represents the number of countries in
which that cancer is the leading cause of death among men in sub-Saharan Africa. Source: World Health Organization (WHO).

age-​specific lung cancer rates (Figure 8–​32) follow generational (birth
cohort) patterns of smoking that were established many decades ear-
lier. Birth cohort patterns reflect exposures (or patterns of exposure)
that become fixed early in life, change across successive generations,
and cause disease later in life. Figure 8–​32 plots age-​specific incidence
rates of lung cancer by 10-​year intervals of attained age on the y axis,
versus 5-​year intervals of year of birth (birth cohorts) on the x axis. The
peak in lung cancer incidence in every category of attained age corre-
sponds to the birth cohort with the maximum lifetime smoking. This
peak shifts toward earlier birth cohorts as age increases, because these
older birth cohorts preceded the period of peak smoking in the United
States. Other examples of birth cohort effects include the elevated liver
cancer rates in US baby boomers (Altekruse et al., 2009), thought to
reflect the high prevalence of hepatitis C virus infections among intra-
venous drug users during 1960s–​1980s (Armstrong et al., 2006), and
the patterns of testicular cancer in several countries (Bergstrom et al.,
1996; Liu et al., 2000; Verhoeven et al., 2008).
In contrast, period effects result from changes in detection or expo-
sures that affect cancer risk in all age groups at the same time. This
is manifested by an increase or decrease in risk at all ages during the
same calendar year of diagnosis or death (Rosenberg and Anderson,
2011). Figure 8–​33 illustrates the “period” increase in prostate cancer
 12

Patterns of Cancer Incidence, Mortality, and Survival 121

Prevalence
Incidence Mortality (5 years)

Breast Cervix uteri

Breast

27.6%
38.1% 43.9%
61.9% 56.1%
Breast
Cervix uteri 72.4%
Cervix uteri

Liver
Liver Corpus uteri
Colorectum Colorectum
Ovary
Kaposi sarcoma Ovary Colorectum

370,000 247,000 864,000

New cases Deaths Persons

Cervix uteri
Malawi
Mozambique
Comoros
Zimbabwe
Tanzania
Zimbia
Burundi
Swaziland
Mall
Uganda
Madagascar
Senegal
Rwanda
Kenya
Guinea
Congo, Democratic Republic of
Ghana
Lesotho
Angolo
Somalia
South Sudan
Sierra Leone
Liberia
Nigeria
Cameroon
South African Republic
Congo, Republic of
Botswana
Guinea-Bissau
Mauritania
Cape Verde
Benin
Incidence Ethiopia
Equatorial Guinea
Cervix uteri (28) Burkina Faso
Central African Republic
Cote d Ivoire
Breast (19) Togo
Gabon
Chad
No data Eritrea Eastern Africa
Djibouti
Mauritius Middle Africa
Not applicable France, La Reunion
Namibia Southern Africa
The Gambia Western Africa
Niger

0 1 2 3 4 5 6 7 8
Incidence cumulative risk, female, 0–74 years (%)

The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization
concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps
represent approximate border lines for which there may not yet be full agreement.

Figure 8–​18.  The cancer burden in sub-​Saharan Africa, females, 2012. The parentheses following the cancer type represents the number of countries in
which that cancer is the most commonly diagnosed among women in sub-Saharan Africa. Source: World Health Organization (WHO).

incidence in the early 1990s in SEER areas of the United States, fol-
lowing the introduction of prostate specific antigen (PSA) testing in
late 1980s. PSA testing was recommended for men age 50 years and
older (Brawley, 2012; Hankey et al., 1999a; Potosky et al., 1995). The
increase in detection produced a dramatic increase in the recorded inci-
dence of prostate cancer, followed by a sharp decrease, reflecting the
depletion of unrecognized prevalent disease and decreases in PSA test-
ing (Brawley, 2012; Welch and Albertsen, 2009). Period effects can be
identified by plotting calendar year of diagnosis or death on the x axis.
Another example of a period effect is the sharp decrease in breast
cancer incidence rates in postmenopausal women between 2002 and
2003, coinciding with the reduction in use of hormone replacement
therapy (HRT; Jemal et al., 2007; Ravdin et al., 2007). This followed
a major publication associating HRT use with breast cancer and other
conditions (Rossouw et al., 2002).
The age-​period-​cohort (APC) model provides a somewhat more for-
mal statistical approach for partitioning age, cohort, and period effects.
It is based on a log-​linear model of temporal trends in cancer rates.
The APC analysis can be carried out through a freely available and
user-​friendly web tool developed by NCI (http:/​analysistools.nci.nih.
gov/​apc/​) (Rosenberg et al., 2014) and other similar tools (Carstensen,
2007; Rutherford et  al., 2010). Unfortunately, the interpretability of
results from this model is limited by collinearity between attained age,
period, and birth cohort (Rosenberg and Anderson, 2011). Because
12

122 Part II: The Magnitude of Cancer

Prevalence
Incidence Mortality (5 years)

Lung Prostate
Lung

Prostate Bladder
49.0% Liver 48.4% 47.1%
51.0%
51.6% 53. 0%
Bladder
Prostate Colorectum

Colorectum Colorectum
Lung
Liver Bladder Larynx

274,000 187,000
492,000
New cases Deaths
Persons

Lung

Armenia
Turkey
Tunisia
Georgia
Lebanon
Israel
Libya
Jordan
Morocco
Syrian Arab Republic
Iraq
State of Palestine
Bahrain
Azerbaijan
Algeria
Qatar
Western Sahara
Incidence United Arab Emirartes
Lung (13) Egypt
Kuwait
Colorectum (6)
Saudi Arabia
Prostate (2)
Oman
North Africa
Leukemia (1) Yemen West Asia
Liver (1) Sudan

Non-Hodgkin lymphoma (1)

0 2 4 6 8
Not applicable Incidence cumulative risk, male, 0–74 years (%)

The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization
concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps
represent approximate border lines for which there may not yet be full agreement.

Figure 8–​19.  The cancer burden in North Africa and West Asia, males, 2012. The parentheses following the cancer type represents the number of countries
in which that cancer is the most commonly diagnosed among males in North Africa and West Asia. Source: World Health Organization (WHO).

these variables are linearly dependent, their effects cannot be uniquely
and simultaneously determined without unverifiable assumptions
(Clayton and Schifflers, 1987a, 1987b; Holford, 1983).
Sex Relationships
For nearly all types of cancer that affect both sexes, men have higher
age-​standardized incidence and death rates than women. In high-​
income countries, the few exceptions to this, other than breast can-
cer, include cancers of the thyroid, gallbladder, and anus (Table 8–​1).
For these sites, the female-​to-​male rate ratio in GLOBOCAN 2012
ranges from 1.15 for anal cancer to over 120 for breast cancer. By
comparison, the ratio of male-​to-​female incidence rates for cancer
sites that are more common in men ranges from 1.25 for colon cancer
to 11.8 for Kaposi sarcoma.
When all age groups are considered, the ratio of male to female
incidence rates is 1.35 for all cancers combined. This ratio varies
by age, however, as shown for the United States in Figure 8–​34. At
younger ages (approximately age 20–​55  years), the incidence rate
of all cancers combined is higher in women than in men, mostly
due to premenopausal breast cancer. Above age 55  years, this pat-
tern reverses. In contrast, the mortality rate is higher in men than in
women at all ages.
 123

Patterns of Cancer Incidence, Mortality, and Survival 123

Prevalence
Incidence Mortality (5 years)

Breast
Breast Breast
31.9%
48.6%
45.0%
51.4% Colorectum 55.0%
68.1%
Colorectum Lung Thyroid
Thyroid Stomach Colorectum
Non-Hodgkin
lymphoma Corpus uteri
Liver Cervix uteri
Ovary

264,000 146,000 658,000

New cases Deaths Persons

Breast

Israel
Lebanon
Armenia
Jordan
Syrian Arab Republic
Kuwait
Egypt
Qatar
Algeria
Georgia
Iraq
State of Palestine
Bahrain
United Arab Emirartes
Morocco
Turkey
Western Sahara
Tunisia
Saudi Arabia
Yemen
Sudan
Incidence
Oman
Breast (24) Azerbaijan
North Africa
West Asia
Not applicable Libya

0 2 4 6 8
Incidence cumulative risk, female, 0–74 years (%)

The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization
concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps
represent approximate border lines for which there may not yet be full agreement.

Figure 8–​20.  The cancer burden in North Africa and West Asia, females, 2012. The parentheses following the cancer type represents the number of coun-
tries in which that cancer is the most commonly diagnosed among females in North Africa and West Asia. Source: World Health Organization (WHO).

For some cancers, the gender disparity largely reflects differences
in exogenous exposure to carcinogens, whereas for others it reflects
endogenous exposures or inherent biological differences (Walter et al.,
2013; Wiren et al., 2014). For example, the higher rates of lung cancer
and other smoking-​related cancers in men than women reflect the his-
torically higher prevalence of male smoking (Jemal et al., 2008; Thun
et al., 2013), whereas the elevated breast cancer risk in women com-
pared to men reflects both endogenous and exogenous exposure to hor-
mones. Because the decrease in smoking began earlier and was larger
among men than women in the United States, the male-​to-​female rate
ratio for lung cancer decreased from 3 in 1975 to 1.4 in 2008–​2012
(Jemal et al., 2003b). The male and female incidence rates of smoking-​
related oral cavity cancer also converged (Brown et al., 2012), whereas
the gender difference in HPV-​related oropharyngeal cancers widened
because of differential changes in sexual behavior (Chaturvedi et al.,
2008; Simard et al., 2012). In populations of European origin, the inci-
dence rate of melanoma is higher in women than men before age 40,
but not at older ages, possibly because of the use of artificial sun beds
by young women (Heckman et al., 2008). After age 40, the incidence
rate becomes progressively higher in men (Chapters 57 and 58).
124

124 Part II: The Magnitude of Cancer

Prevalence
Incidence Mortality (5 years)

Prostate
Prostate
Prostate
Lung
44.5% 47.0% 39.5%
55.5%
Lung 53.0%
60.5%
Stomach
Colorectum
Colorectum
Colorectum Stomach
Stomach Bladder
Bladder Liver Lung

484,000 284,000 1.1 million

New cases Deaths Persons

Prostate

Guyana
Uruguay
Suriname
Belize
Paraguay
Venezuela
Ecuador
Brazil
Argentina
Costa Rica
Panama
Chile
Bolivia
Nicaragua
Colombia
Honduras
Mortality Guatemala
Prostate (13) Peru
Stomach (5) EI Salvador
South America
Lung (3) Mexico
Central America
No data French Guyana
Not applicable
0 1 2 3 4
Mortality cumulative risk, male, 0–74 years (%)

The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization
concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps
represent approximate border lines for which there may not yet be full agreement.

Figure 8–​21.  The cancer burden in Central and South America, males, 2012. The parentheses following the cancer type represents the number of countries
in which that cancer is the leading cause of death among men in Central and South America. Source: World Health Organization (WHO).

Race/​Ethnicity
Differences in the risk of specific types of cancer in relation to
race or ethnicity have been widely reported (Moore et  al., 2015).
In many instances, it is difficult to separate racial and ethnic dif-
ferences from socioeconomic disparities (discussed in Chapter 9).
It is also difficult to separate inherited genetic susceptibility from
cultural differences that affect exposures. The examples discussed
here are drawn from the United States (blacks vs. whites) and
Australia (Indigenous vs. all others) (Cunningham et  al., 2008;
Moore et al., 2010).
One example of genetic predisposition that is indisputably associ-
ated with race is skin pigmentation. Melanin deposits in the skin protect
against both melanoma (Chapter 57) and non-​melanoma skin cancer
(Chapter 58). The incidence rate of melanoma among Caucasians in
the United States are more than 10 times higher than in blacks (Jemal
et al., 2011), due to the joint factors of sunlight and lack of melanin.
 125

Patterns of Cancer Incidence, Mortality, and Survival 125

Prevalence
Incidence Mortality (5 years)

Breast
Breast Breast

Cervix uteri 29.6%

43.1%
49.4% 50.6%
Cervix uteri 57.0% Lung 70.4%
Cervix uteri

Colorectum Colorectum
Colorectum
Lung
Stomach Thyroid
Stomach Corpus uteri

520,000 266,000 1.4 million

New cases Deaths Persons

Breast

Argentina

Uruguay
Brazil

Guyana
Suriname
Costa Rica

Panama

Paraguay
Venezuela

Belize
French Guyana

Colombia
Chile
Incidence
Mexico
Breast (15)
Ecuador
Cervix uteri (6)
Peru
No data Nicaragua

Not applicable EI Salvador

Honduras
South America
Bolivia
Central America
Guatemala

0 1 2 3 4 5 6 7 8
Incidence cumulative risk, female, 0–74 years (%)

The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization
concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps
represent approximate border lines for which there may not yet be full agreement.

Figure 8–​22.  The cancer burden in Central and South America, females, 2012. The parentheses following the cancer type represents the number of coun-
tries in which that cancer is the most commonly diagnosed among women in Central and South America. Source: World Health Organization (WHO).

For most cancers, however, differences in risk between racial/​
ethnic groups are due largely to differences in exposures and access
to preventive services, rather than differences in genetic susceptibil-
ity. For example, compared to the rest of the Australian population,
Indigenous Australians have a two-​fold higher risk of lung cancer
and a seven-​fold higher risk of cervical cancer (Cunningham et al.,
2008; Moore et  al., 2010). This reflects the higher prevalence of
smoking and lower frequency of cervical cancer screening among
Indigenous Australians than in the general population.
It is noteworthy that large differences in cancer risk can exist within
subpopulations of the same racial or ethnic group, as well as those in
different groups. For example, the lung cancer incidence rate among
Hispanic men in the United States is twice as high in those of Cuban
descent as in Mexican Americans, because of the historically high
126

126 Part II: The Magnitude of Cancer

Prevalence
Incidence Mortality (5 years)

Prostate Lung
Prostate

29.6%
38.2% 41.8%
58.2%
Lung 61.8% Prostate
70.4%
Colorectum
Colorectum Colorectum
Bladder
Bladder Pancreas Melanoma of skin
Melanoma of skin Liver Lung

920,000 363,000 2.7 million

New cases Deaths Persons

Prostate

12

10

Incidence cumulative risk, male, 0–74 years (%)

8

Incidence
Prostate (2) 0
United Canada
No data States
of America

North America

The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization
concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps
represent approximate border lines for which there may not yet be full agreement.

Figure 8–​23.  The cancer burden in North America, males, 2012. The parentheses following the cancer type represents the number of countries in which
that cancer is the most commonly diagnosed among men in North America. Source: World Health Organization (WHO).

prevalence of smoking among Cubans (Martinez-​Tyson et al., 2009;
Pinheiro et al., 2009; Siegel et al., 2015a).
METHODS USED FOR GLOBOCAN 2012
The purpose of GLOBOCAN 2012 is to provide a comprehensive
global picture of the risks and burden from 27 cancer types and all
sites combined in 184 countries for the year 2012 (http://​globocan.
iarc.fr). The methods are described in detail elsewhere (Ferlay et al.,
2015). Briefly, IARC uses a hierarchical approach that draws on dif-
ferent sources, depending on the availability and accuracy of local
data. Information on incident cases and survival are obtained from
population-​based registries where available. PBCRs routinely col-
lect demographic data on the age, sex, place of residence, country
of origin, and date of migration (if applicable) of each case. Clinical
information is collected on the anatomic site of the tumor, and its
histologic characteristics, date of diagnosis, stage at diagnosis, report-
ing hospital or cytology/​pathology lab, first course of treatment, and
survival. IARC publishes updated incidence rates in the database
 127

Patterns of Cancer Incidence, Mortality, and Survival 127

Prevalence
Incidence Mortality (5 years)

Lung
Breast
Breast
29.5%
37.1% 37.9%
Breast 62.1%
Lung 62.9%
Colorectum 70.5%

Colorectum Colorectum Corpus uteri

Corpus uteri Pancreas Thyroid
Thyroid Ovary Lung

865,000 329,000 2.6 million

New cases Deaths Persons

Breast

10

Incidence cumulative risk, female, 0–74 years (%)

8

Incidence
Breast (2) 0
United Canada
No data States
of America

North America

The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization
concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps
represent approximate border lines for which there may not yet be full agreement.

Figure 8–​24.  The cancer burden in North America, females, 2012. The parentheses following the cancer type represents the number of countries in which
that cancer is the most commonly diagnosed among women in North America. Source: World Health Organization (WHO).

CI5, through collaboration with the global network of PBCRs and
the IACR (http://​www.iacr.com.fr; http://​ci5.iarc.fr/​). The number
of high-​quality registries included in CI5 has increased markedly
over the last half-​century, as shown in Table 8–​2 (Bray et al., 2015c;
Forman et  al., 2014; Parkin, 2006). The most recent (10th) volume
presents information from 290 PCBRs in 68 countries for cancers
diagnosed during 2003–​2007.
Incident cases are classified according to the codes of the
International Statistical Classification of Diseases and Health-​Related
Problems, 10th Revision (ICD-​10). Where possible, tumors are also
classified by histologic type and stage of disease. In the 62 countries
where incidence data are unavailable, the estimates of cancer inci-
dence in GLOBOCAN 2012 are made from regional data and statisti-
cal modeling, often based on neighboring countries. In countries that
have only mortality data, a registry-​based ratio of incidence to mortal-
ity is used to estimate incidence.
Less than a fifth of all countries collect national data on newly diag-
nosed cancer cases and deaths, however (Bray et al., 2015a). In places
where no vital statistics are available, cancer-​specific mortality rates
are estimated using interpolated incidence and survival probabilities,
128

128 Part II: The Magnitude of Cancer

Prevalence
Incidence Mortality (5 years)

Lung Lung Lip, oral cavity

Lip, oral cavity Stomach Prostate

44.0% 48.4% 42.1%

Lip, oral cavity 51.6% Colorectum

Stomach 56.0% 57.9%

Colorectum Esophagus Other Pharynx

Other Pharynx Other Pharynx Larynx

675,000 506,000 1 million

New cases Deaths Persons

Lip, oral cavity

Maldives

Sri Lanka

Bangladesh

Pakistan

India

Nepal

Afghanistan
Incidence
Lip, oral cavity (7) Bhutan
Stomach (3)
South Asia
Lung (2)
Iran, Islamic Republic of
Not applicable

0 0.5 1 1.5 2
Incidence cumulative risk, male, 0–74 years (%)

The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization
concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps
represent approximate border lines for which there may not yet be full agreement.

Figure 8–​25.  The cancer burden in South Asia, males, 2012. The parentheses following the cancer type represents the number of countries in which that
cancer is the most commonly diagnosed among men in South Asia. Source: World Health Organization (WHO).

based on macroeconomic measures and scaled to the WHO mortality
estimates wherever possible.
A relatively small subset of registries, representing about 30% of
the world’s population, submit high-​quality mortality data to the WHO
mortality database. Reasonably reliable national information is cur-
rently available for 38 countries; these include all of the economically
developed countries and a subset of developing countries (Parkin and
Bray, 2006). The remaining countries provide either lower-​quality
cause-​of-​death data or, in 74 (mainly low-​resource) countries, no such
data at all. The Global Health Observatory (GHO; http://​www.who.
int/​gho/​) publishes tables of estimated coverage and completeness of
mortality statistics in their database (Mathers et al., 2005). Even inclu-
sion in the WHO database is not a guarantee of data quality, however; in
some countries and/​or time periods, population coverage is manifestly
incomplete, and the mortality rates produced are implausibly low.
Death certificates record information on the person dying, and the
cause of death, as certified, usually by a medical practitioner. The
International Classification of Diseases (ICD) provides a uniform sys-
tem of nomenclature and coding, and a recommended format for the
death certificate (WHO, 1992).
As noted earlier, the survival of patients with cancer is measured
conventionally for the first 5 years after diagnosis. In settings where
 129

Patterns of Cancer Incidence, Mortality, and Survival 129

Prevalence
Incidence Mortality (5 years)

Breast
Breast
Breast

27.5%
38.6% 44.2%
61.4% Cervix uteri 55.8%
72.5%
Cervix uteri
Cervix uteri
Ovary
Ovary
Colorectum Ovary
Colorectum
Corpus uteri
Lip, oral cavity Stomach Lip, oral cavity

759,000 466,000 1.7 million

New cases Deaths Persons

Breast

Pakistan

Afghanistan

Sri Lanka

Maldives

Iran, Islamic Republic of

India

Incidence Bangladesh
Breast (7)
Cervix uteri (2)
Nepal
Not applicable
South Asia
Bhutan

0 1 2 3 4 5
Incidence cumulative risk, female, 0–74 years (%)

The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization
concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps
represent approximate border lines for which there may not yet be full agreement.

Figure 8–​26.  The cancer burden in South Asia, females, 2012. The parentheses following the cancer type represents the number of countries in which that
cancer is the most commonly diagnosed among women in South Asia. Source: World Health Organization (WHO).

follow-​up for vital status is not feasible, the ratios of cases to deaths
expressed as percent are used to estimate survival. The 5-​year survival
has been increasing rapidly in high-​income countries.
FUTURE DIRECTIONS
Population-​based surveillance data have become essential for cancer
control. They allow governments to monitor the occurrence and disease
burden from cancer in their population, to assess needs, to establish
priorities, to evaluate the effectiveness of programs in prevention and
treatment, and to forecast future healthcare needs (Anderson, 2009;
Glaser et al., 2005; Hankey et al., 1999b; Parkin, 2008). Surveillance
data have documented that the implementation of organized cervical
cancer screening programs, beginning in the Nordic countries in the
early 1960s, was associated with a dramatic reduction in cervical can-
cer mortality by the late 1980s (Laara et al., 1987). A national hepa-
titis B infant vaccination program in Taiwan, which began in 1984,
has reduced liver cancer rates by over 70% in vaccinated children
and adolescents (Chiang et al., 2013) (Chapter 62.3). Thun and Jemal
130

130 Part II: The Magnitude of Cancer

Prevalence
Incidence Mortality (5 years)

Lung Stomach
Lung

Colorectum 37.5%
Stomach 31.8% 24.8%
Liver
68.2% 75.2%
Lung 62.5%
Liver
Stomach

Colorectum Prostate
Esophagus
Esophagus Colorectum Liver

2.8 million 2.0 million 4.6 million

New cases Deaths Persons

Lung

Korea, DPR

Timor–Leste

Korea, Republic of

China

Viet Nam

Japan

Singapore

Philippines

Brunei

Mongolia

Thailand

Malaysia

Indonesia

Myanmar
Incidence
Lung (7) Lao PDR
Southeast Asia
Liver (5)
Cambodia East Asia
Colorectum (2)
Stomach (2)
0 1 2 3 4 5 6 7
No data Mortality cumulative risk, male, 0–74 years (%)
Not applicable

The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization
concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps
represent approximate border lines for which there may not yet be full agreement.

Figure 8–​27.  The cancer burden in East and Southeast Asia, males, 2012. The parentheses following the cancer type represents the number of coun-
tries in which that cancer is the most commonly diagnosed among men in East and Southeast Asia. Source: World Health Organization (WHO).

estimated that tobacco control activities since the 1960s accounted for
40% of the decrease in overall cancer death rates between the early
1990s and 2000 in the United States (Thun and Jemal, 2006).
The value of population-​based data on cancer outcomes is enhanced
if survey data on cancer risk factors and screening are also available.
Even ecological data (pertaining to populations, not individuals) can
be highly informative for cancer control. Lung cancer incidence has
decreased more rapidly in California, where comprehensive tobacco
control measures were implemented earlier and more rigorously
than in other states (CDC, 2000; Jemal et  al., 2008). Robbins et  al.
described a shift toward earlier stage diagnosis of cervical cancer and
increases in receipt of fertility-​sparing treatment among young women
aged 21–​25 years, following expansion of the Affordable Care Act to
cover young adults on their parents’ health insurance plans until age
26 years (Robbins et al., 2015).
The infrastructure for population-​ based cancer surveillance has
expanded greatly since 1975, when IARC first estimated the global
burden of cancer (IARC, 1966). Despite this, the coverage and
 13

Patterns of Cancer Incidence, Mortality, and Survival 131

Prevalence
Incidence Mortality (5 years)

Breast Lung
Breast

Lung Liver 36.5%

43.9% 40.2%
59.8% Colorectum
56.1% 63.5%
Stomach
Colorectum
Cervix uteri
Breast
Stomach Corpus uteri

Liver Colorectum Thyroid

2.1 million 1.2 million 4.8 million

New cases Deaths Persons

Breast

Singapore

Brunei

Japan

Philippines

Korea, Republic of

Indonesia

Malaysia

Timor-Leste

Korea, DPR

Thailand

Viet Nam

Myanmar

China
Incidence
Breast (10) Cambodia

Liver (2) Lao PDR

Southeast Asia
Lung (2)
Mongolia East Asia
Cervix uteri (1)
Thyroid (2) 0 1 2 3 4 5 6 7
No data Incidence cumulative risk, female, 0–74 years (%)
Not applicable

The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization
concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps
represent approximate border lines for which there may not yet be full agreement.

Figure 8–​28.  The cancer burden in East and Southeast Asia, females, 2012. The parentheses following the cancer type represents the number of countries
in which that cancer is the most commonly diagnosed among women in East and Southeast Asia. Source: World Health Organization (WHO).

granularity of the data are highly uneven. Less than 10% of the popula-
tions of Africa and South America are covered, in contrast to over 95%
of the population of North America. The Global Initiative for Cancer
Registry Development is an international partnership established to
develop the infrastructure for high-​quality PBCRs in 50 countries
over the next decade (GICR; http://​gicr.iarc.fr). This effort supports
the global monitoring framework established by WHO to reduce non-​
communicable diseases in LMICs by 25% by 2025. Studies have
established that it is feasible to collect reliable local information at
the population level, even in the lowest income settings (Bray et al.,
2015c; Tangka et al., 2010).
Linkage of cancer registry data with other administrative databases
provides opportunities to study the quality and cost of care, access to
care, and quality of life (Glaser et al., 2005; Hiatt et al., 2015; Howe
et al., 2003; Wingo et al., 2005). A recent study in the United States
documented substantial regional variation in Medicare spending for
132

132 Part II: The Magnitude of Cancer

Prevalence
Incidence Mortality (5 years)

Prostate
Lung Prostate

32.8%
Lung 37.4% 41.0%
62.6% Colorectum 59.0%
Colorectum
67.2%
Colorectum Prostate
Bladder
Bladder Stomach Lung
Stomach Pancreas Kidney

1.8 million 976,000 4.5 million

New cases Deaths Persons

Lung

Hungary
FYR Macedonia
Serbia
Montenegro
Poland
Croatia
Belarus
Romania
Mortality Latvia
Lithuania
Lung (39) Bulgaria
Belgium
Prostate (1) Russian Federation
Estoria
Bosnia Herzegovina
No data Greece
Ukraine
Slovenia
Czech Republic
Slovakia
Spain
France
Republic of Moldova
The Netherlands
Denmark
Albaria
Luxembourg
Italy
Germany
Austria
Ireland
United Kingdom
Portugal
Norway
Malta Eastern Europe
Switzerland Western Europe
Iceland
Finland Northern Europe
Cyprus Southern Europe
Sweden

0 2 4 6 8
Mortality cumulative risk, male, 0–74 years (%)
The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization
concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps
represent approximate border lines for which there may not yet be full agreement.

Figure 8–​29.  The cancer burden in Europe, males, 2012. The parentheses following the cancer type represents the number of countries in which that cancer
is the leading cause of death among men in Europe. Source: World Health Organization (WHO).

advanced cancers without a meaningful correlation between the amount
expended and survival (Brooks et al., 2013). Linkage of cancer registry
data with claims data and biomarkers can provide valuable information
on the prognosis of disease in relation to the quality and cost of care
(Hiatt et al., 2015; Huckman and Kelley, 2013; Institute of Medicine
[IOM], 2013; Lipscomb and Gillespie, 2011; Spinks et al., 2011).
In addition, the lack of information by which to classify tumors
according to molecular characteristics, rather than anatomic or
morphologic characteristics, has been identified as a major gap in
high-​income countries, which impedes efforts to evaluate quality
of care (Hewitt and Simone, 2000; IOM, 2013). Numerous tumor
markers are already informative about the prognosis and treatment
of various cancers. Examples include (1) oncotype DX (which pre-
dicts recurrence and the effectiveness of chemotherapy after sur-
gery for early stage, estrogen positive breast cancer); (2) mutations
in the gene encoding epidermal growth factor receptor (EGFR)
(which indicates the sensitivity of advanced non-​small-​cell lung
cancer to EGFR tyrosine kinase inhibitors); (3)  BRAF mutation
 13

Patterns of Cancer Incidence, Mortality, and Survival 133

Prevalence
Incidence Mortality (5 years)

Breast
Breast
Breast
32.9%
Colorectum
41.0% 45.1%
54.9%
Colorectum 59.0%
Lung Colorectum 68.7%

Lung
Pancreas Corpus uteri
Corpus uteri
Melanoma of skin
Ovary Stomach Cervix uteri

1.6 million 779,000 4.6 million

New cases Deaths Persons

Breast

Belgium
Denmark
Iceland
The Netherlands
United Kingdom
Germany
Finland
Ireland
France
Italy
Luxembourg
Switzerland
Malta
Incidence Sweden
Cyprus
Breast (40) FYR Macedonia
Norway
No data Czech Republic
Serbia
Austria
Slovenia
Croatia
Spain
Portugal
Slovakia
Bulgaria
Montenegro
Hungary
Poland
Latvia
Estoria
Romania
Lithuania
Albaria
Russian Federation
Belarus Eastern Europe
Republic of Moldova Western Europe
Ukraine Northern Europe
Greece Southern Europe
Bosnia Herzegovina

0 2 4 6 8 10 12
Incidence cumulative risk, female, 0–74 years (%)

The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization
concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps
represent approximate border lines for which there may not yet be full agreement.

Figure 8–​30.  The cancer burden in Europe, females, 2012. The parentheses following the cancer type represents the number of countries in which that
cancer is the most commonly diagnosed among women in Europe. Source: World Health Organization (WHO).

(for treatment of advanced melanoma), and (4)  KRAS mutations
(which predict the resistance of colon cancers to treatment with
EGFR inhibitors (Chang et  al., 2015). According to American
Society of Clinical Oncology, routine testing of colon cancer
patients for KRAS mutations in the United States could save at
least US$ 600 million a year from the cost of drugs, in addition to
avoiding unnecessary toxicity and suffering among tens of thou-
sands of patients (Poste, 2011).
Population-​based surveillance data on cancer are still widely unde-
rused, given their potential to monitor progress or lack thereof and to
drive preventive interventions (Howe et al., 2003; Jemal et al., 2003a;
Siegel et al., 2015b; Wingo et al., 2005), largely because of a lack of
skilled manpower in surveillance research. There is an urgent need to
attract and train young investigators in innovative methods of surveil-
lance research. A study by Glaser and colleagues found that none of
the 34 accredited schools of public health in the United States offered
134

1000
Oral cavity & Esophagus Stomach Colon
100 pharynx

10

0.1

1000 Melanoma
Rectum Pancreas Lung &
bronchus
100

10

0.1

1000
Breast Cervix Uterus Ovary
Rate per 100,000

100

10

0.1

1000
Prostate Bladder Kidney Brain & ONS
100

10

0.1

1000
Hodgkin lymphoma Non-Hodgkin Multiple myeloma Leukemia
lymphoma
100

10

0.1
0 20 40 60 80 0 20 40 60 80 0 20 40 60 80 0 20 40 60 80
Age

Male Female

Figure 8–​31.  Age-​specific incidence rates for select cancers by sex, 2012. Source: SEER.
 135

Males Table 8–​1. Incidence Rate and Male-​to-​Female Incidence Ratios for All

1000 Races Combined, 2008–​2012, SEER Registries
80–84 Cancer Sites Male Female RR (M vs. F) 95% CI
75–79
70–74 All sites 578.3 428.5 1.35 1.3–1.4
65–69 Oral cavity and 16.0 6.6 2.41 2.3–2.5
pharynx
60–64 Esophagus 8.2 2.1 3.98 3.7–4.2
Stomach 11.7 5.6 2.09 2.0–2.2
100 55–59 Colon and rectum 64.1 47.3 1.36 1.3–1.4
Anus, anal canal, 1.3 1.5 0.86 0.8–0.9
and anorectum
Liver and 8.6 3.2 2.67 2.5–2.8
Rate per 100,000

50–54
intrahepatic
bile duct
Gallbladder 0.9 1.4 0.62 0.5–0.7
45–49
Other biliary 1.9 1.3 1.48 1.4–1.6
Pancreas 13.1 10.1 1.29 1.3–1.3
Larynx 6.8 1.5 4.56 4.3–4.9
10 40–44 Lung and 83.2 52.2 1.60 1.6–1.6
bronchus
Bones and joints 1.0 0.8 1.31 1.2–1.5
Soft tissue 3.7 2.4 1.50 1.4–1.6
including
heart
35–39 Melanoma of the 23.5 15.6 1.51 1.5–1.5
skin
Breast 1.1 138.8 0.01 0.0–0.0
1 Cervix uteri 8.1
Corpus and 25.2
30–34 uterus, NOS
0.5 Ovary 14.4
1865
1870

1880

1890

1900

1910

1920

1930

1940

1950

1960

1972

Prostate 181.2
Year of birth Testis 5.6
Urinary bladder 38.3 9.7 3.69 3.9–4.1
Figure  8–​32. Age-​specific lung cancer rates among men in the United Kidney and renal 17.1 8.4 2.03 2.0–2.1
States by year of birth. Source: SEER. pelvis
Brain and other 8.1 5.6 1.43 1.4–1.5
nervous
system
1800 Brain 7.7 5.2 1.47 1.4–1.5
Cranial nerves, 0.4 0.4 0.98 0.8–1.2
other nervous
1600 system
Thyroid 4.2 11.5 0.36 0.3–0.4
1400 Hodgkin 3.1 2.5 1.25 1.2–1.3
Incidence rate per 100,000 males

lymphoma
Non-​Hodgkin 24.1 16.6 1.45 1.4–1.5
1200
lymphoma
70–79
Myeloma 7.5 4.8 1.55 1.5–1.6
1000 Leukemia 17.8 10.4 1.71 1.7–1.8
80+ Mesothelioma 2.1 0.4 5.37 4.7–6.2
800 Kaposi sarcoma 1.5 0.1 11.77 9.5–14.7
60–69
Using incidence-​SEER 9 Regs Research Data, Nov 2014 Sub (1973–​2012) Katrina/​
600 Rita Population Adjustment; rates per 100,000 and age-​adjusted to the 2000 US Std
Population (19 age groups; Census P25-​1130) standard; confidence intervals (Tiwari
mod) are 95% for rates and ratios.
400 ~
Statistic could not be calculated.

200 50–59

40–49
0
1980 1983 1986 1989 1992 1995 1998

Figure 8–​33.  Prostate cancer incidence rates by calendar year of d­ iagnosis.

Source: SEER.
136

136 Part II: The Magnitude of Cancer

3000 Incidence 3000 Mortality

2750 2750
2500 Male 2500
2250 2250
Rate per 100,000

2000 2000
1750 1750 Male
1500 1500
Female
1250 1250
1000 1000
750 750
500 500 Female
250 250
0 0

01 0
05–04
10 09
15 14
20 9
25 24
30 29
35 34
40 39
45 4
50 49
55 54
60 59
65 4
70 69
75 74
80 79
4
+
01 0
05–04
10 09
15 14
20 9
25 24
30 9
35 34
40 39
45 4
50 49
55 4
60 59
65 4
70 69
75 74
80–79
4
+

–1

–4

–6

–8
85
–1

–2

–4

–5

–6

–8
85

–
–
–
–
–

–
–
–
–

–
–
–
–
–

–
–

–
–
Age (years) Age (years)

Figure 8–​34.  Age-​specific incidence and mortality rates by sex, 2012. Source: SEER.

a course in cancer surveillance in their catalogs for 2003–​ 2004. to 8.3 billion by 2030. Most of the increase will be in LMICs, where
Educators and academic institutions have not yet integrated cancer large numbers of young adults are now surviving to older ages, when
surveillance research into the teaching curriculum. The current lack cancer becomes common. The increase is likely to be even higher
of postgraduate training and fellowship in the United States will not than predicted from the demographic changes alone, because of
be adequate to train future generations of surveillance researchers the ongoing adoption of Western patterns of diet, physical inactiv-
(Glaser et al., 2005). This is also true in most parts of the world. ity, delayed reproduction, and cigarette smoking. Consequently, the
future cancer burden will increasingly fall on LMICs that can least
afford it.
THE FUTURE SCALE AND PROFILE OF CANCER 2030
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 14
9 Socioeconomic Disparities in Cancer Incidence and Mortality
CANDYCE KROENKE AND ICHIRO KAWACHI
OVERVIEW
The relationship between socioeconomic status (SES) and cancer is
complex, dynamic, and evolving. Associations depend on SES mea-
sures, cancer type, sociodemographic factors including race/​ethnicity,
and historical trends. However, socioeconomic disadvantage is often
associated with a higher risk of cancer, particularly cancers diagnosed
at a late stage, as well as worse prognosis once diagnosed. Research
on secular trends over the past 70  years has shown reversals of the
socioeconomic gradient for lung and colorectal cancer consistent with
differential trends by SES in patterns of smoking, diet, and obesity.
Rates of these cancers are now currently higher in socioeconomi-
cally disadvantaged groups. SES is considered to be a “fundamental”
determinant of health outcomes, and this appears true throughout the
cancer spectrum—​from cancer incidence, to detection, treatment, and
survival. Population-​level research on SES and cancer still predomi-
nantly employs area-​level measures (as a proxy for individual SES),
though investigations over the past decade have increasingly consid-
ered the simultaneous impact of individual SES and area-​level SES (as
a contextual influence) on health outcomes. Investigations of the link
between SES and cancer will continue to benefit from more sophisti-
cated approaches to the measurement of SES, including evaluation of
socioeconomic trajectories and modeling of cumulative disadvantage
over the life course. Programs or policies designed to reduce the bur-
den of cancer need to pay heed to reducing and ultimately eliminating
socioeconomic disparities.
INTRODUCTION
The association between socioeconomic status (hereafter abbreviated
as SES) and health status is so robust and consistent that epidemiolo-
gists routinely adjust for it as a potential confounding variable when
evaluating the etiological role of other risk factors for disease. The
present chapter turns this logic on its head, to focus on SES as a fun-
damental determinant of disease, specifically cancer incidence and
mortality.
The association between SES and health status has been recorded
throughout history. William Farr, viewed as an intellectual founder of
epidemiology, documented the existence of socioeconomic disparities
in mortality in nineteenth-​century Britain, and concluded that “[n]‌o
variation in the health of the states of Europe is the result of chance;
it is the direct result of the physical and political conditions in which
nations live” (quoted in Beaglehole & Bonita, 1997). The persistent
and pervasive association between lower socioeconomic position and
worse health status accounts for the belief that SES may be a “fun-
damental” determinant of individual and population health; no mat-
ter what the current health threats confronted in any given society,
disadvantaged groups are worse off in terms of their achieved health
(Phelan, Link, & Tehranifar, 2010; Sistino & Ellis, 2011).
Freese and Lutfey (2011) identified four meta-​mechanisms by which
SES is linked to health: (1) the means by which individuals use SES-​
related resources to gain a health advantage; (2) spillovers, in which
people benefit from being embedded in contexts in which others (e.g.,
spouses, neighbors, coworkers) are attentive to health concerns; (3) a
health habitus, in which socially structured preferences for a “healthy
lifestyle” shape health outcomes; and (4) the influence of institutions
that treat people differently depending on their diverse socioeconomic
backgrounds.
Rather than simply reflecting health disparities at a single time
point, however, this theoretical model helps to explain secular trends
in socioeconomic disparities, which may emerge or widen with dispa-
rate gains in knowledge or adoption of practices across SES groups.
Disparities may narrow as new knowledge diffuses through the popula-
tion and as low-​SES individuals adopt practices that are initially more
common among those of high SES, such as screening for colorectal
cancer, or when efforts are targeted to improve outcomes among the
socioeconomically disadvantaged. However, disparities have often
widened because those of higher SES learn, incorporate, and benefit
from new information about cancer prevention before those of lower
SES do.
Exceptions to these rules do exist (e.g., low and late parity among
women of high SES, leading to a higher risk of breast cancer)
(Pudrovska & Anikputa, 2012). However, rather than high SES rep-
resenting adversity, the absence or reversal of a socioeconomic dis-
parity often reflects lack of knowledge about a particular cause of
cancer or mortality risk factors. Evidence suggests that once associa-
tions are elucidated and disseminated, those of high SES are the first
to take advantage of novel findings, resulting in widening disparities
(Eckersley, Dixon, & Douglas, 2001). Thus, the relationship between
SES and health is dynamic, and may change (or even reverse) over
time. Major risk factors for cancer, such as cigarette smoking, physical
inactivity, and obesity, were each more prevalent among higher SES
groups in industrialized societies during earlier periods of economic
development, but the patterns reversed during more recent history so
that the same risk factors now exhibit higher prevalence among disad-
vantaged groups (Eckersley et al., 2001).
There is an important exception to this generalization:  the direc-
tion of causation does not uniformly run from SES to health. Some
evidence suggests that health status can exert influences on socioeco-
nomic attainment, such as when a diagnosis of cancer early in life
adversely impacts educational attainment and employment prospects,
particularly in women (D. Lee & Jackson, 2015). In fact, socioeco-
nomic attainment and health status exert reciprocal influences on each
other, though the current evidence more often supports the influence of
SES on cancer than the reverse (DiMartino, Birken, & Mayer, 2016).
When describing the relationships between SES and cancer out-
comes, it is important to be specific about the exact site and type of
cancer, as well as the class of outcome measure (incidence versus
survival) (Krieger, 2005). The incidence of some cancers, notably
breast cancer and melanoma, is higher among more advantaged SES
groups, presumably reflecting the underlying socioeconomic distri-
bution of risk factors. For breast cancer, the higher incidence among
higher SES women has been attributed to reproductive factors includ-
ing earlier age at menarche, later age at first birth, and lower fertility.
However, recent secular trends show that age at menarche, declining
overall, is falling at a faster rate among girls of low SES. Moreover,
with the publication of research about the adverse cardiac effects of
hormone therapy, a known risk factor for breast cancer, the use of hor-
mone therapy declined markedly (Hersh, Stefanick, & Stafford, 2004;
Steinkellner et al., 2012), particularly among women from advantaged
socioeconomic backgrounds, notable because initial use of hormone
therapy in low-​SES women was lower (Krieger, Chen, & Waterman,
2010). On the other hand, survival following the diagnosis of breast
141
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142 Part II: The Magnitude of Cancer
cancer consistently favors higher SES women, due, among other rea-
sons, to earlier detection, better access to effective treatment (Lochner
& Kawachi, 2000), and beneficial social networks (C. H.  Kroenke,
Kubzansky, Schernhammer, Holmes, & Kawachi, 2006; C. H. Kroenke
et al., 2013).
This chapter expands upon the previous version published over a
decade ago. While the overall literature has not changed markedly
(i.e., low SES continues to predict worse cancer incidence and out-
comes generally), particular associations or changing trends between
SES and cancer reflect changing secular trends in behaviors and other
factors. This chapter will cover those discussions, as well as the advent
of new kinds of research (e.g., epigenetics), which may help shed light
on the relationships between SES and cancer. We have also updated
literature when available, particularly data incorporating secular trends
and new insights. Finally, we will briefly describe needed research in
the area and consider future trends.
The present chapter is organized into four major sections. The
first section will define the concept of SES and describe the various
approaches to its measurement. The second section will summarize
the observations and updates on the general nature of the associations
between area-​level and individual-​level SES, and cancer morbidity,
mortality, and survival. The third section will outline the general cat-
egories of explanations, both causal and non-​causal, that have been put
forward to account for the association between SES and cancer. The
fourth section will provide a survey of the specific causal mechanisms
underlying the relationship between SES and cancer. This section is
organized into two subsections dealing, respectively, with early life
and adult risk factors that potentially account for the observed dispari-
ties in cancer incidence. We conclude the chapter with a summary and
thoughts about needs for future research.
WHAT IS SES? DEFINITIONS AND MEASUREMENT
Sociologists and allied social scientists have studied social strati-
fication and its consequences for over 150  years (Grusky, 1994).
Epidemiologists who study the effects of social stratification on health
have, for the most part, followed the conceptual approach established
by Max Weber (1864–​ 1920) (Liberatos, Link, & Kelsey, 1988).
According to Weber, “socioeconomic status” is defined as groups
within society that are relatively homogeneous with respect to life
chances and opportunities (Grusky, 1994). In turn, life opportunities
(and hence, SES groups) have been measured by socioeconomic indi-
cators, such as educational attainment (years of schooling, educational
credentials gained), income and wealth, as well as occupational sta-
tus or prestige (Lynch & Kaplan, 2000). SES is therefore a multidi-
mensional concept that is intended to capture the manifold, and often
subtle, differences between individuals with respect to their access to
life opportunities. Other terms that are commonly used in the social
epidemiologic literature to characterize social stratification include
socioeconomic position (SEP) and social class, among others. While
each term has a different theoretical meaning and origin (see Glymour,
Avendano, & Kawachi, 2014), we specifically use the broader term
“socioeconomic status” (SES), because it encompasses economic/​
material resources (e.g., income, wealth) as well as psychosocial dif-
ferences (e.g., occupational prestige), each of which influence health
over the life course (C. Kroenke, 2008).
Individual-​level measures, including education, occupation,
income, and wealth, are linked across the life course, so that more
schooling determines an individual’s ability to access higher status
jobs, which in turn determines the rate of monetary compensation,
and so on. It is not surprising, then, that indicators of SES are usually
found to be correlated with each other. That said, epidemiologists have
often used three of the individual indicators of SES (education, occu-
pation, income) in an interchangeable manner, even though they may
be in fact linked to health outcomes through different mechanisms.
For example, schooling and education are believed to influence health
through the acquisition of knowledge in one or more forms—increased
knowledge about health-​promoting behaviors, enhanced ability to pro-
cess and act upon that information, as well as the ability to interact
with and “navigate” medical care systems and options (Yen & Moss,
1999). Income, on the other hand, enables individuals to purchase the
various goods and services that are necessary for maintaining and pro-
moting health. Occupational status often determines an individual’s
exposure to hazards (including carcinogens) in the workplace (Pearce
& Matos, 1994), in addition to access to psychosocial resources, such
as prestige, respect, and security. Wealth can help to cushion eco-
nomic shocks in the case of job loss, minimize psychosocial risk (e.g.,
depressive symptoms, anxiety) associated with economic insecurity,
or enhance social capital. In the past decade, researchers have endeav-
ored to more carefully distinguish and clarify the mechanisms for each
variable so that researchers can be more thoughtful about the ways in
which they measure SES (P. A. Braveman et al., 2005) and their inter-
related influences over the life course.
The example of cigarette smoking illustrates some potential pitfalls
of the uncritical use of SES measures. Higher educational attainment is
strongly inversely associated with cigarette smoking in most advanced
industrialized societies, including the United States (Pamuk, Makuc,
Heck, Reuben, & Lochner, 1998). The inverse association between
smoking and education is thought to be mediated by knowledge about
the hazards of cigarette smoking. In support of this hypothesis, an
association between education and smoking among young adults did
not exist prior to 1953, when the health hazards of smoking had yet
to be established (Fuchs, 1983). Educational differentials in smoking
emerged soon after the first (1964) US Surgeon General’s report on
smoking and health. Higher incomes are also correlated with a lower
prevalence of smoking, although less strongly than is the case with
education (Pamuk et al., 1998). Increased income should result in the
enhanced ability to afford more goods, including cigarettes, all other
things being equal. Historically, during the economic development
of societies, as real personal income rose, so did per capita cigarette
consumption.
Also, within certain subgroups in the population, such as teenag-
ers, higher incomes (in the form of more pocket money, for example)
have been shown to be associated with more cigarette consumption
(Scragg, Laugesen, & Robinson, 2002). And in fact, the implementa-
tion of excise taxes to raise the price of cigarettes has been shown
to decrease cigarette consumption particularly among youth (Kostova
et al., 2014; van Hasselt et al., 2015) and those with lower disposable
income (Levy, Mumford, & Compton, 2006). So why is higher income
associated with lower cigarette consumption?
The reason is unlikely to be due to a direct causal effect of income
on smoking. Rather, higher incomes are most likely associated with
other variables that reduce the probability of smoking. For example,
teenagers with greater discretionary dollars to spend are also more
likely to come from higher socioeconomic backgrounds, so that the
effect of higher parental education (and stronger family socialization),
as well as social norms associated with higher education and prohibi-
tions on smoking, may override the effect of having more money on
cigarette consumption. Put simply, education and income may influ-
ence cigarette smoking through different, multiple, and even coun-
tervailing mechanisms. Care is therefore warranted in specifying the
indicator of SES used when describing its association with health out-
comes. For the remainder of the chapter, the term “socioeconomic dis-
parities” will be used as a broad descriptive term to refer to variations,
inequalities, or differences in cancer outcomes by SES. The specific
indicator of SES used will be described wherever appropriate.
Three additional points are worth noting with respect to the mea-
surement of SES. First, SES can be conceptualized and measured at
both the individual level and at the area level (for example, the neigh-
borhoods in which individuals reside). A great deal of recent research
has made use of area-​level socioeconomic measures, including median
household income from Census tracts; average SES of residents; and
neighborhood social, physical, and food environments. An individual
with a given level of income or educational attainment could experi-
ence different chances of health depending upon the average SES level
of his or her neighborhood (for example, as measured by the median
household income of a Census tract). Capturing area-​level SES is
therefore of intrinsic interest over and above measuring individual
SES. This is a different argument from using area SES as a proxy for
 143
Socioeconomic Disparities in Cancer Incidence and Mortality 143
individual SES when the latter measures are not available on data
sets. The reason that area SES is believed to contribute independently
to health outcomes is based on the differential quality of neighbor-
hood environments according to the average SES level of its resi-
dents, a phenomenon referred to as residential segregation (Kawachi
& Berkman, 2003). Examples of such neighborhood-​level patterning
include differential access to services and amenities (e.g., mammog-
raphy screening services, supermarkets that sell fresh fruits and veg-
etables); the physical environment (e.g., air pollution, the presence of
parks and recreational playgrounds for physical activity, differential
exposures to outdoor tobacco advertising); and the social context (e.g.,
social support among neighbors) (Kawachi & Berkman, 2003). In
turn, the differential distribution of these protective and risk factors at
the neighborhood level is thought to contribute to the disease risks of
residents, including cancer risk. Since the publication of the previous
version of this chapter, a growing number of articles have examined
the independent effects of area-​level and individual-​level SES mea-
sures. Investigators have often, though not always, found independent
effects of these, though area-​level effects are often more weakly asso-
ciated than individual-​level SES factors with cancer outcomes.
Second, in addition to the dimension of place, researchers have
increasingly emphasized the importance of the dimension of time in
conceptualizing and measuring SES and its effects on health. SES sel-
dom remains static across the life course. Individuals exhibit upward
(or downward) social mobility, for example, when they quit jobs to
return for more schooling, when they are involuntarily laid off, when
they are promoted to higher positions, and so on. Accordingly, the
measurement of SES at any single point in time is unlikely to capture
the dynamic, as well as cumulative, effects of SES on health. Income
dynamics, in the form of accumulated spells of poverty, have been
shown to predict mortality and other health outcomes (McDonough,
Duncan, Williams, & House, 1997). Childhood socioeconomic cir-
cumstances have been shown to predict health outcomes in later life
(Davey-​ Smith, Gunnell, & Ben-​ Shlomo, 2001), including cancer
(Vohra, Marmot, Bauld, & Hiatt, 2016), independently of, or in com-
bination with, SES attained in adulthood.
Beyond the fact that SES can change over time, there are other
important life course considerations. First, there are cumulative effects
of low SES on health outcomes. The concept of “allostatic load” cap-
tures the accumulated “wear and tear” on the body’s physiologic sys-
tems as a result of lifelong exposure to adverse social circumstances
(Kubzansky, Seeman, & Glymour, 2014). Second, there are believed
to be “critical periods” in development during which socioeconomic
disadvantage may have particularly adverse impacts on the trajecto-
ries of subsequent health (C. Kroenke, 2008). Though socioeconomic
disadvantage at any point in the life course can result in health insults,
low SES during infancy and childhood may have profound effects
on health. For example, spells of income poverty during the prenatal
and infancy period have been linked to increased risk of adult obesity,
more so than exposure during subsequent periods of childhood (Ziol-​
Guest, Duncan, & Kalil, 2009).
There are, additionally, powerful cohort effects that influence socio-
economic trajectories over the life course with possible ramifications
for cancer and other health outcomes. In work by Elder, military con-
scription during World War II of men in their twenties and thirties as
they were establishing themselves in their careers profoundly altered
their life chances as compared with those who were conscripted in
their late teens (G. H. Elder, Jr., Shanahan, & Clipp, 1994). They had
lower lifetime earnings and attainment of wealth and a higher divorce
rate. Late entrants were shown to have higher mortality than early
entrants due to these factors (G. H.  Elder, Clipp, Brown, Martin, &
Friedman, 2009). Though the consequences for cancer were not spe-
cifically addressed, a major mechanism to adverse health outcomes
included alcohol consumption, a known predictor of several types of
cancer.
In more recent history, crushing levels of educational debt and com-
promised job prospects, particularly among “millennials” who gradu-
ated around the 2008 downturn, threaten to limit their earning and
occupational potential compared with earlier cohorts. It is yet uncer-
tain how such differences will influence health outcomes since adult
millennials have been shown to live with their parents at a higher rate
than previous generations (Fry, 2015); parental resources may buffer
some of the socioeconomic difficulties. Future work may incorporate
new SES measures as current individual-​and neighborhood-​ level
measures fail to capture familial resources.
An additional point worth mentioning about the measurement
of socioeconomic disparities in health is in regard to its distinction
from racial disparities in health. This point is particularly pertinent
in the United States, where official statistics have often conflated
racial disparities in health with socioeconomic disparities (Williams,
1997). Race and SES are not synonymous or interchangeable. Race is
emphatically not a proxy for SES, despite the fact that racial minori-
ties in the United States are overrepresented among lower SES groups,
stemming from discrimination and the denial of opportunities through-
out history. The finding that race is often associated with morbidity
and mortality independent of SES emphasizes that race is more than
SES. Accordingly, understanding the sources of racial disparities in
health requires attention to a separate set of causes and mechanisms,
including the potential influence of racial discrimination on health out-
comes. Fortunately, this has been increasingly reflected in the research
literature. There is also the growing realization that elucidating pat-
terns of health by socioeconomic status may be insufficient to under-
stand and describe those patterns and that ultimately, research may be
needed to understand how the combination of SES and race, as well as
other social factors (e.g., urban/​rural status, immigrant status/​nativity),
influence patterns of associations.
The SES Gradient in Cancer Incidence and Mortality
Individuals from lower SES backgrounds, whether measured by edu-
cational attainment, income and wealth, or occupational status, gen-
erally experience worse health outcomes than those higher on the
socioeconomic hierarchy (Adler et  al., 1993). This widely observed
pattern of the rise in health status with each level of SES has been
referred to as the SES “gradient” in health. It is a “gradient” because
there is no apparent threshold or cut-​point in the relationship between
SES and health, that is, the excess morbidity and mortality risks of
disadvantaged groups are not solely confined to those who are poor by
officially defined criteria. Instead, at each level of the SES hierarchy,
people experience better health compared to those immediately below
them, even among groups that are considered middle class and above.
SOCIOECONOMIC STATUS AND CANCER: 
GENERAL REMARKS
Socioeconomic disadvantage, whether measured by low income, low
educational attainment, low occupational status, or area-​level socio-
economic measures, has been linked with both higher overall cancer
incidence and mortality (Doubeni, Laiyemo, et  al., 2012; Enewold,
Horner, Shriver, & Zhu, 2014; Harper et al., 2009; Hastert, Beresford,
Sheppard, & White, 2015; Krieger et al., 2006; Ma, Xu, Anderson, &
Jemal, 2012). However, in contrast to the SES gradient reported for
other major health outcomes, such as cardiovascular disease (CVD)
or infectious diseases, the SES gradient across cancer incidence and
mortality is often not as strong or consistent (Hastert et  al., 2015;
Steenland, Henley, & Thun, 2002).
Three major reasons for the weaker associations between SES
and overall cancer incidence and mortality are (a)  the heterogeneity
of associations between SES and specific cancer sites; (b) the length
of the induction period between exposure to low SES conditions and
cancer onset; and (c) differences that reflect the current state of knowl-
edge about CVD and cancer (i.e., we know more about CVD preven-
tion and treatment than we do about cancer prevention and treatment).
With regard to the first point, cancer (unlike CVD) involves a highly
heterogeneous mix of diseases that are caused by different sets of risk
factors, many of which may be unrelated to, or related in opposite
directions to, SES. Thus, an association between overall cancer inci-
dence and/​or mortality with SES at any given point in time reflects
14
144 Part II: The Magnitude of Cancer
the weighted contribution of the component sites, each of which may
have a different relationship with SES. For example, as the contribu-
tion of lung cancer deaths outgrows the contribution of breast cancer
in overall cancer mortality rates for US women, the SES gradient in
total cancer deaths can be expected to grow stronger (G. K.  Singh,
Miller, Hankey, Feuer, & Pickle, 2002). The analysis of SES gradi-
ents in overall cancer incidence and mortality is therefore of limited
value in understanding etiological relationships, though it may serve a
broader purpose in monitoring population trends in health disparities.
With regard to the second point, most cancers (unlike CVD) are
associated with lengthy induction periods between exposure (in this
case, to the living conditions associated with low SES) and the onset
of disease. Induction periods for cancers are typically on the order
of decades, whereas they may be just a few years for heart disease
or infectious diseases, or other health outcomes that exhibit strong
SES gradients. The length of the induction period for most cancers
produces measurement error in exposure status, as individuals move
out of poverty, or experience upward job mobility, and so forth, with
the result that the association between SES and cancer outcomes may
be biased in the direction of the null. Also, it may take decades for
a socioeconomic gradient in cancer mortality (e.g., lung cancer) to
emerge, even after SES gradients in health behaviors (e.g., smoking)
have become well established—​such was the case for the educational
gradient in lung cancer mortality among women in the United States
(Steenland et al., 2002). Changes in behaviors impact CVD event rates
considerably faster than they do cancer rates.
However, it is important to note that trends in socioeconomic
disparities in cardiovascular factors could portend future trends in
socioeconomic disparities for certain types of cancer. Kanjilal and
colleagues (Kanjilal et al., 2006) found between 1971 and 2002 that
while CVD risk factors, including high blood pressure, high choles-
terol, and smoking, declined at all socioeconomic levels, socioeco-
nomic disparities widened (on a difference scale) for smoking and
high cholesterol because of greater improvements among those of
high SES. Socioeconomic disparities also widened for type 2 diabe-
tes, but this was due to larger increases among those of low SES.
Smoking and diabetes are each risk factors for cancer, portending
widening future cancer disparities for lung cancer and gastrointesti-
nal and other cancers influenced by metabolic dysregulation, even if
overall cancer incidence declines. Researchers should nonetheless be
cognizant that trends in disparities on relative versus absolute scales
can yield diverging conclusions about whether disparities are increas-
ing or decreasing.
With regard to the third point, there is a great deal we do not know
about the causes of, or how to screen for, certain types of cancer, as
reflected by the very high mortality rates for certain kinds of cancer,
including pancreatic and ovarian cancers. As knowledge around risk
factors, treatment, and methods of screening have improved, there is
evidence that socioeconomic disparities favoring those of higher SES
have increased. Those cancers for which this statement is true include
cancers more amenable to improvements among those of lower SES.
Notes on Area-​Level and Individual-​Level
SES and Cancer
In the previous edition of this book, we reported a dearth of population-​
level cancer incidence studies in the United States that had data on
SES at the individual level. This continues to be true, due in large
part to the lack of socioeconomic information available within official
sources of data, including cancer registries. In the 1990s, Krieger and
colleagues (Krieger, Chen, & Ebel, 1997)  conducted a survey of all
cancer registries in the United States to ascertain the availability of
SES information. Of the 45 state cancer registries that responded to
their mailed survey, 36 (80%) collected some information on occu-
pation, but only 4 routinely reported occupational data, reflecting the
constraints posed by the accuracy and reliability of socioeconomic
data available from patients’ medical records (the principal source
of cancer registry data). Only two of the state cancer registries col-
lected information on education, and none of the registries collected
information on income. Individual-​level socioeconomic data are not
routinely available in patient hospital records.
In recent years, there have been increasing calls—​as from the
Institute of Medicine’s Committee on Public Health Strategies to
Improve Health (Institute of Medicine, 2011)—​for more compre-
hensive approaches to collecting individual and community SES
measures to improve public health surveillance (P. Braveman, 2011;
P. A. Braveman et al., 2005; Gottlieb, Sandel, & Adler, 2013; Koh,
2011; Sadana & Harper, 2011). Work has also been done to link
large cohort data sets with data available on individual SES mea-
sures to population-​ level Surveillance, Epidemiology, and End
Results (SEER) data with area-​level measures (Clegg et al., 2009;
Doubeni, Laiyemo, et  al., 2012; Du, Lin, Johnson, & Altekruse,
2011; Hastert et  al., 2015). Insights from this work suggest that
area-​and individual-​level socioeconomic variables exert indepen-
dent effects on outcomes, though specific effects differ by cancer,
study, and country (C. M.  Chang et  al., 2012). In the absence of
individual-​level SES information, US researchers have contin-
ued to examine area-​level (e.g., county, zip code, census tract, or
block group) SES disparities in cancer incidence as a proxy for
individual SES (Harper et  al., 2009; Hastert et  al., 2015; Krieger
et al., 2006; L. Liu, Cozen, Bernstein, Ross, & Deapen, 2001; Tao,
Ladabaum, Gomez, & Cheng, 2014). More recent studies are begin-
ning to examine the independent or combined effects of area-​and
individual-​level SES on cancer incidence (Doubeni, Schootman,
et al., 2012; Hastert et al., 2015) and cancer mortality (C. M. Chang
et  al., 2012; Enewold et  al., 2014)  or individual-​level SES factors
and cancer outcomes (Clegg et al., 2009; Kinsey, Jemal, Liff, Ward,
& Thun, 2008; Ma et al., 2012).
SES AND CANCER INCIDENCE
Cancer in Adults
With regard to incidence rates, the cancer sites in adults exhibiting
the strongest and most consistent associations with low SES are
cancers of the lung, upper aerodigestive tract (e.g., oral, esopha-
geal, laryngeal), stomach, and cervix (Boscoe, Henry, Sherman, &
Johnson, 2016; Clegg et  al., 2009; Faggiano, Partanen, Kogevinas,
& Boffetta, 1997; Kogevinas, Pearce, Susser, & Boffetta, 1997;
Kogevinas & Porta, 1997; Lochner & Kawachi, 2000; Merletti,
Galassi, & Spadea, 2011). Low SES also appears to be related to
a higher incidence of liver cancer (E. T. Chang et al., 2010; Shebl,
Capo-​Ramos, Graubard, McGlynn, & Altekruse, 2012). By contrast,
hormonally related cancers, such as prostate and breast cancer, and
melanoma are cancers in which incidence rates appear to be higher
in individuals of higher SES (Boscoe et al., 2016; Clegg et al., 2009;
Faggiano et al., 1997). Direct associations of SES with colon cancer
and ovarian cancer were previously reported (Kogevinas & Porta,
1997). However, inverse relationships of SES with colon and ovar-
ian cancer have been reported in more recent years (Praestegaard
et al., 2016). Gaps in prostate and breast cancer incidence have been
shrinking (Krieger, Chen, Kosheleva, & Waterman, 2012), but low
SES is associated with higher risks of late-​stage breast and prostate
cancers. Patterns of association between SES and cancer incidence
are summarized in work by Boscoe and colleagues (Boscoe et  al.,
2016) (Figure 9–​1). In this diagram, lower SES is related to a higher
risk of several cancers, but most particularly, late-​stage cancers.
Higher SES is related to a higher risk of several types of cancer, and
these are generally local tumors.
Area-​Level SES and Cancer Incidence
In the previous version of the chapter, we reported on area-​level find-
ings and incident cancer in a study by Krieger and colleagues (Krieger
et  al., 1999). They examined associations between cancer incidence
and SES, measured at the Census block group level in California’s San
Francisco Bay area. A Census block group is a division of a Census
tract, typically containing 1000 residents, with boundaries drawn to
maximize social homogeneity. The results of this study, which were
 145

Socioeconomic Disparities in Cancer Incidence and Mortality 145

0.5 1.0 1.5 2.0 2.5 3.0
Larynx 3.2
Cervix
HPV-related
Oral
Liver
Lung
Tobacco-related
Esophagus
Prostate
Kidney
Bladder
Colorectal
Female breast
Stomach
All stageable cancers
Testis
Brain Distant
Uterus Local

Melanoma
HL
Pancreas
Thyroid
Ovary
NHL
0.5 1.0 1.5 2.0 2.5 3.0

Figure 9–​1.  Relative risk of cancer incidence between highest (over 20%) and lowest (<5%) poverty category, based on census tract, by site and stage,
United States, 2005–​2009. Source: Boscoe (2015).

also stratified by race/​ethnicity, indicated a strong area-​SES gradient
for lung cancer and cervix cancer with lower SES related to higher
cancer risks. However, and counter to other race/​ethnic groups, there
was a positive association between higher area SES and excess risk of
lung cancer in Hispanic women and men. The authors speculated that
this Hispanic “paradox” may reflect the persistently higher smoking
prevalence among professional classes in immigrant populations from
Latin America (Krieger et al., 1999).
In a more recent study using data from the California Cancer
Registry, Yin and colleagues (Yin et  al., 2010)  corroborated the
apparent paradox in Hispanics and also reported other complexi-
ties. Using the relative index of inequality (RII), the authors found,
consistent with previous findings, that women of low SES had a
lower risk of breast cancer and a higher risk of cervical cancer com-
pared with women of high SES; these patterns held for all race/​
ethnic groups. Parallel associations were seen in men for prostate
cancer, as for breast cancer. The consistencies ended there. Similar
to findings in Krieger, women and men of low SES had higher risks
of lung cancer in whites, blacks, and Asians and Pacific Islanders
(APIs), whereas they had a lower risk of lung cancer in Hispanics.
Showing even greater complexity, men and women of low SES had
higher risks of colorectal cancer among non-​Hispanic whites, no
difference in risk of colorectal cancer in blacks and Hispanic men,
and a lower risk of colorectal cancer in Hispanic women and API
men and women, compared with those of higher SES (Table 9–​1).
The authors surmised that the opposite SES gradient in the Hispanic
population may be partly explained by relationships between SES
and cancer risk factors including diet, obesity, and smoking, that run
counter to relationships in other racial/​ethnic groups. Few studies
have explored the influence of SES on cancer incidence in multi-
racial populations, but studies have shown variation in the patterns
of association between SES and cancer incidence by type of cancer
and by race/​ethnicity.
Individual-​Level SES and Cancer Incidence
Few studies have evaluated individual-​level socioeconomic factors and
surveillance data because SES data are not available in patient hospital
records and are therefore not routinely reported by cancer registries
in the United States. However, in 1999, the National Cancer Institute
(NCI) initiated a study resulting in the linkage of population-​based
SEER cancer registry data to data from the US representative National
Longitudinal Mortality Study (NLMS) study with self-​ reported
socioeconomic data from the Social and Economic Supplement to
the Census Bureau’s Current Population Survey (CPS). Using these
data, Clegg and colleagues (2009) evaluated associations of education,
income, poverty status, and employment status to cancer incidence in
11,464 people from 26 NLMS cohorts. Education was most strongly
associated with cancer; lower education levels were related to a higher
risk of colorectal cancer and lower risks of prostate and breast can-
cer but higher risks of late-​stage prostate and breast cancer. Parallel
patterns of association for income, poverty status, and employment
status and cancer were reported, but associations were less often sta-
tistically significant (Table 9–​2). Educational attainment is more stable
than income, poverty status, and employment status, which may help
explain the stronger findings for education, though it is important to
consider that different socioeconomic variables could be differently
predictive by type of cancer. Future research incorporating both area-​
and individual-​level SES measures will enable multilevel evaluations
of socioeconomic effects on cancer.
Area-​and Individual-​Level SES and Cancer
In addition to individual-​level analyses, researchers have begun to
examine the independent effects of area-​and individual-​level SES
on cancer incidence. In the ongoing prospective NIH-​AARP Diet
and Health Study of 506,488 residents in six US states and two met-
ropolitan areas, Doubeni and colleagues (Doubeni, Laiyemo, et al.,
2012)  reported significant independent associations of area-​level
 146
Table 9–​1. Relative Index of Socioeconomic Inequality and Cancer Incidence by Race

Breast Cancer Prostate Cancer Cervical Cancer Colorectal Cancer Lung Cancer

Female Male Female Male Female Male Female

RII 95% CI RII 95% CI RII 95% CI RII 95% CI RII 95% CI RII 95% CI RII 95% CI

Non-​Hispanic White 0.78 (0.76, 0.80) 0.80 (0.78, 0.83) 2.98 (2.61, 3.40) 1.25 (1.19, 1.31) 1.19 (1.12, 1.25) 2.40 (2.31, 2.50) 1.71 (1.63, 1.79)

Black 0.85 (0.78, 0.93) 0.86 (0.81, 0.91) 2.77 (2.01, 3.81) 1.03 (0.91, 1.17) 1.11 (0.97, 1.27) 1.54 (1.41. 1.68) 1.26 (1.12, 1.43)

Hispanic 0.50 (0.47, 0.52) 0.58 (0.56, 0.60) 2.18 (1.93, 2.46) 0.60 (0.56, 0.64) 0.62 (0.57, 0.67) 0.82 (0.77, 0.87) 0.60 (0.55, 0.65)

Asian/​Pacific Islander 0.66 (0.61, 0.77) 0.76 (0.70, 0.81) 2.26 (1.77, 2.89) 0.99 (0.89, 1.10) 0.88 (0.78, 0.99) 1.46 (1.33, 1.60) 1.16 (1.02, 1.33)

The relative index of inequality (RII) represents the ratio of cancer incidence in the lowest to the incidence in the highest socioeconomic group for socioeconomic status and 95% confidence intervals (CI) of cancer incidence rates by sex
and race/​ethnicity (consistent with the census 2000, race/​ethnicity categories were not mutually exclusive): selected cancer sites, California, 1998–​2002.
  147
Table 9–2. Age-​Adjusted Incidence Ratesa and Covariate-​Adjusted Rate Ratios (RR)b by Selected Socioeconomic Characteristics: Colorectal, Prostate, and Female Breast Cancer

Colorectal Cancer
(Both Sexes Combined) Prostate Cancer Female Breast Cancer

Characteristic No. Rate SE RR 95% CI No. Rate SE RR 95% CI No. Rate SE RR 95% CI

Total population 1467 68.39 1.69 –​ –​ –​ 1995 218.11 4.64 –​ –​ –​ 1739 149.10 3.54 –​ –​ –​

Educational attainment (years of education)

< HS graduates (≤11) 512 71.94 3.26 1.45 1.31 1.61 622 203.50 7.91 0.79 0.70 0.90 407 124.93 6.87 0.74 0.63 0.86

HS graduates (12) 527 69.50 2.90 1.22 1.04 1.44 592 211.14 8.43 0.83 0.74 0.94 708 151.23 5.65 0.88 0.77 1.01

Some post HS (13–​15) 217 64.39 4.14 1.13 0.93 1.36 308 221.75 12.19 0.89 0.77 1.03 333 164.23 8.87 0.96 0.82 1.13

College education or beyond (16+) 211 66.31 4.07 1.00 Reference 471 253.34 11.64 1.00 Reference 290 167.82 9.95 1.00 Reference

Family income (1990 dollars)

< $12,500 286 69.55 4.33 1.20 1.02 1.43 245 201.15 12.81 0.84 0.72 0.98 304 136.35 8.82 0.90 0.77 1.05

$12,500–​$24,999 353 69.63 3.62 1.20 1.02 1.43 430 207.05 9.40 0.87 0.77 0.99 397 152.73 7.89 0.98 0.85 1.12

$25,000–​$34,999 217 72.85 4.78 1.21 1.02 1.43 268 207.64 12.14 0.86 0.74 0.99 225 139.22 9.29 0.87 0.74 1.02

$35,000–​$49,999 208 66.53 4.39 1.05 0.88 1.25 332 220.30 12.11 0.92 0.81 1.05 268 151.15 9.27 0.94 0.81 1.09

$50,000+ 347 64.09 3.51 1.00 Reference 655 232.47 9.58 1.00 Reference 502 158.60 7.50 1.00 Reference

Poverty status (ratio of family income to poverty threshold)

At or below 100% 157 69.87 5.47 1.24 1.30 1.60 136 209.09 17.06 0.87 0.72 1.00 185 135.48 10.13 0.89 0.73 1.07

100%–​200% 280 64.53 3.79 1.11 0.93 1.34 285 177.27 10.04 0.71 0.61 1.06 314 136.93 7.94 0.90 0.76 1.06

200%–​400% 525 73.21 3.02 1.21 1.03 1.42 711 230.86 8.09 0.93 0.82 1.05 586 148.28 6.08 0.94 0.88 1.09

400%–​600% 291 69.67 3.91 1.10 0.92 1.31 435 212.20 10.10 0.87 0.76 1.00 381 160.76 8.21 1.03 0.88 1.20

Above 600% 214 63.29 4.09 1.00 Reference 428 236.44 11.31 1.00 Reference 273 157.61 9.66 1.00 Reference

HS: High School
Source: SEER-​NLMS Record Linkage Study. Based on the 1979–​1998 follow-​up of residents of 11 SEER Registries (Iowa, Hawaii, Seattle, Connecticut, Detroit, Utah, Los Angeles, San Francisco/​Oakland/​San Jose/​Monterey,
Greater California, Louisiana, and Kentucky) who were 25 years of age or older on their CPS survey date.
a
Rates are per 100,000 population and are age-​adjusted to the 2000 US standard population by the direct method.
b
Rate ratios were estimated from Cox regression models that stratified for age at survey and CPS cohort and controlled for sex when relevant.
148
148 Part II: The Magnitude of Cancer
SES and education with colorectal cancer incidence. Neighborhood
deprivation was associated with a 16% increased risk (95% CI: 5%,
28%; p-​trend  =  0.002) of colorectal cancer compared with the
least deprived neighborhoods, and those with < 12 years of formal
schooling had a 19% increased risk (95% CI:  7%, 31%; p-​trend
< 0.001) of colorectal cancer compared to those with a post-​
graduate education.
Though area-​level measures have enabled researchers to evaluate
associations between SES and cancer, a potentially important goal is
to be able to distinguish contextual (e.g., environmental, neighborhood,
policy) from compositional (i.e., people living in low-​SES areas are
themselves of lower SES) effects. We previously cautioned against over-
interpretation of area-​level SES data for this reason. This concern also
motivated recent work in the VITamins and Lifestyle (VITAL) study.
In this study, which included 52,186 participants, the authors (Hastert
et al., 2015) found that the lowest quintile of area-​level SES, measured
as the 2000 Census block group-​level index of social disadvantage, was
not significantly associated with total cancer, regardless of adjustment
for education and household income (Hastert et  al., 2015). A  direct
association of area SES and prostate cancer was explained by individ-
ual SES factors. By contrast, area-​level SES was significantly associ-
ated with lung cancer and, of borderline significance, associated with
colorectal cancer after adjustment for individual SES variables (Hastert
et al., 2015). The area-​level measure was unrelated to breast cancer in
any analysis. Area-​level effects may be more relevant for those cancers,
including lung and colorectal cancer, that are influenced by lifestyle risk
factors such as diet, smoking, and obesity. Additional multilevel studies
are needed to understand the independent effects of area-​and individual-​
level SES on cancer.
Secular Trends
Breast cancer incidence continues to be higher among women of
higher SES. The Women’s Health Initiative (WHI) Trial findings,
released in 2003, showed that hormone therapy in the form of the
combination of estrogen plus progestin increased the risk of cor-
onary heart disease (Manson et  al., 2003), prompting an abrupt
decline in the use and prescription of hormone therapy. There was
a corresponding decline in the rate of breast cancer incidence, with
possible implications for socioeconomic disparities in this out-
come, though there are mixed findings:  some researchers found a
steeper decline in the use of hormone therapy after the WHI report,
using area-​level measures (Krieger et  al., 2010), and others found
proportional reductions by SES, using individual-​level data from
221,378 women from five health maintenance organizations (F. Wei
et al., 2005).
In summary, the patterns of SES gradients with cancer are com-
plex, and can vary according to the setting (i.e., region or country of
the world), time period, and population. Patterns “defy easy general-
ization” (Krieger et al., 1999) and warrant careful attention to meth-
odological issues, such as the level at which SES is being measured
(area-​level or individual-​level or both) and stratification by race/​ethnic
group or other sociodemographic factors.
Cancer in Children and Youth
A large part of the literature on SES and cancer focuses on adult
cancers, in part because of the higher rates of cancer with increas-
ing age. Many known causes of adult cancer are risk factors asso-
ciated with socioeconomic status that influence the development
of cancer over many years. The causes of cancer in children have
not been historically related to SES and were attributed instead to
random genetic mutations. However, increasing research has evalu-
ated the impact of risk factors, particularly environmental toxins,
on the risk of childhood cancer early in life, discussed later in this
chapter. Given that families and children of low SES are known to
be exposed to higher levels of environmental toxins compared to
children from high SES backgrounds, this research has important
implications for understanding socioeconomic disparities on cancer
outcomes.
SES AND CANCER SURVIVAL AND MORTALITY
Cancer in Adults
Even though lower SES is not universally associated with increased
risks of cancer incidence across different sites, lower SES is consis-
tently related to worse prognosis and survival following the diagnosis
of cancer, and several large studies have demonstrated associations
between SES, whether measured at the individual or area level, and
mortality from cancer (Byers et al., 2008; Hastert et al., 2015; Kish,
Yu, Percy-​Laurry, & Altekruse, 2014; Parise & Caggiano, 2013; Tao
et al., 2014). Even for those cancers with a positive SES gradient with
incidence, people of lower SES have a greater risk of mortality follow-
ing the diagnosis of cancer. For example, the positive SES gradient for
breast cancer incidence but reversal in the SES gradient for breast can-
cer mortality has been frequently documented in the literature. Though
women of higher SES have higher breast cancer rates, mortality rates
are lower and survival times better with increasing SES among those
diagnosed.
Area-​Level SES Measures and Secular Trends
In the absence of individual-​level SES information, investigators have
continued to document the long-​term trends in the relationship between
area-​level SES measures and cancer mortality (Du, Fang, & Meyer,
2008; Hastert et al., 2015; Kish et al., 2014; G. K. Singh, Miller, &
Hankey, 2002; G. K. Singh, Miller, Hankey, et al., 2002). As a proxy
for individual SES, the main drawback of the use of area-​level (e.g.,
zipcode) information is measurement error; SES based on zipcode
does not necessarily correlate with individual-​level SES. Additionally,
there is the risk of committing an ecological fallacy whenever we use
aggregated data (on both the exposure and outcome side) to make
inferences about individual-​ level associations. With these caveats,
area-​level SES measures have been useful in predicting cancer mortal-
ity and in demonstrating changes in patterns of associations between
SES and cancer outcomes that have occurred over the past 65 years.
Singh and colleagues (G. K. Singh, Miller, & Hankey, 2002) devel-
oped an area SES index at the level of the 3097 counties of the United
States, in order to track the evolution of the SES gradient in cancer
mortality between 1950 and 1998. The SES index was composed of
11 variables available on the US Census, including aggregate indi-
cators that assessed the domains of education (percent of the county
population with less than 9 years of education; percent with at least
a high school education), occupation (percent of employed persons
in white collar occupations; the unemployment rate), and income/​
wealth (median county-​ level family income; county-​ level income
inequality; median home value; median gross rent; percent of families
below the poverty level; percent occupied housing units without tele-
phone access; and percent of occupied housing units without complete
plumbing). The authors found a dramatic change in the area SES pat-
tern of cancer mortality during the 40-​year study period (Figures 9–​2
and 9–​3). Singh et al. (2002) showed reversals of the socioeconomic
gradient in men and younger women and a narrowing of the gradient
in older women.
Throughout the 1950s and 1960s, there was a positive SES gradient
(i.e., higher cancer mortality rates in areas of higher SES than areas of
lower SES), which was true for both men and women. For example, in
1950–​1952, cancer mortality was 49% higher in the highest SES areas
compared to the lowest (95% CI: 41%, 59%). The positive SES gradi-
ent narrowed in the 1970s for men, and by the late 1980s, the gradient
began to reverse and then widen. Between 1997 and 1998, male cancer
mortality rates were 19% higher (95% CI: 11%, 28%) in the lowest
versus the highest SES areas. Among women, an interaction was found
with age group. For women over 65 years, cancer mortality rates were
higher in higher SES areas throughout the study period, though the gra-
dient narrowed over time. In younger women (aged 25–​64), the SES
gradient was reversed in the early 1990s. By 1998, the cancer mortal-
ity rate in younger women was 13% higher (95% CI: 9%, 16%) in the
lowest versus the highest SES areas (G. K. Singh, Miller, & Hankey,
2002). Similar reversals of the SES gradient in cancer mortality were
 149

Socioeconomic Disparities in Cancer Incidence and Mortality 149

All Ages Age 25–64 Years Age 65+ Years
240 190 1600

180 1500

220

170 1400
Age-Adjusted Death Rate per 100,000 Population

Age-Adjusted Death Rate per 100,000 Population

Age-Adjusted Death Rate per 100,000 Population
1970 US Population Used as Standard

1970 US Population Used as Standard

1970 US Population Used as Standard
200 160 1300

150 1200

180

140 1100

160 1000
130

120 900

140 1st Quintile (Low SES) 1st Quintile (Low SES) 1st Quintile (Low SES)
2nd Quintile 2nd Quintile 2nd Quintile
3rd Quintile 110 3rd Quintile 800 3rd Quintile
4th Quintile 4th Quintile 4th Quintile
5th Quintile (High SES) 5th Quintile (High SES) 5th Quintile (High SES)
120 700
100
1950
1954
1958
1962
1966
1970
1974
1978
1982
1986
1990
1994
1998

1950
1954
1958
1962
1966
1970
1974
1978
1982
1986
1990
1994
1998
1950
1954
1958
1962
1966
1970
1974
1978
1982
1986
1990
1994
1998
Figure 9–​2.  Cancer mortality rates for US men by age and socioeconomic status (SES) index, 1950–​1998. Source: Singh et al. (2002a).

reported in Britain, Canada, and Australia (G. K.  Singh, Miller, & time period were smaller than those for lung and colorectal cancer. By
Hankey, 2002; G. K. Singh, Miller, Hankey, et al., 2002). contrast, low SES was associated with higher cervical cancer mortality
In a more recent analysis, Krieger (Krieger et  al., 2012)  reported throughout the study period.
secular trends of area-​level SES between 1960 and 2006 and incident Similar to previous studies showing different patterns of associa-
cancer by type of cancer. These data also showed reversals in associa- tion by race/​ethnicity, Tao and colleagues (Tao et al., 2014) found that
tions between SES and lung, prostate, colorectal, breast, and stomach associations between area-​level socioeconomic measures and colorec-
cancer, consistent with the pattern seen in Singh (G. K. Singh, Miller, & tal cancer mortality in the Hispanic population differed by nativity. An
Hankey, 2002; G.  K. Singh, Miller, Hankey, et  al., 2002). Of note, inverse association between area-​level SES and colorectal cancer mor-
disparities for prostate, breast, and stomach cancer by the end of the tality was seen in US-​born, but not foreign-​born, Hispanics, possibly

All Ages Age 25–64 Years

Age 65+ Years
160 165
900
1st Quintile (Low SES)
1st Quintile (Low SES) 1st Quintile (Low SES) 2nd Quintile
155 160
2nd Quintile 2nd Quintile
3rd Quintile
3rd Quintile 3rd Quintile 850 4th Quintile
4th Quintile 155 4th Quintile
Age-Adjusted Death Rate per 100,000 Population

150
Age-Adjusted Death Rate per 100,000 Population
Age-Adjusted Death Rate per 100,000 Population

5th Quintile (High SES)

5th Quintile (High SES) 5th Quintile (High SES)
1970 US Population Used as Standard
1970 US Population Used as Standard
1970 US Population Used as Standard

150
145 800

145
140
750
140
135
135
700
130
130
125
125 650

120
120
600
115
115

110 110 550

1950
1954
1958
1962
1966
1970
1974
1978
1982
1986
1990
1994
1998

1950
1954
1958
1962
1966
1970
1974
1978
1982
1986
1990
1994
1998
1950
1954
1958
1962
1966
1970
1974
1978
1982
1986
1990
1994
1998

Figure 9–​3.  Cancer mortality rates for US women by age and socioeconomic status (SES) index, 1950–​1998. Source: Singh et al. (2002a).
150
150 Part II: The Magnitude of Cancer
related to dietary differences in immigrants compared with those born
in the United States (Tao et al., 2014).
Individual-​Level SES Measures and Secular Trends
Still among the largest cohort studies to be conducted of individual-​
level SES measures and cancer mortality are the two American Cancer
Society cohorts—​the Cancer Prevention Study I (CPS-​I) and Cancer
Prevention Study II (CPS-​II). Steenland, Henley, and Thun (2002)
examined the association between educational attainment and can-
cer mortality rates in the two cohorts. The CPS-​I cohort comprised
1,051,038 men and women enlisted by American Cancer Society vol-
unteers in 1959, whose vital status was followed until 1972. The CPS-​
II cohort consisted of 1,184,657 men and women enlisted by American
Cancer Society volunteers in 1982 and followed until 1996.
Lung cancer mortality rates increased between the two study peri-
ods for both men and women. Among men, there was a significant
educational gradient in both periods, but the SES gradient grew stron-
ger in the second period (CPS-​II). By contrast, among women, there
was no statistically significant educational gradient during the 1960s
(CPS-​I)—​only women with the highest educational attainment (col-
lege graduates) had a lower mortality rate from lung cancer compared
to all other women. However, during the second period (1982–​1996,
CPS-​ II), a statistically significant educational gradient emerged.
Adjusting the rate ratios for smoking, diet, and alcohol intake (among
other things) attenuated, but did not remove, the excess risks among
lower educational groups, suggesting that these factors alone did not
explain the educational gradient.
In the CPS cohorts, Steenland and colleagues (2002) also found no
consistent educational gradient in colorectal cancer mortality for the
earlier period, but 20%–​30% lower mortality rates for the most edu-
cated men and women in the later cohort (CPS-​II). A  weak inverse
gradient was also found for prostate cancer death rates (lower educa-
tion → higher death rates), which was stronger among the 0.6% of men
with prevalent disease at baseline.
Although the American Cancer Society cohorts provide intriguing
data for the 1960s–​1980s, caution is warranted in interpreting the find-
ings, as the CPS cohort members were not representative of the general
US population. More recent research has incorporated individual-​level
SES variables into more population-​representative studies of cancer
mortality. Investigators (Clegg et al., 2009; Du et al., 2011) linked data
from the NLMS to SEER registry data. In the NLMS-​SEER data, Du
and colleagues (2011) evaluated associations between individual-​level
socioeconomic factors (education, income, poverty status, and health
insurance) on treatment and survival. With simultaneous adjustment
for the individual-​level socioeconomic variables, the authors found
that lower levels of education, income, and government insurance
were significantly related to both higher overall and cancer-​specific
mortality (Table 9–​3).
In other work, investigators evaluated education and cancer mortal-
ity, obtaining education data from death certificates from the National
Center for Health Statistics (NCHS) and population denominator data
from the US Bureau of the Census for 47 US states and Washington,
DC (Albano et al., 2007; Kinsey et al., 2008). Examining by black and
white race, comparing those with ≤ 12 years versus > 12 years of educa-
tion, Albano and colleagues (2007) found disparities in cancer mortality
in black men (RR = 2.38; 95% CI: 2.33, 2.43), white men (RR = 2.24;
95% CI:  2.23, 2.26), black women (RR  =  1.43; 95% CI:  1.41, 1.46)
and white women (RR = 1.76; 95% CI: 1.75, 1.78). Associations were
strongly influenced by lung and colorectal cancer–​specific associations.
Expanding on Albano’s work (Albano et  al., 2007), Kinsey and
colleagues (2008) evaluated trends over time in associations between
individual SES and cancer mortality. Specifically, they compared rates
of lung, colorectal, breast, and prostate cancers in 1993 and 2001 by
race (black and white) and level of education, obtaining education
level from death certificates and population data from the US Bureau
of Census Current Population Survey. In men, rates of lung cancer
declined in all educational groups, but declines were significantly
larger in those with greater education in both white (p-​trend = 0.001)
and black (p-​trend = 0.004) men. A similar gradient was seen in white
women (p-​trend = 0.009) and black women (p-​trend = 0.059), though
lung cancer mortality rates increased in white women with < 12 years
of education (annual percent change = +2.4%, p < 0.001), and declining
mortality rates among women college graduates were less pronounced
than in men (annual percent change (APC) = –​2.2% in black women
and  –​2.9% in white women vs.  –​4.9% in white men and  –​6.8% in
black men). The authors also noted larger declines in colorectal cancer
mortality with greater education, particularly in black men and white
men and women, though the rate of colorectal cancer mortality among
those with < 12 years of education increased significantly in black men
(+2.7%, p < 0.001). There were also larger declines in breast cancer
mortality and prostate cancer mortality among those with higher levels
of education in both blacks and whites. Deaths rates and rate ratios at
the two time periods, by level of educational attainment, are repro-
duced for the cancer sites examined (Table 9–​4).
Independent Effects of Individual and Area-​Level
SES Measures
In addition to individual-​level analyses, researchers have begun to
examine the independent effects of area-​and individual-​level SES
on cancer mortality outcomes (Hastert et  al., 2015; Shariff-​Marco
et al., 2014; Steenland, Henley, Calle, & Thun, 2004). In the VITAL
study in western Washington, area-​level SES was consistently asso-
ciated with overall cancer mortality; residents in the lowest quintile
of area SES had a 40% elevated risk of mortality (95% CI:  16%,
69%, p-​trend < 0.001) (Hastert et al., 2015). In 179,383 persons from
the American Cancer Society Nutrition Cohort, however, Steenland
(Steenland, Henley, et al., 2004) found independent effects of area-​
level SES (census block composite score) and education and cancer
mortality in men, but no significant associations of either area-​or
individual-​level SES and cancer mortality in women (Steenland, Hu,
& Walker, 2004).
Steenland (Steenland, Hu, et  al., 2004)  further evaluated secular
trends. As noted, men and women from higher SES backgrounds
showed higher cancer mortality rates for certain types of cancer; how-
ever, that pattern has shifted, with higher mortality rates observed in
those from lower SES backgrounds, a finding that has been repeat-
edly corroborated. In a population-​based representative sample of US
employed adults ages 35–​64 years, residing in 27 states spanning the
period 1984–​1997, Steenland, Hu, and Walker (2004) reported higher
rates of mortality among low-​SES men for lung and colorectal cancer,
and among low-​SES women for lung cancer. These differences grew
throughout the 1990s and 2000s. Patterns in women differed by type
of cancer. They found a direct association of SES and breast cancer
mortality, but this was due to mixed effects of SES with incidence and
mortality since the association was reversed in those with prevalent
disease. They found no association for colorectal cancer in women
(Steenland, Hu, et  al., 2004). These data thus provide evidence of
persistent or growing socioeconomic disparities over the past several
decades, when SES is measured as an individual-​level factor, paral-
lel to that seen in research on area-​level SES factors, and in a pat-
tern that generally reflects the theory of fundamental cause (Phelan
et al., 2010).
Cancer in Children and Youth
Advances in treatment have led to dramatic improvements in survival
of childhood cancer over the past few decades. At the same time, soci-
oeconomic disparities in cancer survival in children have emerged as
well. Gupta and colleagues (Gupta, Wilejto, Pole, Guttmann, & Sung,
2014)  conducted a systematic review of SES and survival of child-
hood cancer in low-​, middle-​, and high-​income countries and found
consistent socioeconomic gradients with cancer survival among child-
ren (Gupta et al., 2014). A more recent meta-​analysis found socioeco-
nomic disparities in survival after childhood leukemia (Petridou et al.,
2015)  and concluded that the benefits of life-​saving treatment have
accrued disproportionately to children from more affluent SES back-
grounds. Findings, however, have not been totally consistent. Kent
and colleagues (2015) showed a narrowing of SES survival disparities
in lymphoma in adolescents and young adults. When socioeconomic
 15

Socioeconomic Disparities in Cancer Incidence and Mortality 151

Table 9–​3. Hazard Ratios of Mortality According to Individual-​Level Socioeconomic Factors Among Patients with Invasive Tumors

Hazard Ratio (95% CI) of

Hazard Ratio (95% CI) of All-​Cause Mortality Cancer-​Specific Mortality

Attributes No. Model-​1 No. Model-​2 Model-​1 Model-​2

Health Insurance

Employer/​Medicare/​Private  –​ –​ 5595 1.0 (Referent) –​ 1.0 (Referent)

Government  –​ –​ 78 1.5 (1.1, 2.1) –​ 1.6 (1.1, 2.3)
Medicaid/​Not-​insured  –​ –​ 694 1.4 (1.2, 1.5) –​ 1.3 (1.1, 1.4)
Years of Education

< 12 3607 1.3 (1.2. 1.4) 1605 1.2 (1.1, 1.4) 1.4 (1.3, 1.5) 1.3 (1.1, 1.4)
12  4814 1.2 (1.1, 1.2) 2306 1.1 (1.0, 1.2) 1.2 (1.1, 1.3) 1.2 (1.1, 1.3)
≥ 13  4810 1.0 (Referent) 2456 1.0 (Referent) 1.0 (Referent) 1.0 (Referent)
Annual Family Income

< $10,000 1288 1.3 (1.2, 1.5) 646 1.3 (1.1, 1.6) 1.2 (1.1, 1.4) 1.2 (1.0, 1.5)
$10,000–​$34,999  4921 1.2 (1.1, 1.3) 2404 1.2 (1.0, 1.3) 1.1 (1.0, 1.2) 1.1 (1.0, 1.3)
≥ $35,000  6314 1.0 (Referent) 3024 1.0 (Referent) 1.0 (Referent) 1.0 (Referent)
Unknown  711 1.1 (1.0, 1.2) 293 0.2 (0.0, 2.2) 1.0 (0.9, 1.2) 0.3 (0.0, 2.5)
Family Poverty Status (1990 threshold)

≤ 100%  1007 1.0 (0.9, 1.2) 473 0.9 (0.7, 1.1) 1.0 (0.8, 1.2) 0.9 (0.7, 1.1)
100%–​400%  6090 1.0 (1.0, 1.1) 1248 1.0 (0.9, 1.2) 1.1 (1.0, 1.2) 1.1 (0.9, 1.2)
≥ 400%  5982 1.0 (Referent) 1721 1.0 (Referent) 1.0 (Referent) 1.0 (Referent)
Unknown  155 1.1 (1.0, 1.2) 2925 4.9 (0.5, 43.7) 1.0 (0.9, 1.2) 3.8 (0.4, 34.5)

Model 1: Hazard ratios simultaneously adjusted for age, sex, tumor stage, education, poverty, family income, surgery, and radiotherapy.
Model 2: Adjusted additionally for health insurance in those with these data.

disparities have been documented, lack of health insurance and other
barriers to care appear to be major sources of survival differences.
EXPLANATIONS FOR THE ASSOCIATION BETWEEN
SES AND CANCER OUTCOMES
Having described the general patterns of association between various
indicators of SES and cancer outcomes, we now consider the general
categories of explanation for the observed gradients. Generally speak-
ing, there are three types of explanations for the repeatedly observed
correlation between SES and cancer. First, the association may arise
through reverse causation, that is, the diagnosis of cancer may result
in loss of employment or loss of income (or both). Alternatively, lower
socioeconomic position may be causally linked to cancer incidence
and/​or survival, through mechanisms described in detail in the fol-
lowing. Finally, the correlation between SES and cancer may be the
spurious artifact of a third, unobserved variable that affects both SES
and cancer risk, for example, inherited personality characteristics that
cause people to strive harder and succeed at upward social mobility
and at the same time invest in their personal future health (including
steps to prevent cancer). These three explanations are not necessarily
mutually exclusive (Glymour, Avendano, & Kawachi, 2014).
The reverse causation hypothesis is sometimes referred to as the
“drift” hypothesis, meaning that the onset of illness (such as cancer)
can act as a potent trigger for individuals to drift downward on the
socioeconomic hierarchy. Conversely, healthier people are more likely
to succeed in moving up the socioeconomic hierarchy. The implica-
tion is that health disparities are due to selective social mobility, which
sorts healthy and unhealthy people into different socioeconomic posi-
tions (Pais, 2014; Wilkinson, 1996). So-​called birth cohorts, in which
individuals are followed up from birth, with repeated assessments
of health status and SES, are ideally suited to test for these kinds of
effects. The analysis of such birth cohorts has documented that health
status can (and does) affect later social mobility. However, the general
magnitude of the drift effect is too small to explain away the observed
SES gradient in health. That said, almost all of the studies of the drift
phenomenon have been carried out in studies of SES differentials in
all-​cause mortality. Whether reverse causation accounts for some of
the SES differential in cancer outcomes is unresolved. One of the
more convincing examples of this phenomenon is the evidence show-
ing that cancer in childhood may jeopardize educational and occupa-
tional attainment, particularly in women, through adverse effects on
development, cardiovascular risk, lower attainment of adult height,
and higher levels of obesity (Ater, 2015; Barrera, Shaw, Speechley,
Maunsell, & Pogany, 2005; Kuehni et al., 2012; Maule et al., 2016;
Wilson et al., 2014).
Investigators may minimize the influence of reverse causation by
carefully selecting the indicator of SES. For example, in adulthood,
educational attainment is less susceptible to drift effects, compared
to other indicators of SES such as income or occupational status.
The reason is because educational attainment is usually completed
in early adulthood before individuals succumb to most forms of can-
cer. However, even educational attainment might be plausibly subject
to reverse causation (i.e., effects running from health status to edu-
cational attainment). For example, the 1958 British National Child
Development Study suggested that “health shocks” in the form of low
birthweight resulted in a persistent deleterious effect on O-​level exam-
ination performance (the O-​levels were national examinations taken
by British students at about age 16 prior to 1988, the results of which
determine whether or not one can proceed with further schooling)
(Currie & Hyson, 1999). Low birthweight might thus predict lower
educational attainment (Litt et al., 2012), as well as reduced risks of
prostate and breast cancer (Davey-​Smith et  al., 2001). According to
this scenario, it is not lower educational attainment that causes lower
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152 Part II: The Magnitude of Cancer

Table 9–​4. Trends in Age-​Adjusted Rates* of Death from Four Major Cancers by Educational Attainment, Ages 25–​64 Years, 43 States and the District
of Columbia, 1993–​2001

White Non-​Hispanic Black Non-​Hispanic

1993 Rate 2001 Rate APC‡ P value§ 1993 Rate 2001 Rate APC‡ P value§

Lung and bronchus, Male    

Education < 12 years 88.1 87.3 −0.1 .905 98.3 90.4 −0.2 .705
12 years             59.5 53.2 −1.5 .001 98.6 73.7 −3.2 .009
13–​15 years             32.7 24.2 −3.5 < .001 45.6 32.2 −4.7 < .001
≥ 16 years             20.7 13.7 −4.9 < .001 38.3 21.0 −6.8 < .001
Rate ratio¶ 4.2 (4.1–​4.4) 6.4 (6.2–​6.6) < .001 2.6 (2.5–​2.8) 4.3 (3.9–​4.8) < .001
     Ptrend# .001 .004
Lung and bronchus, Female    
Education < 12 years 45.5 55.4 2.4 < .001 32.7 30.4 0.8 .476
12 years             32.1 33.1 0.1 .657 37.3 35.7 −0.7 .191
13–​15 years             19.8 16.6 −1.7 .003 20.1 19.3 −1.3 .282
≥ 16 years             13.9 11.6 −2.9 < .001 14.8 16.7 −2.2 .246
Rate ratio¶ 3.3 (3.1–​3.5) 4.8 (4.5–​5.0) < .001 2.2 (1.8–​2.7) 1.8 (1.6–​2.1) .090
     Ptrend# .009 .059
Colon and rectum, Male
Education < 12 years 14.1 16.0 0.9 .237 17.4 20.9 2.7 < .001
12 years             14.6 13.9 −0.9 .130 21.9 23.9 1.0 .341
13–​15 years             9.2 8.1 −1.1 .006 15.4 11.7 −2.7 .161
≥ 16 years             9.3 7.9 −2.4 < .001 16.3 11.5 −4.8 .011
Rate ratio¶ 1.5 (1.4–​1.6) 2.0 (1.9–​2.2) < .001 1.1 (0.9–​1.3) 1.8 (1.5–​2.2) < .001
     Ptrend# .039 .010
Colon and rectum, Female    
Education < 12 years 9.5 10.4 1.4 .073 11.0 10.3 −0.3 .745
12 years             9.7 9.2 −1.0 .010 16.1 17.8 −0.3 .730
13–​15 years             6.4 5.5 −1.6 .006 9.4 10.0 0.7 .659
≥ 16 years             6.8 5.4 −3.0 < .001 15.6 12.2 −2.6 .030
Rate ratio¶ 1.4 (1.3–​1.6) 1.9 (1.7–​2.1) < .001 0.7 (0.6–​0.9) 0.8 (0.7–​1.0) .232
     Ptrend# .063 .288
Breast (Female)   
Education < 12 years 27.4 24.1 −1.4 .029 30.0 28.7 0.1 .855
12 years             30.6 25.4 −2.9 < .001 45.3 43.4 −1.5 .078
13–​15 years             23.2 17.3 −3.6 < .001 35.3 30.0 −0.9 .447
≥ 16 years             27.4 20.1 −4.3 < .001 45.7 35.8 −3.8 < .001
Rate ratio¶ 1.0 (1.0–​1.1) 1.2 (1.1–​1.3) < .001 0.7 (0.6–​0.7) 0.8 (0.7–​0.9) .004
     Ptrend# .025 .046
Prostate
Education < 12 years 4.0 3.4 −1.6 .054 10.4 9.6 −1.6 .133
12 years             4.3 3.3 −3.5 .003 16.2 12.7 −1.6 .171
13–​15 years             3.4 2.3 −5.5 < .001 10.3 5.3 −7.4 .003
≥ 16 years             3.8 2.3 −6.3 < .001 7.6 4.8 −5.9 .071
Rate ratio¶ 1.1 (0.9–​1.2) 1.5 (1.3–​1.7) .001 1.4 (1.0–​1.8) 2.0 (1.5–​2.7) .054
     Ptrend# .022 .211

*
Single-​year rates per 100 000 people were age adjusted to the 2000 US standard population for ages 25–​64 years.
‡
Annual percent change (APC) estimated from weighted least squares linear regression models fit to the log-​transformed age-​adjusted death rates for years 1993–​2001.
§
Value adjacent to APC indicates test for APC statistical difference from 0, two-​sided. Value adjacent to rate ratios indicates test for statistical difference between rate ratios for single
years 1993 and 2001.
¶
Rate ratio (95% confidence interval) comparing age-​adjusted rate for less than 12 years education to 16 or more years education for the indicated year.
#
Test for trend in APC over levels of education using inverse variance weighted linear regression.

risks of breast and prostate cancer; rather, low birthweight may be the
factor underlying both.
The argument that the correlation between SES and health may be
due to (unobserved) third variable bias is often made by economists
(Farrell & Fuchs, 1982; Fuchs, 1983), and has been increasingly con-
sidered by epidemiologists. The argument is based upon observations
such as the timing of the onset of educational differentials in cigarette
smoking. In a cohort of young persons with 12–​18 years of completed
schooling, Farrell and Fuchs (1982) found that the strong negative
relationship between schooling and smoking observed at age 24 was
almost completely accounted for by differences in smoking behavior
observed at age 17, when all subjects were still in the same grade. In
other words, the amount of formal schooling that a person will even-
tually achieve predicts their smoking behavior before their schooling
is actually completed. Achieving the additional years of schooling
beyond age 17 had no additional effect on smoking behavior. It is pos-
sible that schooling is effective in preventing smoking uptake only up
to the 12th grade, and not thereafter. However, the authors rejected
this unlikely explanation in favor of underlying “third variables” that
are related to both schooling and health maintenance. The problem of
omitted variable bias can be generalized to the entirety of empirical
evidence linking SES to diverse health outcomes, including cancer. In
 153
Socioeconomic Disparities in Cancer Incidence and Mortality 153
other words, the challenge of research in this field is to move beyond
documenting associations between SES and health, toward testing
causal connections. The key issue is that the same factors that prompt
people to seek more education and better jobs, such as higher abilities,
higher family socioeconomic background, more patience, and less
impulsiveness (i.e., what economists refer to as higher time discount—​
or the willingness to incur current costs for future benefits)—​are also
likely to be determinants of health behaviors and future health.
In an attempt to overcome the problem of unobserved heterogeneity
and omitted variable bias, researchers have begun to consider instru-
mental variable (IV) analysis to identify the causal relationship of SES
and health outcomes (Greenland, 2000). These methods are not with-
out their own problems, however, and the most convincing approach
(short of experimentation) to establish the causal link between SES
and health remains to measure and control for the array of potential
“third variables” that are related to both socioeconomic position and
health (Rehkopf, Glymour, & Osypuk, 2016). Ultimately, the clearest
understanding of how SES influences cancer incidence and mortality
may come about as the result of examining the multiplicity of contex-
tual and individual socioeconomic variables over the life course (or
over multiple generations) on these outcomes.
Even after a causal relationship between SES and cancer has been
established, many unresolved questions remain about the exact mech-
anisms by which the link occurs. Broadly speaking, there are two sets
of pathways by which higher SES may improve cancer outcomes.
One direct pathway is through the ability of higher SES individu-
als to gain access to various resources that help to prevent cancer, or
improve outcomes following the onset of cancer. For example, more
years of schooling may result in greater ability to translate health
knowledge into health-​ promoting behaviors (avoiding smoking,
maintaining regular physical activity, presenting for regular screening
check-​ups) (Pampel, Krueger, & Denney, 2010). Health literacy may
also enable individuals to “navigate” medical treatment options, and
to maximize the effectiveness of cancer therapy (Institute of Medicine
Committee on Health Literacy & Development, 2004). In the words
of Grossman (1975), additional years of schooling make an individual
a more efficient producer of his or her own health. Income may also
operate directly to reduce an individual’s cancer risk by determin-
ing his or her level of access to material resources—​for example, the
ability to afford nicotine replacement therapy, or the ability to afford
a health plan that offers regular screening services for the detection
of cancer. Higher incomes may also enable individuals to move to
higher quality residential neighborhoods, with access to safe recre-
ational spaces (for maintaining exercise), or supermarkets and grocer-
ies with ready availability of fresh produce. Finally, the labor market
tends to sort individuals into workplaces and jobs with differential
exposures to carcinogens (e.g., chemical exposures, indoor tobacco
smoke pollution).
An alternative pathway from SES to health (including, potentially,
cancer outcomes) is through differential exposure to psychosocial
mediators, such as stress, a sense of control, social support, and so on
(Ross & Wu, 1995). In turn, psychosocial factors such as stress and
social support may influence health outcomes through health-​related
behaviors, as well as through direct effects on physiological mecha-
nisms, such as altered immune and neuroendocrine function.
In the final section, we shall survey and summarize the known risk
(and protective) factors for cancer incidence and mortality that are
believed to be patterned according to SES, and hence offer potential
clues about the mediating causal mechanisms linking the two.
MECHANISMS LINKING SOCIOECONOMIC
STATUS TO CANCER
Cigarette smoking is a risk factor par excellence that is linked to low
SES (in industrialized societies like the US) as well as to cancer out-
comes. The relationship between low SES and smoking-​related can-
cers is well established. However, as the previous section implied,
socioeconomic position is also associated with a host of other risk
(and protective) factors beyond cigarette smoking. Moreover, it is
problematic from the point of view of prevention that many risk fac-
tors tend to cluster together or “crystallize” around low SES. As the
chapter emphasized at the outset, SES is a multidimensional construct,
with complex pathways linking it to cancer outcomes. Accordingly,
reducing or eliminating socioeconomic disparities in cancer is unlikely
to be accomplished by focusing on and acting to remove one risk fac-
tor at a time.
The remainder of this section will summarize the known risk factors
for cancer that also exhibit SES patterning. The section is subdivided
into early life risk factors and adult risk factors.
Early Life Exposures
Prenatal and Early Postnatal Exposures
Still relatively little is known about the effects of prenatal exposures
linking SES to childhood cancer. Early work explored the link between
certain occupational exposures or lifestyle exposures (such as cigarette
smoking or diet) in relation to specific childhood cancer, as well as
the impacts of viruses and body size on adult cancer. However, there
has been substantial growing interest in understanding how environ-
mental prenatal exposures influence childhood cancer, as evidenced
by the growth of the research literature in this area over the past few
years (Chuang et al., 2011; Malecki et al., 2006; Spycher et al., 2015).
Current evidence is still very limited for most exposures, but the evi-
dence is generally consistent in suggesting that toxic environmental
exposures, which predominantly affect children of lower SES, increase
the risk of childhood cancer.
Infection and Viruses.  There is substantial evidence on several
viruses that may be transmitted vertically from mother to child in
utero or during childbirth or breastfeeding, including human lympho-
tropic virus-​type I (HTLV-​1) and hepatitis B virus (HBV), which are
both patterned by SES and which can lead to cancer in adulthood (De
Flora & Bonanni, 2011; De Flora et al., 2015; Schottenfeld & Beebe-​
Dimmer, 2015). Both of these viruses, which are endemic in some
countries, are far rarer in the United States.
Unlike HTLV-​1 and HBV, hepatitis C (HCV), a major cause of liver
cancer, is far more common among underserved, low SES popula-
tions in the United States (Denniston et  al., 2014)  and is primarily
transmitted through injection drug use (IDU). In 2014, the US Centers
for Disease Control and Prevention reported that 68% of all HCV
cases nationwide occurred as a result of IDU. Low SES rural com-
munities in the southern United States have been particularly hit, with
IDU accounting for 73% of all HCV cases in Kentucky, Tennessee,
Virginia, and West Virginia between 2006 and 2012 (J. Zibbell, 2015).
However, the risk of perinatal transmission of hepatitis C has been
suggested to be low.
Birth Size.  There has also been some exploration of birth weight
and future cancer risk (Cook, Gamborg, Aarestrup, Sorensen, &
Baker, 2013; Lope et  al., 2016). Trichopoulos (1990) hypothesized
that prenatal exposure to high concentrations of pregnancy estrogens,
related to fetal growth rate, may influence subsequent risk of breast
cancer. Studies have found positive or J-​shaped associations between
birth weight, birth length, or head circumference and breast cancer
(McCormack et al., 2003; Vatten et al., 2002). Since low SES is associ-
ated with a higher prevalence of low birth weight (Parker, Schoendorf,
& Kiely, 1994), this may be one mechanism through which higher SES
is related to an elevated risk of breast cancer.
Fewer studies have examined birth size and other cancer outcomes.
Sandhu and colleagues (Sandhu, Luben, Day, & Khaw, 2002) found a
J-​shaped association of birth weight and colorectal cancer—​a positive
association corroborated by Smith and colleagues (N. R. Smith et al.,
2016). These results are consistent with findings on birth weight and
adult obesity (Elks et  al., 2012; Leong et  al., 2003). However, in a
retrospective analysis of birth weight and prostate cancer in the Health
Professionals Follow-​up Study, Platz and colleagues (1998) found no
154
154 Part II: The Magnitude of Cancer
association between birth weight and prostate cancer, though a more
recent study found an association between pre-​term birth and risk for
non-​epithelial ovarian cancer in 1.5  million Swedish women (Sieh,
Rothstein, McGuire, & Whittemore, 2014).
Environmental Pollutants. As indicated earlier, there has
been considerable growth in the literature on environmental risk fac-
tors experienced prenatally or early in life. Between 1990 and 2007,
based on the California Cancer Registry, air toxin exposures during
pregnancy/​infancy from industrial and road traffic sources—​including
acetaldehyde 1,3-​butadiene, benzene, tolune, ortho-​dichlorobenzene,
and polycyclic aromatic hydrocarbons—​have been associated with
higher risks of brain tumors before 6  years of age (von Ehrenstein
et al., 2015). Intra-​uterine exposure to pesticides, either through occu-
pational or home exposures, have been related to an increased risk
of brain tumors (Kunkle, Bae, Singh, & Roy, 2014), testicular germ
cell tumors (Le Cornet et al., 2015), and childhood leukemia (Bailey
et al., 2015). Three meta-​analyses (Van Maele-​Fabry, Hoet, & Lison,
2013; Van Maele-​Fabry, Lantin, Hoet, & Lison, 2010; Wigle, Turner,
& Krewski, 2009), summarizing studies occurring over decades, pro-
vided consistent support for an association between pesticide exposure
and childhood leukemia. Another study showed associations between
parental exposure to solvents such as benzene and childhood brain
tumors (Peters et al., 2014). Yet another showed support for an asso-
ciation between prenatal air toxin exposure and risk of Wilms’s tumor
in children 0–​5 years of age (Shrestha et al., 2014). Children growing
up in disadvantaged circumstances are disproportionately affected by
such exposures (Adler & Rehkopf, 2008; Hogue, 2011). In one of the
only papers of its kind, in a case-​control study, investigators evalu-
ated the impact of a well-​documented, distinct period of high arsenic
concentrations in drinking water in Chile during 1958–​1970 on cancer
risk and found that high early life exposure (> 800 vs. ≤ 110 μg/​L)
predicted 5-​fold higher rates of lung and 8-​fold higher rates of bladder
cancer decades later (Steinmaus et al., 2014).
Postnatal and Later Exposures
Major mechanisms for postnatal exposures have included childhood
infection, lifestyle behaviors, and secondhand exposure to tobacco
smoke. Population-​ level dietary trends, combined with reductions
in physical activity, have led to an unprecedented rise in childhood
obesity, which has disproportionately affected children from low SES
households. The childhood obesity epidemic in the United States (and
in many other parts of the globe) has dire implications for future can-
cer risk and disparities in cancer incidence. The latency period for can-
cer incidence is typically decades, but these factors may lead to an
accelerated risk of the development of cancer early in life, particularly
cancers (e.g., colon cancer) that share many of the same risk factors as
CVD and diabetes.
Childhood and Adolescent Infection.  There is substantial
evidence that infections are likely causal factors in several types
of cancer, including lymphoma, cancers of the liver, nasophar-
ynx, cervix, and stomach. Earlier studies showed that these types
of cancers accounted for up to 20% of cancer worldwide (Eckhart,
1998), though recent studies indicate that cancers caused by infec-
tions are more than three times more prevalent in developing (26%)
than in developed (8%) countries (Thun, DeLancey, Center, Jemal,
& Ward, 2010).
Viruses linked to human tumors include Epstein-​Barr virus (EBV)
(B-​cell lymphomas, Burkitt’s lymphoma, nasopharyngeal cancer,
Hodgkin lymphoma, T-​cell lymphomas, and gastric cancer); hepati-
tis B virus (hepatocellular carcinoma); papillomavirus types including
16, 18, 31, 33, 35, 39, 45, 52, 56, 58 (cervical and anogenital cancer);
and HTLV-​1 (adult T-​cell leukemia) (Chelimo, Wouldes, Cameron,
& Elwood, 2013; F.  Liu et  al., 2016; G.  S. Taylor, Long, Brooks,
Rickinson, & Hislop, 2015; Zane & Jeang, 2014). Transmission and
timing of infection have been linked to SES.
EBV is involved in about 35%–​50% of cases of Hodgkin disease.
Though most adults have had an EBV infection, and are thus carriers
of these viral genes (Evans & Mueller, 1997), higher SES groups tend
to be infected at later ages than those of lower SES. EBV infection at
a later age is associated with more severe clinical sequelae, namely
infectious mononucleosis and Hodgkin lymphoma, in higher SES
populations (Gutensohn, 1982).
Findings strongly indicate that chronic Helicobacter pylori infec-
tion is involved in the development of non-​cardia gastric adenocar-
cinoma and mucosal-​ associated B-​ cell lymphoma (International
Agency for Research on Cancer Ad Hoc Working Group, 1994;
Nightingale & Gruber, 1994). About two-​thirds of the world’s pop-
ulation and half of all adults over age 50 in the United States are
infected with H. pylori (Correa & Piazuelo, 2011). Since the 1930s,
modernization, leading to clean water, fewer children sharing a bed,
smaller families, and possibly the increasing use of antibiotics in
children (Blaser, 1999), has contributed to reductions in H.  pylori
transmission and prevalence (Parsonnet, 1995). The infection is
typically acquired in childhood and there are fewer children in the
United States today with H. pylori infection than in previous periods.
H. pylori is found more often in lower socioeconomic groups in the
United States, many of whom report one or more risk factors for
infection, including a history of crowding in childhood, a mother
who carries H. pylori, a large number of siblings, presence of older
siblings (< 4-​year age difference), and unclean water sources. In turn,
several of these factors are associated with lower SES (Goodman &
Correa, 1995).
Lifestyle Behaviors and Obesity.  The US Centers for Disease
Control and Prevention reported that the number of overweight chil-
dren more than doubled in the last three decades of the twentieth cen-
tury (Centers for Disease Control and Prevention, 1997). More recent
evidence suggests that rates of obesity have stabilized in the past cou-
ple of decades (Ogden, Carroll, Fryar, & Flegal, 2015; Ogden, Carroll,
Kit, & Flegal, 2012; Ogden et  al., 2016; Ogden, Lamb, Carroll, &
Flegal, 2010), but overweight and obesity are more prevalent among
children and adolescents from lower SES backgrounds, and 12.7 mil-
lion children and teens ages 2–​18 (17% of the entire population) are
currently overweight or obese (Ogden, Carroll, Kit, & Flegal, 2014).
Maternal obesity, also predominant in adults from lower SES back-
grounds, is strongly linked with childhood obesity (Strauss & Knight,
1999). Low SES children often live in areas with large numbers of fast
food restaurants and stores that sell primarily low-​quality, nutritionally
poor, and calorie-​dense foods. Studies also have shown that children
in lower SES families are more likely to be exposed to advertisements
that promote eating large portions of obesity-​promoting foods, includ-
ing sugar-​sweetened beverages, fast food, and processed foods (Harris,
Pomeranz, Lobstein, & Brownell, 2009; Piernas & Popkin, 2011;
Powell, Szczypka, & Chaloupka, 2010; Powell, Wada, & Kumanyika,
2014). Childhood overweight and obesity in turn may track into adult-
hood overweight and obesity, which are major causes of cancer in
later life.
Dietary habits, which begin in childhood, are also predictive of
future dietary patterns. Lack of local availability of fresh produce,
cultural patterns of food consumption (R. E.  Lee & Cubbin, 2002),
norms accepting of overweight (Becker, Yanek, Koffman, & Bronner,
1999; Crawford, Story, Wang, Ritchie, & Sabry, 2001), and sedentary
behaviors are each related to lower SES and overweight. In addition to
habits that are developed in the context of a lack of resources, current
overweight predicts future overweight. Girls who are overweight have
earlier maturational timing, which is associated with later overweight
(Adair & Gordon-​Larsen, 2001), and is also an independent risk fac-
tor for breast cancer (Cancer, 2012). Adolescents who are obese are
far more likely to be obese as adults, with long-​term, multiple conse-
quences for morbidity (Dietz, 1998a, 1998b; Micic, 2001). Patterns
established in childhood and adolescence therefore predispose people
from lower SES backgrounds to worse health outcomes, including
cancer, in later adulthood.
 15
Socioeconomic Disparities in Cancer Incidence and Mortality 155
Smoking and Secondhand Exposure to  Cigarette
Smoke.  Children from lower SES backgrounds are more likely to
be exposed to environmental tobacco smoke (ETS) in their homes (K.
M. Emmons et al., 2001; Schuster, Franke, & Pham, 2002). Though a
meta-​analysis found no increased association of parental smoking and
lung cancer of the grown child (Boffetta, Tredaniel, & Greco, 2000),
ETS has been associated with an increased risk of lung cancer in
spouses (adult non-​smoking women) (Kreuzer et al., 2002; R. Taylor,
Cumming, Woodward, & Black, 2001).
Low-​SES youth are subsequently more prone to take up smoking
compared to youth from more affluent backgrounds. Factors that may
be related to the higher initiation of smoking among low-​SES youth
include parental smoking, though especially for white adolescents
(Griesler & Kandel, 1998; Tyas & Pederson, 1998), greater exposure
to peer norms of smoking (Alexander, Piazza, Mekos, & Valente, 2001;
Tyas & Pederson, 1998), as well as greater targeting by the tobacco
industry, a strong predictor of adolescent onset of smoking (Altman,
Levine, Coeytaux, Slade, & Jaffe, 1996; Pierce, Choi, Gilpin, Farkas,
& Berry, 1998). Low-​SES youth are also more likely to start smoking
at an earlier age, which has been linked to greater difficulty in quitting
later on (Pampel, Mollborn, & Lawrence, 2014). Furthermore, it has
been hypothesized that early smoking occurring during adolescence, a
“critical period” in lung development, may be particularly hazardous,
in that tobacco carcinogens may induce genetic alterations that make
the early smoker more susceptible to the damaging effects of contin-
ued smoking (Wiencke & Kelsey, 2002).
Environmental Exposures. A meta-​analysis and a registry-​
based case control study showed that postnatal exposure to traffic
pollution and air toxics, particularly benzene, was related to a higher
risk of childhood leukemia (Amigou et  al., 2011; Filippini, Heck,
Malagoli, Del Giovane, & Vinceti, 2015). Recently, there has also been
a growing research emphasis on the potential cancer-​causing effects
of plasticizers, chemicals, and flame retardants. Though exposure in
daily life is nearly ubiquitous, there is evidence that children from low-​
SES households have higher exposures to flame retardants because of
exposure to household furniture in poor condition (Schreder, Uding, &
La Guardia, 2016). These chemicals have been shown to cause cancer
in animal studies, though researchers are only beginning to understand
the potential impact of these unregulated chemicals on the develop-
ment of cancer and on the implications for the SES-​cancer gradi-
ent (Costa, Pellacani, Dao, Kavanagh, & Roque, 2015). Research in
humans is not well established. In addition to direct effects of chemi-
cals on risk of cancer, plasticizers have been hypothesized to be related
to higher estrogens in children, leading to earlier menarche in girls,
and potentially an increasing risk of breast cancer in girls of low SES
(M. Lee, 2012).
Adult Exposures
Lifestyle and Related Factors
Major lifestyle factors in adult life linked to cancer incidence include
smoking, poor diet, alcohol consumption, physical inactivity, and
overweight or obesity. Many of these factors are associated with
each other and tend to cluster together. Several health-​related behav-
iors (e.g., smoking, heavy alcohol consumption, overeating) are
used by individuals to cope with stress, a fact that has not escaped
the notice of manufacturers and advertisers who target vulnerable
audiences. In combination with physical inactivity, an imprudent
diet can increase the risk of being overweight or obese. The chang-
ing temporal socioeconomic patterns in US lung and colorectal can-
cer mortality may be attributable in part to changing socioeconomic
patterns in these factors.
Smoking.  Smoking continues to be among the most important fac-
tors responsible for the SES gradient in cancer. Cigarette smoking is
the leading determinant of lung cancer; 90% of those with lung cancer
were smokers (Pesch et  al., 2012). Reducing or eliminating smok-
ing would prevent the bulk of lung cancer cases, as well as drasti-
cally reduce socioeconomic disparities in lung cancer incidence. In
response to declining cigarette consumption in the United States, par-
ticularly among higher SES groups, the tobacco industry substantially
increased expenditures on marketing and advertising promotions,
such as “Marlboro Miles” and Camel Cash,” and tobacco promotional
items (Federal Trade Commission, 1999). After the Master Settlement
Agreement of 1998 banned the distribution of branded merchandise,
tobacco companies invested in discounts and point-​of-​sale advertis-
ing, which are disproportionately targeted to people—​and especially
youth—​ from lower SES backgrounds (Robert, Cheney, & Azad,
2009). Within the past decade, electronic cigarettes (e-​cigarettes) have
also come into use. Several studies have reported on disparities in
awareness and use of e-​cigarettes by income levels (Carroll Chapman
& Wu, 2014) but the links to SES and to health are as yet unclear.
Diet.  Higher SES is positively correlated with higher quality diet,
including greater consumption of fruit, vegetables, and legumes
(Centers for Disease Control and Prevention, 2000; Pechey &
Monsivais, 2016), and lower consumption of foods with high salt/​
fat/​sugar content (Pechey & Monsivais, 2016). Factors such as fat
intake, red meat consumption, inadequate vegetable consumption,
high caloric intake, physical inactivity, and heavy alcohol consump-
tion have been suggested as important risk factors for colorectal cancer
(Vargas & Thompson, 2012). Each of these factors has been related to
lower SES, both at the individual level and the area (neighborhood)
level (Centers for Disease Control and Prevention, 2000; Diez-​Roux
et  al., 1999; Kamimoto, Easton, Maurice, Husten, & Macera, 1999;
Li et al., 2000).
However, the apparent correlation between low SES and unhealthy
diet has not always been direct. A study of dietary trends by Popkin
and colleagues (Popkin, Siega-​Riz, & Haines, 1996) found large dif-
ferences in dietary quality in 1965, with whites of high SES eating the
least, and blacks of low SES eating the most healthful diet as meas-
ured by a diet quality index. By the 1989–​1991 survey, the diets of all
groups studied were relatively similar. Of particular note, grain and
legume consumption declined among low SES blacks since the 1960s
but increased among higher SES whites. The study also indicated that
people from both lower and higher SES backgrounds showed improve-
ments in diet, based on increases in fruit and vegetable intake and then-​
current recommendations for reductions in fat intake. Higher SES
groups initially had more improvements to make, but dietary quality
was similar across SES groups by the early 1990s after the advent of
recommendations to reduce fat (≤ 30%), saturated fat (< 10%), and
cholesterol (< 300 mg/​day) intake; to increase consumption of fruits
and vegetables (5+ per day) and complex starches (6+ servings/​day);
to limit sodium intake (≤ 2400 mg/​day); and to maintain proper cal-
cium (RDA) and protein (< 2 times RDA) intake (Popkin et al., 1996).
In 1998, Shi noted that changing patterns in diet may have reflected
a greater receptivity of higher SES people to public health messages
about consuming foods of high nutritional quality (L. Shi, 1998).
Although the authors did not discuss the consumption of junk food,
studies throughout the 2000s have shown that the potential benefits of
relatively healthier diets in blacks compared with whites in the 1960s
were reversed in the following decades, related to increased intakes
of low-​quality foods (Bahr, 2007; Darmon & Drewnowski, 2008,
2015; Hiza, Casavale, Guenther, & Davis, 2013; Siega-​Riz & Popkin,
2001; Thompson et al., 2009; Vargas & Thompson, 2012; C. Y. Wang
et al., 2014).
Thus the rise in obesity prevalence among lower SES groups has
been influenced by increased consumption of low-​quality foods and
overall caloric consumption, even while efforts were made toward
meeting dietary recommendations (Harnack, Jeffery, & Boutelle, 2000;
Heini & Weinsier, 1997; Siega-​Riz & Popkin, 2001). Trends toward
increased consumption may be due to increases in availability and rel-
ative affordability of food items, increased marketing of low-​quality
food items (Chandon & Wansink, 2012; C. Y. Wang et al., 2014), and
increases in portion sizes (Nielsen & Popkin, 2003). Associated with
these, changes may be attributed to changes in agricultural practices,
156
156 Part II: The Magnitude of Cancer
subsidizing of corn production, and food technologies leading to cheap
production of low-​quality foods (Franck, Grandi, & Eisenberg, 2013;
Rickard, Okrent, & Alston, 2013).
Alcohol.  Though wealthier people are more likely to engage in
moderate alcohol consumption, which has been linked to lower lev-
els of insulin, body weight, and risk of diabetes (Gepner et al., 2015;
Wakabayashi, 2014), heavy alcohol consumption is more predomi-
nant among lower SES groups (Esser et al., 2014). Considerable evi-
dence suggests a connection between heavy alcohol consumption and
increased risk for cancer, with an estimated 5.8% of total cancer deaths
attributable directly or indirectly to alcohol (Rothman, 1980). Alcohol
consumption is an established cause of cancers of the mouth, pharynx,
larynx, esophagus, liver, and, in women, breast (Boffetta, Hashibe, La
Vecchia, Zatonski, & Rehm, 2006). For each of these cancers, risk
increases substantially with intake of more than 2 drinks per day,
though regular consumption of even a few drinks per week has been
associated with an increased risk of breast cancer in women (Shield,
Soerjomataram, & Rehm, 2016).
Other research suggests that other lifestyle factors associated with
low SES, in combination with heavy alcohol consumption, such as
malnutrition (Giskes, Turrell, Patterson, & Newman, 2002; Su & Arab,
2001) or smoking, may interact to further increase risk of certain types
of cancer (Jones, Bates, McCoy, & Bellis, 2015). Alcohol consump-
tion combined with low folate consumption appears to predict higher
levels of colon cancer (Vargas & Thompson, 2012), and combined
with tobacco use, increases risk of cancers of the mouth, larynx, and
esophagus more than the independent effect of either drinking or
smoking (Hashibe et al., 2009).
Obesity and Physical Activity. Overweight and obesity are
associated with several cancers, including postmenopausal breast
cancer, colon cancer, endometrial cancer, prostate cancer, renal cell
carcinoma, esophageal adenocarcinoma, ovarian, cervical, and thyroid
cancers.
In addition to changing diets, the disproportionate prevalence of
obesity among people from lower SES backgrounds may help to
account for the changing SES gradient for colorectal cancer. As indi-
cated, obesity has increased dramatically over the past several decades,
though the prevalence has stabilized over the past decade or so (Flegal,
Carroll, Kit, & Ogden, 2012; Flegal, Carroll, Ogden, & Curtin, 2010;
Yanovski & Yanovski, 2011), but lower SES groups, especially
women, are much more likely to be overweight than people from
higher SES backgrounds (Robbins, Vaccarino, Zhang, & Kasl, 2000;
Sharpe, Whitaker, Alia, Wilcox, & Hutto, 2016). As socioeconomic
disparities in overweight have widened, the SES gradient in colorec-
tal cancer incidence and mortality is likely to increase. Similarly, the
gradient will likely change as well for other cancers related to obesity.
Higher SES is generally positively correlated with physical activity,
which in turn has been associated with lower levels of obesity-​related
cancers. As an independent risk factor, the evidence for decreased risk
with higher physical activity is classified as convincing for breast,
colon, and endometrial cancers, probable for prostate cancer, and
possible for lung cancers (American Cancer Society, 2016; Clague
& Bernstein, 2012; Friedenreich & Orenstein, 2002). In recent years,
research has been extended to examine the potential effects of physical
activity on other types of cancer.
The hypothesized biological mechanisms for the association
between physical activity and cancer include changes in endogenous
sex hormone levels and growth factors, decreased obesity and central
adiposity, and possibly changes in immune function. Central adiposity
has been implicated in metabolic conditions that promote carcinogen-
esis. Evidence is also increasing that exercise influences other aspects
of the cancer process, including cancer detection, coping, rehabilita-
tion, and survival (Friedenreich & Orenstein, 2002). Based on existing
evidence, the American Cancer Society has issued physical activity
guidelines for cancer prevention, generally recommending at least 30
minutes of moderate-​to-​vigorous intensity physical activity on 5 or
more days per week, or vigorous activity for 75 minutes or more per
week (American Cancer Society, 2016).
Sexual Behavior.  Aspects of sexual behavior and sexually trans-
mitted infections (STIs) have been linked to reproductive cancers such
as cervical and prostate cancers (Castellsague et al., 2002). There are
limited data available for assessing rates of STIs by SES, and when
data exist, associations are generally weaker than those seen for race/​
ethnicity and STIs, though some studies do show elevated rates of STIs
among disadvantaged groups (Harling, Subramanian, Barnighausen,
& Kawachi, 2013).
Cervical cancer is more common among women from lower SES
backgrounds, who are less likely to receive regular screening and early
treatment (Churilla et al., 2016). Other important factors related to the
development of cervical cancer include a woman’s history of sexual
exposure, her partners’ history of sexual exposure, use of barrier
methods of contraception (protective), and the age at which a woman
becomes sexually active (Chelimo et al., 2013). Risk of cervical can-
cer is also increased when a woman is exposed to the virus before full
maturation of the cervix. In turn, several of these factors have been
shown to be related to SES, especially level of education.
In a study by Hogan, Sun, and Cornwell (2000), adolescent females
whose parents were better educated (greater than high school educa-
tion) were 28% less likely to initiate sexual intercourse and 52% more
likely to use a contraceptive at first intercourse. Similar findings in
other studies also suggest that females with lower income or parental
educational attainment are more likely to have an early age at first inter-
course (Blum et al., 2000; Lammers, Ireland, Resnick, & Blum, 2000;
Santelli, Lowry, Brener, & Robin, 2000; S. Singh, Darroch, & Frost,
2001), and subsequently they have more and/​or concurrent sexual part-
ners (Coker et al., 1994; O’Donnell, O’Donnell, & Stueve, 2001) and
are less likely to use barrier contraception (Bankole, Darroch, &
Singh, 1999). Roura and colleagues (2014) noted that compared to
women who never smoked, women who currently smoked were 1.9
times more likely to develop cervical cancer, due to the damage ciga-
rette smoking causes to cervical cells.
Reproductive Factors
Reproductive factors associated with SES and with cancer incidence
include age at menarche, parity, age at first birth, age at menopause,
and use of exogenous hormones. Higher SES women have been shown
consistently to have higher rates of breast cancer. They are more likely
to have first children at a later age and to have fewer children. They have
been more likely to take exogenous hormones after menopause. These
factors have in turn been associated with an increased breast cancer risk.
Early age at menarche is also associated with higher risk of breast
cancer. Higher SES has been historically associated with earlier age
at menarche, which has been observed both within countries, as well
as in comparisons of developed versus less developed countries. On
the other hand, with the obesity epidemic growing disproportionately
among low-​SES children, early menarche may increasingly weigh
against lower SES women in the United States, thereby leading to a
further narrowing of the SES gap in breast cancer incidence in the
future.
As previously discussed, declines in the use of exogenous hormones
after 2003 led to declines in breast cancer incidence, but particularly
in women of higher SES who were taking hormone therapy at a higher
rate than women of low SES.
Occupational Exposures
Blue-​collar and manual workers experience greater exposure than
white-​collar workers to chemicals, diesel fumes, dyes, and other agents
in the workplace, including inorganic gases, organic compounds, sol-
vents, mineral and wood dusts, silica, metals, and bioaerosols, which
are established carcinogens (Boffetta et al., 2000; Kauppinen, Teschke,
Savela, Kogevinas, & Boffetta, 1997; Kogevinas & Porta, 1997; US
Department of Health and Human Services, 2002; Weston, Aronson,
Siemiatycki, Howe, & Nadon, 2000).
Blue-​collar workers are also more likely to be exposed to environ-
mental tobacco smoke (ETS) (Curtin, Morabia, & Bernstein, 1998).
Percent of white-​collar workers was a predictor of more restrictive
smoking policies in a national sample of worksites (K.M. Emmons,
 157
Socioeconomic Disparities in Cancer Incidence and Mortality 157
2000). Furthermore, the interactive effects of smoking and chemical
exposures may put workers of low SES at additional increased risk of
cancer. The combination of asbestos exposure and cigarette smoking,
both correlated with low SES, has been associated with a synergisti-
cally increased risk of lung cancer (Gustavsson et al., 2002).
Though not all shift workers occupy lower SES positions (e.g.,
healthcare professionals), shift work is more common among persons
from lower SES backgrounds (e.g., jobs in the service industry, trans-
port, security work, manufacturing, etc.) (Boggild, Suadicani, Hein,
& Gyntelberg, 1999). Longer durations (> 20 years) of rotating night-​
shift work have been linked to immune dysfunction (Nakata, 2012) and
rotating night-​shift work has been linked to increased risks of breast
and colon cancer (Schernhammer et  al., 2001, 2003a). In particular,
working 30 or more years on the night shift was associated with a
moderate elevation in risk of breast cancer (RR = 1.36; 95% CI: 1.04,
1.78) and working 15 or more years on rotating night shifts was associ-
ated with an increase in colon cancer (RR = 1.35; 95% CI: 1.03, 1.77).
The mechanism is believed to be through the suppression of melatonin
production, caused by prolonged exposure to light during night-​time
(melatonin, in turn, is believed to have oncostatic action).
The Social Environment
Neighborhood Environments.  Much empirical work on SES
and cancer to date has focused on individual-​level exposures and rela-
tionships. However, increasing attention has been paid more recently
to the independent contribution of area-​level socioeconomic factors
on health outcomes (Kawachi & Berkman, 2003)  including cancer
(Gomez et  al., 2015), and research to identify contextual effects on
health outcomes has expanded markedly over the past decade. A study
by Merkin and colleagues (Merkin, Stevenson, & Powe, 2002) found
that living in areas with lower levels of education and income
increased the odds of presenting with advanced-​stage breast cancer
by 50% for black women and by 75% for white women. One study
found that those in severe poverty or near poverty were, respectively,
3.0 and 1.6 times more likely to live in areas of higher-​than-​expected
incidence of late-​stage breast cancer when compared with women liv-
ing in non-​poverty (MacKinnon et al., 2007). However, a recent study
in Michigan in 1992–​2009 found that women with breast cancer living
in low-​SES areas showed greater declines in mortality rates compared
to those living in high-​SES areas, resulting in a narrowing of the SES-​
mortality gap (Akinyemiju et al., 2013).
Community and neighborhood level factors, including the avail-
ability of green space (for physical activity), access to stores and
grocers, as well as social norms and social cohesion, may have an
influence on health above and beyond individual factors, including
individual SES (Kawachi & Berkman, 2003). Special study designs
and analytical techniques (multilevel analysis) are required to detect
the presence of contextual effects. Obstacles abound in drawing
causal inferences from such data. Nevertheless, redirecting the focus
of interventions from individuals toward improving the quality of
the places where they reside may result in new potential solutions to
improve outcomes. The potential existence of contextual influences
on cancer risk offers a promising avenue for cancer prevention.
Social Networks.  One major way through which SES may have
differential effects on cancer mortality is through effects on social net-
works. Those with larger personal social networks, defined as the web
of social relationships that surround an individual (Berkman & Glass,
2000), have lower cancer mortality (Beasley et  al., 2010; Ellwardt,
van Tilburg, Aartsen, Wittek, & Steverink, 2015; C. H. Kroenke et al.,
2006, 2013; Rottenberg et  al., 2014)  and specifically breast cancer
mortality, since there is almost no work on social ties and cancer
outcomes for cancers other than breast cancer. Persons with larger
social networks are said to be more socially integrated, and those with
smaller networks are more socially isolated.
Social isolation may be plausibly hypothesized to influence
outcomes through several mechanisms. First, social relation-
ships and interactions influence behaviors and health outcomes by
“contagion” (K. Smith & Christakis, 2008; Valente, 2009), through
norms (Berkman & Glass, 2000; K. Smith & Christakis, 2008), peer
modeling (Bandura, 1986), and via access to “social capital”—​defined
as the informational and material resources exchanged through social
ties (Moore, Daniel, Paquet, Dube, & Gauvin, 2009). Depending on
network structure (Granovetter, 1973), cancer patients may have dif-
ferent levels of access to resources, referrals, advice, opportunities
to participate in clinical trials, and knowledge about the side effects
and outcomes of treatment. Identification with social network mem-
bers may increase the likelihood of adopting behaviors (Christakis &
Fowler, 2007; Pachucki, Jacques, & Christakis, 2011) through influ-
ences on shared behaviors and norms.
Social networks may also bring costs or burdens related to social roles
that can adversely influence health (C. H. Kroenke et al., 2012). Larger
social networks can increase caregiving obligations, disproportionately
true among women of lower SES. While potentially rewarding, caregiving
can be physically and emotionally demanding, leading to poorer self-​care
and worse health outcomes (Cannuscio et al., 2002; Kiecolt-​Glaser et al.,
1987; S. Lee, Colditz, Berkman, & Kawachi, 2003; S. Lee, Kawachi, &
Grodstein, 2004; Schulz & Beach, 1999). The quality of social relation-
ships also appears to differ by SES; high-​strain relationships, more com-
mon in those of low SES, can lead to higher levels of stress.
People of different SES also appear to depend differently on social
networks (August & Sorkin, 2011; Bureau, 2011). Women with
greater education have larger social networks but a greater propor-
tion of distal members. In contrast, women of lower SES are more
likely to have smaller but denser networks of people who live in close
proximity and have more intense, frequent contact with greater inter-
dependency. In men, their spouses are often the most critical mem-
ber of their social network influencing their health; marital status has
been reliably associated with cancer outcomes (Hanske et al., 2016;
Jin et al., 2016; R. L. Shi et al., 2016; van Jaarsveld, Miles, Edwards,
& Wardle, 2006; L.  Wang, Wilson, Stewart, & Hollenbeak, 2011).
However, men of lower SES are less likely to be married (Ajrouch,
Blandon, & Antonucci, 2005; Choi & Marks, 2011; Gomez et  al.,
2016; Villingshoj, Ross, Thomsen, & Johansen, 2006).
Larger social networks predict more optimal cancer mortality risk
factors (C. H. Kroenke et al., 2016) and lower cancer mortality gener-
ally, but associations may depend substantially on the quality of, and
obligations entailed by, those relationships, as well as sociodemo-
graphic factors.
Psychosocial Factors
Several mechanisms have been hypothesized through which psycho-
social factors (such as stress, depression, and social support) may
influence cancer outcomes. First, stress and depression are related to
health behaviors that are linked to cancer, including cigarette smoking,
excessive alcohol intake, and low levels of physical activity. Cigarettes
are a relatively affordable and accessible means of stress reduction,
particularly in the context of poverty (K. M. Emmons, 2000). A recent
meta-​analysis also found that levels of job strain and social support
predicted physical activity (Griep et al., 2015). However, psychosocial
factors may also have direct effects on cancer mortality through a vari-
ety of biological mechanisms (Lutgendorf & Sood, 2011).
Stress and Depression. Psychosocial factors have been also
hypothesized to directly influence immune function (Spiegel, Sephton,
Terr, & Stites, 1998). Acting via the hypothalamic-​pituitary-​adrenal
axis in a complex feedback loop between the central nervous (CNS)
and immune systems, stress increases cortisol levels, which adversely
affects immune function (Segerstrom & Miller, 2004). Frequent corti-
sol release that occurs with chronic stress may lead to persistently high
cortisol levels (Kirschbaum et al., 1995), leading to immune suppres-
sion. Because the immune system is involved in the body’s immune
surveillance mechanism (e.g., eliminating mutated cells), immune
dysfunction may lead to more rapid development of cancer. Stress may
also promote cancer through DNA damage, faulty DNA repair, inhibi-
tion of apoptosis, effects on endocrine parameters, or somatic mutation
158

158 Part II: The Magnitude of Cancer

(Forlenza & Baum, 2000; Jenkins, Van Houten, & Bovbjerg, 2014).
These may be precursors to certain types of cancer such as hormonal
(Riley, 1981; Rowse, Weinberg, Bellward, & Emerman, 1992)  and
lymphatic cancers (Fox, Goldblatt, & Jones, 1985; Levav et al., 2000).
Despite plausible mechanisms linking psychosocial factors to
cancer outcomes, the empirical evidence has been decidedly mixed.
For example, certain types of job stress have been hypothesized to
be linked to increased disease risk, including cancer. According to
Karasek (Karasek & Theorell, 1990), jobs that are both high in psy-
chological demands and low in decision-​making authority (or control)
are hypothesized to result in job strain. High-​strain jobs are typically
over-​represented in lower SES occupations, such as assembly-​line jobs
and certain kinds of jobs in the clerical and service sector. In turn, job
strain has been shown to raise the likelihood of deleterious behavioral
coping responses (such as cigarette smoking, alcohol abuse), thereby
increasing the risk of disease outcomes. While the majority of epide-
miological studies of job strain and CVD have found support for such
an association, the link to cancer still remains elusive. For example,
in the Harvard Nurses’ Health Study, Achat and colleagues (Achat,
Kawachi, Byrne, Hankinson, & Colditz, 2000)  found no evidence
of an association between job strain and breast cancer incidence in
a cohort of nurses. In 2007, in a study with data from The Women’s
Lifestyle and Health Cohort Study (n = 36,332), Kuper and colleagues
(Kuper, Yang, Theorell, & Weiderpass, 2007) found that women with
low job control and high job demands (“job strain”) had only a slightly
higher risk of breast cancer than women with high job control and low
demands (“low strain”) (HR = 1.2; CI: 0.9, 1.6). Though the number
of breast cancer cases was relatively small in both studies (n  =  219
in Achat et  al., and n  =  767 in Kuper et  al.), a follow-​up study by
Schernhammer and colleagues (Schernhammer et  al., 2003b), with
1,030 breast cancer cases, found an inverse, rather than the expected
positive, association between job strain and breast cancer.
Consistent with the finding in the Schernhammer study, Kroenke
and colleagues also found that high stress from caregiving was related
to a possible lower risk of breast cancer (Kroenke et al., 2004). In a
meta-​analysis of 116,056 European men and women, job stress was
not significantly associated with colorectal, breast, or prostate cancer.
It was positively associated with lung cancer in age-​and sex-​adjusted
analyses, but was no longer significantly associated after adjustment
for cigarette smoking. There was a suggestion of an inverse associa-
tion of stress with breast and prostate cancer, though these associations
were not significant (Heikkila et  al., 2013). Gradus and colleagues
found no association between post-​traumatic stress disorder and can-
cer (Gradus et al., 2015). Equivocal effects of stress on cancer may be
due to the result of the combination of behavioral, hormonal, and other
biological effects and the mixed result on cancer incidence, or the pos-
sible methodological issues inherent with the lack of evaluation of
coping in combination with stress, and their influences on outcomes.
2007). There is little work evaluating other types of social interven-
tions on cancer mortality.
Access to Healthcare and Screening
SES is inversely related to the likelihood of obtaining cancer screening
(Katz & Hofer, 1994; Katz, Zemencuk, & Hofer, 2000). In their study,
Challenges in Meeting Healthy People 2020 Objectives for Cancer-​
Related Preventive Services, National Health Interview Survey, 2008
and 2010, Brown and colleagues noted that only women in the highest
income group (with incomes ≥ 400% of the federal poverty level or
FPL) surpassed the 2020 Healthy People’s goal of having 81.1% of
all women engage in breast cancer screening. Among women whose
incomes less than 200% FPL, less than 62% had screened for breast
cancer (US Department of Health and Human Services, 2000). As a
consequence, the poor often present with cancer at later, less treat-
able stages. Bradley and colleagues found that persons < 65 years who
were insured by Medicaid had a greater risk of late-​stage diagnosis
and death for breast, cervical, colon, lung, and prostate cancer than
those not insured by Medicaid (Brewster et  al., 2001). People from
lower SES backgrounds generally present and are diagnosed at later
stages, which explains, in part, their higher mortality rates after cancer
(Boscoe et al., 2016; F. Wang, Luo, & McLafferty, 2010).
Even holding cancer stage constant, the poor have been shown to
have worse survival (Bradley, Given, & Roberts, 2002). A higher prev-
alence of comorbid conditions may complicate recovery. They have
historically had more limited access to healthcare (Bindman et al.,
1995; Hargraves, 2002) and have often received less aggressive treat-
ment (Bristow et al., 2013; Mahal et al., 2014; N. Wang et al., 2015).
The Affordable Care Act (ACA), signed into law in 2010, expanded
health care to 20 million previously uninsured people (Obama, 2016)
and held promise in reducing SES disparities in preventive services
and treatment (O’Keefe, Meltzer, & Bethea, 2015) particularly
through its expansion of affordable Medicaid coverage. However,
these advances may be reversed with the repeal of the ACA and phase
out of Medicaid financing intended by the current administration and
majority Republican congress (Kaplan, 2017).
The socioeconomic pattern of colorectal cancer mortality began to
cross over (from higher rates in persons of higher SES up to the 1980s,
1.05
1
0.95
0.9
Mortality Rate Ratios (MRR)

0.85
Social Support.  Social support—​for example, tangible, emotional,
informational, and appraisal support (Berkman & Glass, 2000)—​is
one means through which social relationships may influence can- 0.8
cer survival. In addition, Sherbourne and Stewart (1991) identified
affectionate support and “positive social interaction” in patients with 0.75
chronic illness. Tangible support could include rides to the hospital,
trips to the pharmacy, or provision of healthy meals (Hirschman & 0.7
Bourjolly, 2005; Woloshin et al., 1997). Network members may pro-
vide informational support through referrals to physicians and clinics
0.65
or alternative types of treatment, or they may buffer stress (Cohen &
Wills, 1985) through provision of emotional support.
Observational studies of women with breast cancer have typically, 0.6

though not always, found increased mortality rates among those with
5

8
–7

–8

–8

–9

–9

–0

–0

–0
71

76

81

86

91

96

01

06

low levels of social support, adjusted for stage of disease and treatment
19

19

19

19

19

19

20

20

factors (Chou, Stewart, Wild, & Bloom, 2012; Goodwin et al., 1996; 5-year groups
Maunsell, Brisson, & Deschenes, 1995; Reynolds et al., 1994).
Average Diffusion Diffusion 1SD above average Diffusion 1SD below average
However, promising results from early trials (Spiegel, Bloom,
Kraemer, & Gottheil, 1989) suggesting that peer support may improve
cancer survival in metastatic breast cancer patients have not been Figure  9–​4. The modified impact of SES (MMRs) with three different
borne out by more recent studies (Goodwin et al., 2001; Spiegel et al., state-​level diffusion speeds, 1971–​2008.
 159
Socioeconomic Disparities in Cancer Incidence and Mortality 159
then lower rates thereafter) prior to the dissemination of colorectal
screening guidelines (G. K. Singh, Miller, & Hankey, 2002), suggest-
ing that other factors besides screening and health insurance status
are responsible for the reversal in the SES gradient for this disease
(Niu, Roche, Pawlish, & Henry, 2013). Screening for colorectal can-
cer has increased since the previous version of this chapter (Meissner,
Breen, Klabunde, & Vernon, 2006), moreso among those of higher
SES, though the SES differential is smaller in states with rapid dif-
fusion of information. Figure  9-​4 shows that states with a higher
propensity for diffusion show smaller socioeconomic disparities for
colorectal cancer mortality over the 40-​year study period, while those
states with a propensity toward slow and moderate rates of diffusion
show wider disparities, suggesting that this mechanism may moderate
socioeconomic disparities (A. Wang, Clouston, Rubin, Colen, & Link,
2012) (Figure 9–​4).
Biological Influences Related to Aging
While there are many biological mechanisms through which socioeco-
nomic disadvantage may influence cancer incidence and mortality, we
briefly focus on two areas of research that have mushroomed since the
last version of this chapter—​epigenetics and telomeres. Epigenetics is
the study of heritable changes in gene expression, without changes to
the underlying DNA, that lead to phenotypic changes in living organ-
isms; DNA methylation is believed to provide a stable and comprehen-
sive record of epigenetic influence (Hochberg et al., 2011). Telomeres
are nucleoprotein structures and the protective caps at the ends of lin-
ear eukaryotic chromosomes that are required for genomic stability
(Chiodi & Mondello, 2016; Meena, Rudolph, & Gunes, 2015). We
address these areas in particular because of their potential relevance to
cumulative socioeconomic disadvantage or “weathering” (Geronimus,
1992) and their potential in future research.
Epigenetics and DNA Methylation. Socioeconomic dis-
advantage may be expressed through epigenetic modifications—​
variations in genetic expression, triggered by changes in DNA
methylation, resulting from external and/​ or environmental influ-
ences (Bhattacharjee, Shenoy, & Bairy, 2016; Sapienza & Issa, 2016;
Trimarchi, Mouangsavanh, & Huang, 2011). Researchers in Canada
and the United Kingdom found that socioeconomic position in child-
hood is associated with DNA methylation differences many years later.
Socioeconomic disadvantage in childhood appears to have a greater
influence on DNA methylation patterns than socioeconomic disad-
vantage in adulthood (Borghol et al., 2012). Thus, having a disadvan-
taged (or advantaged) background may have profound ramifications
for health over the life course, even if socioeconomic circumstances
improve in adulthood. Socioeconomic disadvantage has been related to
DNA methylation of genes involved in inflammation (Needham et al.,
2015; Stringhini et al., 2015), a major predictor of tumor progression.
Abnormal DNA methylation patterns have been associated with devel-
opment of various cancers, including head and neck cancers, breast
cancer, and prostate cancer (Montenegro et  al., 2016; Nelson et  al.,
2007; Shaw et al., 2008; Veeck & Esteller, 2010).
Telomeres.  Low SES in adulthood has been weakly associated
with telomere length (Robertson et al., 2013), though social disadvan-
tage has been linked to shorter telomeres in children (Mitchell et al.,
2014). Chronic stress, common among those of low SES, has also
been related to telomere attrition (Epel et  al., 2004). Aberrations in
telomere maintenance contribute to cancer development (Basu et al.,
2013) and have predicted cancers of the breast, gastrointestinal tract,
larynx, bladder, and ovary, as well as chronic lymphocytic leukemia
and cutaneous melanoma and non-​ melanoma skin cancers (Caini
et al., 2015; Kotsopoulos et al., 2014; Shen et al., 2012; Valls-​Bautista,
Pinol-​Felis, Rene-​Espinet, Buenestado-​Garcia, & Vinas-​Salas, 2015;
R. Wei, DeVilbiss, & Liu, 2015; Willeit, Willeit, Kloss-​Brandstatter,
Kronenberg, & Kiechl, 2011; Willeit et  al., 2010). Telomere short-
ening has been related to cancer progression and earlier mortality
(Duggan et  al., 2014; Kammori et  al., 2015; Svenson et  al., 2008;
Svenson, Oberg, Stenling, Palmqvist, & Roos, 2016; Weischer et al.,
2013; Willeit et al., 2010, 2011; Zhang et al., 2015).
A Note on SES versus Race
SES is correlated with race. African-​Americans and Hispanics are dis-
proportionately represented in low SES groups, whether measured by
education, income, or occupation. A great deal of work has explored
differential cancer outcomes by race, predominantly focusing on dif-
ferences between blacks and whites. In the absence of SES data in
routine sources of data, there has been a tendency to use race as a
proxy for SES (Williams, 1997). Though the practice of conflating
SES with race/​ethnicity has historically posed a barrier to understand-
ing the etiological relationships of each to cancer outcomes, research-
ers have more carefully distinguished SES from race in more recent
research.
For some cancers, SES may entirely “explain” the association of
race and cancer. In a study of Detroit women, Bradley and colleagues
found, after accounting for SES, that race was not related to stage at
presentation or survival after breast cancer diagnosis (Bradley et al.,
2002). Also, after controlling for income, black women were as likely,
or more likely, than white women to report having had a recent mam-
mogram. Black women from higher SES backgrounds experienced
similar rates of breast cancer compared to affluent white women.
In other cases, SES has explained part but not all of the racial dif-
ference in risk (Bristow et al., 2013; Robbins et al., 2000). Tellingly,
race and SES do not always vary in the same direction with respect to
cancer incidence and mortality. When incidence rates were stratified
by race and census block SES, Krieger and colleagues (1999) found
marked heterogeneity in the relationships of SES and race to individ-
ual cancer sites. This was also true in a recent analysis in the California
Cancer Registry (Yin et al., 2010). The strength of association between
SES and cancer may also vary by race. In a study by Yost et al. (Yost,
Perkins, Cohen, Morris, & Wright, 2001), SES was positively related
to breast cancer incidence, but the effect was stronger for Hispanic and
Asian women than it was for whites and blacks.
This chapter has focused specifically on the influence of SES on
cancer outcomes, and fortunately, since the previous edition of this
chapter, there has been a greater tendency, and a greater recognition
of the need, to evaluate the independent and joint effects of SES and
race/​ethnicity on cancer outcomes. Research that evaluates the cross-​
classification of SES and race, as well as other factors including urban/​
rural status, nativity, and residence in ethnic enclaves (Schupp, Press,
& Gomez, 2014), may be the most helpful in trying to understand
health disparities.
NEEDED RESEARCH
Vice President Joseph Biden called for and President Barack Obama
launched a “moonshot” initiative to cure cancer (Conrads & Petricoin,
2016) that would focus on expediting collaborative clinical and labora-
tory research and encourage information sharing. However, given that
lifestyle and environmental factors have a substantial impact on global
cancer incidence and mortality, and that most of these risk factors
are related to socioeconomic factors, national efforts in cancer pre-
vention could be facilitated by focusing on socioeconomic disparities
(Horwitz, 2016) and by evaluating the effects of policies on cancer-​
related health behaviors.
Understanding the effects of SES on cancer over the life course
will necessitate research on the cumulative impact of SES on out-
comes using more complex analytic methodological tools (S. Liu,
Jones, & Glymour, 2010). There is a need for research that considers
other SES measures such as familial wealth. Furthermore, there is a
need to explore more fully the combined effects of multiple sociode-
mographic factors including SES, urban/​rural status (G. K.  Singh,
Williams, Siahpush, & Mulhollen, 2011), race/​ethnicity, and immigra-
tion history on outcomes. To understand the ways in which area-​and
neighborhood-​level environments affect cancer, more specific research
160
160 Part II: The Magnitude of Cancer
will be needed on social and built-​in environments (Hernandez &
Blazer, 2006). Study of environmental factors and cancer outcomes
pertinent to SES disparities may also need to begin to consider the
implications of the progression of climate change on cancer (Portier
et al., 2010).
CONCLUSION
The relationship of SES to cancer is complex and dynamic, and con-
tinues to evolve. It can be difficult to make generalizations about the
relationship, because of the heterogeneity of cancer types and outcome
measures, as well as the differences in approaches to measuring SES
itself (different indicators, different levels of analysis). Whether the
association is causal remains controversial in some cases, even though
several plausible pathways have been identified by which SES could
causally affect the onset and prognostic course of specific cancers.
However, socioeconomic disadvantage is often associated with higher
cancer incidence and worse prognosis once diagnosed. SES may be a
“fundamental” determinant of health outcomes, and this appears true
throughout the cancer spectrum—​from cancer incidence, to detection,
treatment, and survival.
Importantly, there is evidence that the diffusion of knowledge can
mitigate socioeconomic disparities. Investigations of the link between
SES and cancer will continue to benefit from more sophisticated
approaches to the measurement of SES, including multidimensional
measures, measures of familial resources, and more sophisticated
evaluation of socioeconomic trajectories over the life course, as well
as better specification and tests of etiological mechanisms. Such an
exercise is of more than passing academic interest, since any program
or policy to reduce the burden of cancer must also pay attention to
mitigating the existing socioeconomic disparities in cancer outcomes.
ACKNOWLEDGMENTS
We would like to thank Circe Le Compte and Jon Pfefferle for their
assistance in updating references.
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 169
10 The Economic Burden of Cancer in the United States
K. ROBIN YABROFF, GERY P. GUY JR., MATTHEW P. BANEGAS,
AND DONATUS U. EKWUEME
OVERVIEW
With an aging and growing population and improved early detection
and survival following cancer diagnosis in the United States, the preva-
lence of cancer survivorship is expected to increase in the future. Based
only on population trends, national expenditures for cancer care are
projected to increase as well, from $124.6 billion in 2010 to $157.8
billion in 2020 (both in 2010 US dollars). When trends toward greater
intensity of healthcare service use and more expensive treatments are
considered, expenditures are projected to be even greater. Thus, esti-
mating and projecting the economic burden of cancer, including health-
care expenditures and productivity losses for patients and their families,
are increasingly important issues for healthcare policymakers, health-
care systems, physicians, employers, and society overall. In this chap-
ter, we describe measures of the economic burden of cancer, including
(1) direct costs, resulting from the use of resources for medical care for
cancer; (2) indirect costs, resulting from the loss of economic resources
and opportunities associated with morbidity and mortality due to cancer
and its treatment; and (3) psychosocial or intangible costs, such as pain
and suffering. Consistent with the intensity of treatment for initial care,
recurrence, and end-​of-​life care, costs are highest in the initial period
following diagnosis and, among patients who die from their disease, at
the end of life, following a U-​shaped curve. We describe how this tem-
poral cost pattern influences differences in per-​person and aggregate
cost estimates for cancers with excellent prognosis and longer survival
(e.g., breast and prostate) and cancers with poorer prognosis (e.g., pan-
creas and lung) and we present recent per-​person and national esti-
mates of direct and indirect costs overall and by cancer site. Finally, we
describe publicly available data sources and methodologic issues with
measuring economic burden and identify key areas for future research.
INTRODUCTION
In 2014, an estimated 14.5 million Americans were alive with a his-
tory of cancer (American Cancer Society, 2016; Howlander et  al.,
2016). The absolute number of cancer survivors is expected to be sub-
stantially larger in the future because cancer incidence increases with
age, and the US population is both aging and growing (de Moor et al.,
2013; Mariotto et al., 2011). In addition, advances in screening, detec-
tion, and treatment are associated with improved survival following
cancer diagnosis. These developments will also result in increased
cancer prevalence. It is projected that the number of cancer survi-
vors will increase to 19 million by 2024 (American Cancer Society,
2016). This increasing number of cancer survivors will receive
medical care throughout the trajectory of their cancer experiences,
including short-​and long-​term effects of disease and its treatment. As
shown in Figure 10–1, based only on population aging and growth,
national expenditures for cancer care are projected to increase from
$124.6 billion in 2010 to $157.8 billion by 2020 (both in 2010 US
dollars), a 27% increase (Mariotto et al., 2011). When recent trends
toward greater intensity of healthcare service use (Warren et al., 2008;
Dinan et  al., 2010; Conti et  al., 2014) and increasing costs of can-
cer care (Bach 2009; Conti et  al., 2014; Dinan et  al., 2010; Elkin
and Bach, 2010; Howard et  al., 2010; Schrag, 2004; Tangka et  al.,
2010; Warren et al., 2008; Woodward et al., 2007; Wong et al., 2009)
are considered, expenditures in 2020 are projected to be even greater
(Mariotto et al., 2011). Thus, estimating and projecting the economic
burden of cancer, including healthcare expenditures and productivity
losses for patients and their families, are increasingly important issues
for healthcare policymakers, healthcare systems, physicians, employ-
ers, and society overall. In this chapter, we describe measures of the
economic burden of cancer and approaches for estimating economic
burden, and we present recent national estimates. We also describe
publicly available data sources and discuss methodologic issues
with measuring economic burden, and identify key areas for future
research.
WHY MEASURE THE ECONOMIC BURDEN
OF CANCER?
Measurement of the economic burden of cancer is important at many
levels for medical and non-​medical resource allocation, reimbursement
decisions, and the evaluation of specific programs throughout the course
of cancer care, from early detection and diagnosis to treatment, survivor-
ship, and end-​of-​life care. Descriptive studies of the various components
of the economic burden of cancer also serve as an initial step in elucidat-
ing relevant domains in cost-​effectiveness analysis of cancer prevention
and control interventions and identifying priorities and resource needs in
the planning of cancer prevention and control strategies and programs.
HOW IS THE ECONOMIC BURDEN
OF CANCER MEASURED?
Illness and disease create an economic burden for patients, family and
friends, employers, the healthcare system, and society. Cancer and its
treatment may result in pain and suffering, morbidity and reduced qual-
ity of life, financial losses for the patient and family, and in some cases,
premature mortality. The economic burden of cancer also includes the
loss of economic resources and opportunities from the perspective of
employers and society more broadly.
The economic burden of disease is measured by cost, the monetary
valuation of resources used to treat disease and the loss of economic
opportunities related to disease occurrence and treatment. Three cat-
egories of cost domains are typically identified: (1) direct costs, result-
ing from the use of resources for medical care for cancer as well as
care for lasting and late effects of cancer; (2) indirect costs, resulting
from the loss of economic resources and opportunities associated with
morbidity and mortality due to cancer and its treatment; and (3) psy-
chosocial (intangible) costs, such as pain and suffering. Examples of
these categories of costs are listed in Table 10–1 and are described in
greater detail in the following subsections.
Direct Costs
Direct costs include the monetary value of resources used for medi-
cal care in the early detection, diagnosis, and treatment of disease, as
well as for rehabilitation, surveillance, and end-​of-​life care. The dis-
tinguishing characteristic of a direct cost is that it represents resource
169
170

170 PART II:  THE MAGNITUDE OF CANCER

Breast
Colorectal
Lymphoma
Lung
Prostate
Leukemia
Ovary
Brain
Bladder
Kidney
Head_Neck
Uterus
Melanoma
Pancreas
Stomach
Cervix
Esophagus

0 5 10 15 20 25
Billion US$

Expenditures in 2010 Additional Expenditures in 2020

Figure 10–1.  Projected increase in national expenditures in 2020 by cancer site (in billion US$): Based on population changes only. Source: Mariotto AB,
Yabroff KR, Shao Y, Feuer EJ, Brown ML. 2011. Projections of the costs of cancer care in the United States: 2010–​2020. J Natl Cancer Inst, 103, 117–​128.

utilization associated with a direct monetary payment. These payments costs. The majority of studies of the economic burden of cancer report
are usually recorded in the financial records of a healthcare insurance direct medical costs (Yabroff et al., 2012), in part, because these data
system, healthcare providers, or an individual household. Such costs are more readily available. Studies of direct medical costs are typically
include medical resources provided under public or private insurance based on billing system data from insurers, hospital discharge data,
systems, as well as individual out-​of-​pocket expenditures. Direct costs and large nationally representative surveys.
for medical care include hospitalizations, emergency room care, out- In addition to costs for the provision of medical care, the direct
patient care, nursing home and home healthcare, and the services of non-​medical costs are those costs borne by patients, caregivers, and
primary care physicians and specialists as well as other health practi- families. These costs include those associated with transportation to
tioners (Table 10–1). Cancer treatments, such as chemotherapy, immu- and from health providers, child and dependent care costs, and costs
notherapy, and radiation therapy, supportive agents, rehabilitation of relocating temporarily or permanently to improve access to specific
counseling, and other rehabilitation costs, are also included in direct treatments or facilities. Illness can force a family to incur expenses as
part of caring for a cancer patient, including those for routine house-
hold tasks, special diets or clothing, items for rehabilitation, alterations
Table 10–1.  Cost Domains of property, and vocational, social, and family counseling services.
Expenditures for retraining or re-​education and interest lost on with-
DIRECT COSTS Medical Hospitalizations drawal of savings or interest charges on funds borrowed to pay illness-​
Physician visits related expenses are also considered direct non-​medical costs. These
Home healthcare data are not systematically collected as part of billing systems, and as
Hospice care
a result, few studies report direct non-​medical costs.
Chemotherapy
Radiation
Rehabilitation
Supportive agents Indirect Costs
Non-​Medical Transportation to and from medical care Indirect costs are the time and economic output lost or forgone due
Housekeeping services to disease and its treatment and any late and lasting effects of treat-
Costs of relocating ment on the usual activities of patients, family, and friends, including
Alterations to property employment, housekeeping, volunteer activities, and leisure. These
INDIRECT Morbidity Time lost from work/​lost productivity costs are not reflected by direct monetary transactions but do reflect
COSTS Time spent seeking medical care the use of economic resources in response to disease and its treatment
Caregiver time or changes in caregiver that could be used for other purposes in the absence of disease. Indirect
productivity costs are measured as the value of losses of economic output due to
Mortality Economic productivity lost due to morbidity or premature mortality from disease. Cancer survivors may
premature death not be able to fully participate in work or other usual activities because
of morbidity associated with the illness. Family members and others
INTANGIBLE/​PSYCHOSOCIAL Pain
COSTS Suffering
may spend time caring for the patient rather than pursuing other activi-
Grief ties, may make unwanted job changes, or may miss opportunities for
promotion and education.
 17
The Economic Burden of Cancer in the United States 171
Estimated morbidity costs of cancer can include losses measured
by the value of forgone earnings and the imputed value of lost house-
keeping services (measured by wages that would have to be paid to
replace those services). A related type of indirect cost is the time
the patient and/​or family spend receiving medical care, known as
patient or caregiver “time costs.” Longitudinal morbidity data and
patient time data are not collected systematically as part of bill-
ing systems, and as a result, few studies have reported these costs.
However, several studies have reported productivity losses associ-
ated with morbidity costs in a given year using nationally represen-
tative cross-​sectional data (Ekwueme et al., 2014; Guy et al., 2013,
2014). Patient time costs have been estimated from medical service
frequencies (e.g., hospitalizations, physician visits, chemotherapy)
combined with time estimates of medical service duration and values
for that time (e.g., median wages) (Yabroff et al., 2007, 2014).
Mortality costs are the present value of future output lost because of
premature death due to cancer. One of the main components of mor-
tality costs is the remaining life expectancy in the absence of cancer
death—​the person-​years of life lost (PYLL). The other main compo-
nent of mortality costs is the time value of the PYLL. All measures of
indirect costs require a method for estimating the value of time associ-
ated with morbidity, patient time, or the PYLL due to early death from
cancer. Two general approaches are commonly used to value time: the
human-​capital approach and the willingness-​to-​pay approach. In the
human-​capital approach, sex-​and age-​specific earnings are combined
with expected productivity trends and time lost to estimate unreal-
ized lifetime earnings. This approach explicitly values the time of
individuals with higher earning potential as greater than those with
less earning potential, which is one of its limitations. The willingness-​
to-​pay approach, in contrast, incorporates both lost productivity and
the intrinsic value of life by estimating the amount an average indi-
vidual would be willing to pay for an additional year of life. Because
incidence and mortality rates for most cancer sites are highest in the
elderly, a population that is less likely to be in the workforce than their
younger counterparts, comparing results from these two approaches
for valuing time is particularly relevant for estimating the burden of
cancer (Ramsey, 2008).
Few studies have systematically measured indirect costs associated
with cancer care. However, studies that have attempted to measure
components of these costs have reported that these frequently unmea-
sured costs may be substantial (Bradley et al., 2008; Ekwueme et al.,
2008; Li et al., 2010; Yabroff et al., 2007, 2008a).
Psychosocial or Intangible Costs
Disease may also impact the quality of life of the patient, family, and
friends in ways that are not reflected in the categories of direct or indi-
rect costs. These are referred to as psychosocial or intangible costs.
As the result of a cancer diagnosis, its treatment, and late or lasting
effects of treatment, patients may suffer from reduced sexual function-
ing, disfigurement, disability, pain, or fears of life-​threatening disease.
Patients and their families may make changes in life plans, which can
induce anxiety, reduce self-​esteem and feelings of well-​being, or cre-
ate resentment and family conflict. The combination of financial hard-
ship and psychosocial problems can be especially devastating. For the
purposes of cost-​effectiveness analysis, psychosocial cost is conceptu-
alized as a quality of life outcome and is measured in terms of decre-
ments of quality-​adjusted life-​years or in terms of utility. Developing
appropriate concepts and measures of the quality of life ramifications
of cancer and cancer treatment is currently an active area of cancer
research.
WHAT ARE THE TEMPORAL PATTERNS OF
THE ECONOMIC BURDEN OF CANCER?
When measured longitudinally starting from cancer diagnosis, the
monthly patterns of medical care use and the associated costs of
cancer change over time. As noted earlier, and consistent with the
$18,000
$16,000
$14,000
$12,000 36 Month Survival
$10,000
48 Month Survival
$8,000
60 Month Survival
$6,000
72 Month Survival
$4,000
$2,000 84 Month Survival
$0
0 12 24 36 48 60 72 84 96
96 Month Survival
Month After Diagnosis
Figure 10–2.  Monthly Medicare payments for colorectal cancer patients
by length of survival. Source: Yabroff KR, Warren JL, Schrag D, Mariotto
M, Meekins A, Topor M, Brown ML. Comparison of approaches for esti-
mating incidence costs of care for colorectal cancer patients. Med Care.
2009 Jul;47(7 Suppl 1):S56-​63. doi: 10.1097/​MLR.0b013e3181a4f482.
PubMed PMID: 19536010.
intensity of treatment for initial care, recurrence, and end-​of-​life
care, cancer costs are highest in the initial period following diagnosis
and, among patients who die from their disease, at the end of life
(Brown et al., 2002; Fireman et al., 1997; Riley et al., 1995; Taplin
et al., 1996; Yabroff et al., 2007, 2008b, 2009). Costs are lowest in
the period between the initial and end-​of-​life periods, following a U-​
shaped curve. As shown in Figure 10–2, this U-​shaped medical care
cost pattern is consistent across cohorts of cancer patients with very
different survival times following diagnosis (Yabroff et  al., 2009).
The width and height of this U-​shaped cost curve vary by cancer site,
stage at diagnosis, and patient age (Brown et al., 2002; Riley et al.,
1995; Taplin et al., 1996; Yabroff et al., 2007, 2008b, 2009). All of
these factors affect summary measures of costs and inform the meth-
ods used to estimate these costs.
INCIDENCE AND PREVALENCE CANCER COSTS
Direct, indirect, and intangible cancer costs are typically reported
starting at diagnosis for a group of cancer patients defined by clini-
cal characteristics (incidence costs), or for all cancer survivors alive
in a specific year (prevalence costs). An incidence cost estimate in
2015 will include only those patients diagnosed within this year, and
costs will begin accumulating at the high-​cost diagnosis period for all
patients. Incidence cost estimates can range from periods of less than
1 year to a lifetime (for patients diagnosed in 2015 in this example).
A  prevalence cost estimate in 2015 will include all cancer patients
alive at any point during the year, but will only include the portion
of the cost trajectory that occurs during 2015. Prevalence cost esti-
mates are typically reported as annual estimates or for a particular
year. Importantly, the high-​and low-​cost portions of the U-​shaped
curve included in the prevalence cost estimate will vary by cancer
site. For example, because long-​term survival following breast and
prostate cancer diagnosis is high, in any given year, the majority of
breast and prostate cancer survivors will be in the low-​cost bottom of
the U-​shaped curve. In contrast, because survival following pancre-
atic cancer diagnosis is generally poor, in any given year the majority
of pancreatic cancer survivors will be in the high-​cost period follow-
ing diagnosis or at the end-​of-​life, the arms of the “U.” As with other
measures of disease burden, per capita incidence and prevalence cost
estimates in a given year will be relatively similar when survival is
short, because the vast majority of individuals will have high costs
in either arm of the “U,” with few individuals with low costs at the
bottom of the “U” (e.g., pancreatic cancer). For cancers with long sur-
vival (e.g., breast and prostate cancers), per-​capita prevalence costs
172
172 PART II:  THE MAGNITUDE OF CANCER
in a given year will be significantly lower than per-​capita incidence
costs in that year, because the prevalence cost estimate will be pre-
dominantly composed of survivors at the bottom of the “U,” where
costs are lowest. Both incidence and prevalence cost measures can
be useful for resource allocation and policy and program planning.
Incidence costs are commonly used in cost-​effectiveness models, for
decisions about specific therapies or understanding patient and treat-
ment trajectories, whereas prevalence costs are most commonly used
in understanding the overall impact of disease on local, federal, or
health plan budgets.
APPROACHES FOR ESTIMATING CANCER COSTS
Several approaches are commonly used for estimating incidence and
prevalence cancer costs. As with other measures of disease burden,
cohort studies, both retrospective and prospective, can be used for esti-
mating incidence costs. Cross-​sectional data can be used for estimating
prevalence costs, although in some situations, such as the use of billing
records (without linkage to cancer registry data), the prevalence esti-
mate will reflect “treated prevalence,” rather than prevalence cost mea-
sured from all cancer survivors alive in a specific year. Only patients
receiving treatment in a specific year can be identified from claims for
cancer treatment. Other approaches for estimating incidence and prev-
alence costs include modeling or microsimulation. This approach is
typically based on well-​defined hypothetical cohorts of cancer patients
in a natural history of disease model where the probability of medical
events (e.g., hospitalizations for a side effect of treatment) is combined
with cost estimates for each of the medical events (e.g., average hospi-
talization cost for patients with that side effect of treatment).
Another approach, the phase of care approach, uses the U-​shaped
cost pattern described in Figure 10–2 to divide healthcare services,
costs, and observation time for cancer patients into clinically rel-
evant periods or phases in relation to the date of diagnosis and the
date of death. Three phases, corresponding to the arms of the “U”
and the bottom of the “U” (i.e., initial, last year of life, and continu-
ing phases, respectively), have been commonly used. Phase-​specific
estimates can then be used as an input to estimate either incidence or
prevalence costs. Phase-​specific cost estimates can be combined with
survival probabilities following diagnosis to yield modeled incidence
costs (Yabroff et al., 2009) or with phase-​specific cancer prevalence
estimates in a given year to produce prevalence costs for that year
(Mariotto et  al., 2011). The phase-​of-​care approach is a more effi-
cient use of data than a cohort approach because patients can con-
tribute to multiple phases and this can lead to more robust estimates,
particularly for less common cancer sites.
WHAT ARE SOME RECENT ESTIMATES OF
THE COSTS OF CANCER CARE?
In this section, we present recent estimates of the direct medical costs
of cancer and report both incidence and prevalence cost estimates. We
also present estimates of indirect costs of cancer, including annual pro-
ductivity losses due to employment disability, missed workdays, and
lost household productivity, and mortality costs associated with early
death from cancer.
Estimates of Direct Medical Costs
A number of studies have estimated the direct medical costs associ-
ated with cancer (Bernard et  al., 2011; Ekwueme et  al., 2011; Guy
et al., 2013, 2014; Howard et al., 2004; Mariotto et al., 2011; Short
et al., 2011). These studies include estimates of incidence costs among
the newly diagnosed and annual prevalence costs among all cancer
patients alive in a given year.
Incidence Cost Estimates
Costs associated with cancer for newly diagnosed elderly patients in
the first year following diagnosis range from a little more than $10,000
per person for breast and prostate cancer in women and men, respec-
tively, to more than $25,000 per person for colorectal, lung, and pan-
creas cancers (in 2004 dollars; Yabroff et  al., 2008b; Figures 10–3a
and 10–3b). Differences in 1-​year incidence costs by cancer site reflect
differences in the distribution of stage of disease at diagnosis, survival
following diagnosis, and treatment intensity, especially for hospital-
izations, by cancer site. The majority of breast and prostate cancer
patients are diagnosed with early stage disease, have long survival,
and do not require extensive hospitalization, whereas the majority
of lung and pancreatic cancer patients are diagnosed with advanced
disease and have relatively short survival, often requiring extensive
hospitalization.
These per-​person incidence estimates can be applied to national
estimates of the number of newly diagnosed elderly cancer patients
to generate a national incidence cost estimate for a specific year.
Even though the per-​ person 1-​ year estimates of the incidence
costs for pancreas cancer are among the highest ($29,814 in men
and $30,357 in women), approximately 21,000 elderly patients
were diagnosed with pancreatic cancer in 2004, yielding a national
1-​year incidence cost estimate of $642 million. On the other hand,
the per-​person costs associated with female breast cancer and pros-
tate cancer are relatively low ($11,748 and $10,626), but more than
77,000 elderly female breast cancer patients and 118,000 elderly
prostate cancer patients were diagnosed in 2004, yielding much
larger national 1-​year incidence cost estimates of $905 million and
$1,254 million, respectively.
Prevalence Cost Estimates
Several studies have reported prevalence costs for cancer survivors
(Bernard et  al., 2011; Guy et  al., 2013, 2014; Howard et  al., 2004;
Short et al., 2011). Mean annual direct medical costs have been con-
sistently reported to be greater for cancer survivors than for individu-
als without a history of cancer (Bernard et al., 2011; Guy et al., 2013,
2014; Howard et al., 2004; Short et al., 2011). In addition, as shown
in Figure 10–4, mean annual prevalence costs for the recently diag-
nosed are greater than for the previously diagnosed and individuals
without a cancer history in those aged 18–​64 years and 65+ years (Guy
et al., 2013). Mean annual prevalence costs are higher for the older age
group than in the younger age group, reflecting greater comorbidity
burden and healthcare utilization in those ages 65+, for individuals
with and without cancer.
The distribution of costs by type of medical care service also var-
ies between cancer survivors and individuals without a cancer his-
tory (Guy et al., 2013). Among those aged 18–​64 years, ambulatory
care and inpatient care are the most common services for recently
diagnosed cancer survivors (46.2% and 40.5%, respectively), with
prescription medications contributing only a small portion of costs
(8.1%). For previously diagnosed cancer survivors aged 18–​64, pre-
scription medications contribute a larger portion of costs (18.9%);
and for individuals without a cancer history, the contribution of ambu-
latory care (33.9%), inpatient care (27.4%), and prescription medica-
tions (22.6%) are more similar. The distribution of costs by service
type is similar for the older age group, with ambulatory and inpa-
tient care the most common service category in recently diagnosed
cancer survivors (41.2% and 41.9%, respectively); prescriptions are a
larger portion for the previously diagnosed (18.9%), and ambulatory
care (25.9%), inpatient care (34.3%), and prescription medications
(24.3%) have similar distributions for those without a cancer history.
The distribution of direct medical costs by payer type is quite
different between individuals aged 18–​ 64  years and 65+ years
(Figures 10–5a and 10–5b). In the younger group with and without
cancer, private health insurance is the predominant payer for medi-
cal care, whereas in the older group, the Medicare program is the
predominant payer.
A study using the phase-​of-​care approach to estimate national prev-
alence costs in the United States reported costs associated with cancer
of $124.6 billion dollars (in 2010 dollars) (Mariotto et al., 2011). The
highest costs were for female breast ($16.5 billion), colorectal ($14.1
billion), lymphoma ($12.1 billion), lung ($12.1 billion) and pros-
tate ($11.9 billion) cancers, reflecting the absolute number of cancer
 173

The Economic Burden of Cancer in the United States 173

(a)
Bladder $14,313

Breast $11,748

Colorectal $25,903

Corpus uteri $16,485

Head and Neck $22,633

Kidney $23,836

Liver $25,398

Lung $26,764

Pancreas $30,557

$0 $5,000 $10,000 $15,000 $20,000 $25,000 $30,000 $35,000

(b)
Bladder $13,466

Colorectal $25,711

Head and Neck $21,052

Kidney $23,920

Figure 10–3.  (a) Direct medical costs in year

Liver $24,086
following diagnosis, by cancer site in elderly
female patients. (b) Direct medical costs in
Lung $26,449 year following diagnosis, by cancer site in
elderly male patients. Note: Calculations
made using the linked SEER-​Medicare data,
Pancreas $29,814 1999–​2003. Estimates are the net estimates
based on controls. Source:  Yabroff KR,
Lamont EB, Mariotto A, Warren JL, Meekins
Prostate $10,626 A, Topor M, Brown ML. 2008. Cost of care
for elderly cancer patients in the United
$0 $5,000 $10,000 $15,000 $20,000 $25,000 $30,000 $35,000 States. J Natl Cancer Inst, 100, 630–​641.

survivors by phases of care and phase-​specific cost estimates by cancer
site. A larger proportion of prevalence costs occurred in the continu-
ing phase of care for cancers with longer survival, such as breast and
prostate cancers, than for those with short survival, such as lung and
pancreas cancers.
Indirect Costs
To date, the majority of studies estimating indirect costs associated
with cancer have reported prevalence estimates. These studies have
mainly reported productivity losses from employment disability
(being unable to work due to health), missed worked days among the
employed, and lost household productivity (Guy et  al., 2013, 2014)
or mortality costs associated with premature death due to cancer
(Bradley et al., 2008; Ekwueme et al., 2008; Li et al., 2010; Yabroff
et  al., 2008a). As shown in Figures 10–6a and 10–6b, total per-​per-
son productivity losses are highest among recently diagnosed cancer
survivors aged 18–​64 ($4,694 in 2010 US dollars) and 65+ ($6,133 in
2010 US dollars), compared with the previously diagnosed, and indi-
viduals without a cancer history. As shown in Figure 10–7, per-​person
productivity losses are higher for male and female cancer survivors
($3,719 and $4,033 in 2011 US dollars, respectively) than for males
and females without a cancer history ($2,260 and $2,703 in 2011 US
dollars, respectively) (Ekwueme et al., 2014). For all groups, employ-
ment disability is the largest component of productivity loss, followed
by missed workdays and lost household productivity.
A number of studies have estimated mortality costs and the pro-
ductivity losses associated with premature death due to cancer
(Bradley et al., 2008; Ekwueme et al., 2008; Li et al., 2010; Yabroff
et al., 2008a). Table 10–2 lists the number of cancer deaths in 2005,
person-​years of life lost (PYLL), and present value of lifetime earn-
ings by cancer site, using the human capital approach for valuing the
PYLLs (Bradley et  al., 2008). Because this approach uses gender-​
and age-​specific earnings to value the years with unrealized earnings,
cancers that affect individuals with lower earnings potential will have
less productivity loss than cancers that affect individuals with higher
earnings potential. For example, the majority of men who die from
prostate cancer are ages 65 and older, an age when most are retired
and would not otherwise be earning wages from work in the future.
Although the number of prostate cancer deaths is higher than the
number of pancreas cancer deaths, the PYLL is lower, and the pres-
ent value of lifetime earnings is lower ($3.3 billion vs. $6.6 billion).
174

Recently diagnosed $17,170

Ages 18–64
Previously diagnosed $6,485

No cancer history $3,611

Recently diagnosed $23,441

Ages 65+ Previously diagnosed $12,357

No cancer history $8,724

$0 $5,000 $10,000 $15,000 $20,000 $25,000

Figure 10–4.  Mean annual direct medical costs in cancer survivors and individuals without a cancer history. Notes: Calculations using the Medical Expenditure
Panel Survey–​Household Component, 2008–​2010. Estimates are predicted margins from a generalized linear regression model with a gamma distribution
and a log link controlling for age, sex, race/​ethnicity, and number of comorbid conditions. All monetary amounts are in 2010 dollars. Source: Guy GP Jr,
Ekwueme DU, Yabroff KR, et al. 2013. The economic burden of cancer survivorship among adults in the United States. J Clin Oncol, 31(30), 3749–3757. PMCID:
PMC3795887.

(a) Recently diagnosed cancer survivors No cancer history

7.3% 6.1% 9.8%

16.9%
17.1% Out-of-pocket 10.6%

Private health insurance

Medicare 8.2%
2.8%
Medicaid
Other
66.7% 54.6%

$17,170 (95% Cl: $13,433, $20,907) $3,611 (95% Cl: $3,486, $3,736)

(b) Recently diagnosed cancer survivors No cancer history

1.1% 10% 6.9% 8.7%

13.9%
4.4%
11.3%
Out-of-pocket
Private health insurance 13.1%
Medicare
Medicaid
Other
70.7%
59.9%

$23,441 (95% Cl: $18,367, $28,514) $8,724 (95% Cl: $8,302, $9,147)

Figure 10–5.  (a) Annual medical expenditures by payer type, for individuals aged 18–​64 years. (b) Annual medical expenditures by payer type, for individu-
als aged 65+ years. Notes: Calculations using the Medical Expenditure Panel Survey–​Household Component, 2008–​2010. Estimates are predicted margins
from a generalized linear regression model with a gamma distribution and a log link controlling for age, sex, race/​ethnicity, and number of comorbid con-
ditions. All monetary amounts are in 2010 dollars. Source: Guy GP Jr, Ekwueme DU, Yabroff KR, Dowling EC, Li C, Rodriguez J, DeMoor J, Virgo K.
2013. The economic burden of cancer survivorship in the United States. J Clin Oncol, 31(30), 3749–​3757.
 175

The Economic Burden of Cancer in the United States 175

(a) $7,000 $5,000 Employment disability
Employment disability
Missed work days
$6,000 Missed work days
Lost household productivity
Lost household productivity $4,000
$5,000
US dollars

$4,000 $3,000

US dollars
$2,664 $2,961
$3,000 $2,831
$2,000
$2,833 $2,109
$2,000
$1,862
$1,644 $1,585
$1,000 $1,000
$447 $686
$321 $597
$386 $313 $134 $933 $267
$0 $386 $291
$0 $201 $131
Recently Previously No cancer
diagnosed diagnosed history Cancer No cancer Cancer No cancer
cancer survivors cancer survivors history history history history
Women Men

Employment disability
(b) $7,000 Figure 10–7. Annual lost productivity among cancer survivors and indi-
Missed work days
viduals without a cancer history. Notes: Calculations using the Medical
$6,000 Lost household productivity Expenditure Panel Survey–​Household Component, 2008–​ 2011. All mon-
etary amounts are in 2010 dollars. Source: Ekwueme DU, Yabroff KR, Guy
$5,000 GP Jr, et  al. 2014. Medical costs and produc­tivity losses of cancer survivors:
United States, 2008–2011. MMWR Morb Mortal Wkly Rep, 63 (23), 505–510.
US dollars

$4,000 $4,350 PMID: 24918485.

$3,000 $4,485 of cancer are listed in Table 10–3, including the Healthcare Costs and
$3,777 Utilization Program (H​CUP) discharge data, the linked Surveillance
$2,000 Epidemiology and End Results cancer registry–​ Medicare insurance
claims data (SEER-​Medicare), the Medical Expenditure Panel Survey
$1,000 $1,109 (MEPS), and the Medicare Current Beneficiary Survey (MCBS).
$428 $331 Features of these data sources are described in the following, including
$676 $382 $301
$0 population coverage, patient characteristics, information about cancer
Recently Previously No cancer diagnosis, and the availability of information about the burden of cancer,
diagnosed diagnosed history including direct, indirect, and intangible costs. We also discuss whether
cancer survivors cancer survivors these data sources can be used to estimate incidence and prevalence
costs associated with cancer.
Figure 10–6. (a) Annual lost productivity among cancer survivors and
individuals without a cancer history, aged 18–​64 years. (b) Annual lost
productivity among cancer survivors and individuals without a cancer his- Table 10–2.  Lost Productivity Due to Cancer Deaths in the US Among
tory, aged 65+ years. Notes: Calculations using the Medical Expenditure Adults Aged 20 Years and Older by Cancer Site (2005)
Panel Survey–​House­hold Component, 2008–​2010. All monetary amounts are
Number Person-​Years Present Value of
in 2010 dollars. Source: Guy GP Jr, Ekwueme DU, Yabroff KR, Dowling of Deaths of Life Lost Lifetime Earnings
EC, Li C, Rodriguez J, DeMoor J, Virgo K. 2013. The economic burden of in 2005 (in thousands) (in billions of dollars)
cancer survivorship in the United States. J Clin Oncol, 31(30), 3749–​3757.
Lung and bronchus 166,755 2569.8 $36.131
Other approaches to value the PYLL, such as the willingness-​to-​pay Female breast 44,546 874.0 $12.096
approach, incorporate both lost productivity and the intrinsic value Colon and rectum 61,240 861.4 $10.652
of life and place an equivalent value on all years of life. Estimates Pancreas 32,054 472.5 $6.610
of the value of life lost for prostate cancer are substantially higher Brain and other nervous 13,607 314.2 $5.743
system
when the willingness-​to-​pay approach is used to value the PYLL
Leukemia 22,945 390.1 $5.722
(Yabroff et al., 2008a) than a human capital approach because older
Non-​Hodgkin’s 23,850 362.3 $5.511
men dying of prostate cancer have lower earnings potential. lymphoma
The direct medical cost and indirect cost estimates presented in this Liver and intrahepatic 14,502 242.8 $4.420
section were calculated from a variety of existing data sources. In the bile duct
next section, we describe common data sources for estimating eco- Kidney and renal pelvis 12,819 206.2 $3.424
nomic burden of cancer in the United States in more detail. Head and neck 10,830 181.4 $3.413
Prostate 33,642 300.5 $3.301
WHAT DATA SOURCES ARE USED FOR ESTIMATING Stomach 13,351 201.3 $3.225
THE ECONOMIC BURDEN OF CANCER? Melanoma of the skin 8062 155.1 $3.194
Ovary 15,253 274.5 $2.824
In this section, we discuss different types of data commonly used for Cervix uteri 4338 114.9 $1.827
estimating the economic burden of cancer in the United States, includ- Urinary bladder 13,275 150.5 $1.826
ing hospital discharge data, health insurance claims, and household sur- Hodgkin lymphoma 1414 36.4 $0.833
veys (Lund et al., 2009; Yabroff et al., 2011). Selected publicly available
data sources that are commonly used to estimate aspects of the burden Source: Bradley et al., 2008.
176

176 PART II:  THE MAGNITUDE OF CANCER

Table 10–3.  Characteristics of Selected Publicly Available Data Sources/​Research Resources in the US for Estimating Economic Burden of Cancer

SEER-​Medicare MEPS H​CUP MCBS

Nationally Representative
SEER Tumor Registries Linked In-​Person Survey with Inpatient Discharge Data National Survey Linked
Description to Medicare Claims Provider Data Collection from Sampled Hospitals to Medicare Claims

DATA CHARACTERISTICS
National or nationally representative Geographically defined √ √ √
Individual-​level longitudinal data √ 5 panels over 2 years √
Approximate number of cancer > 1,000,000 < 2000 > 1,000,000 < 2000
survivors in 2015
Duration of information Medicare eligibility through 2 years Hospital admission through
death discharge
Health insurance type Medicare fee-​for-​service only All payers All payers All payers
PATIENT INFORMATION
Age distribution Aged 65+ or disabled (any age) Aged 18+ All ages Aged 65+ or disabled
(any age)
Information about patients without cancer In cancer registry regions √ √ √
CANCER INFORMATION
Cancer diagnosis Registry, procedure or diagnosis Self-​report, procedure or Procedure or diagnosis codes Self-​report, procedure or
codes diagnosis codes diagnosis codes
Stage at diagnosis √
Treatment √ √ Inpatient hospital only √
TYPE OF COST ESTIMATE
Incidence √
Prevalence in a specific year √ √ √ √
COST DOMAINS
Direct Medical Cost Components
Hospital √ √ √ √
Physician and other outpatient services √ √ √
Outpatient pharmacy √* √ √*
Out of pocket √ √
Indirect Cost Components
Productivity loss (e.g., days lost √
from work)
Patient time √
Caregiver time
Intangible costs √ √

*Data on Medicare Part D prescription drug services are available starting in 2006. Before 2006, drugs administered parenterally, and their administration was covered by Medicare Part B,
as were Prodrugs, the oral drug equivalent of drugs administered parenterally.
SEER-​Medicare = Surveillance Epidemiology and End Results–​Medicare; MEPS = Medical Expenditure Panel Survey; H-​CUP = Healthcare Costs and Utilization Program;
MCBS = Medicare Current Beneficiary Survey.

Healthcare Costs and Utilization Project (HCUP)
The HCUP is a family of national and state healthcare databases and
tools sponsored by the Agency for Healthcare Quality and Research, and
includes the National (Nationwide) Inpatient Sample (NIS) and State
Inpatient Databases (SID), Nationwide Emergency Department Sample
and State Emergency Department Databases, and State Ambulatory Care
Databases. The NIS and SID include medical care use and associated
costs for individuals of all ages with all types of health insurance, but
for only one aspect of medical care, inpatient hospitalizations (Agency
for Healthcare Research and Quality, 2016). These NIS data have been
available every year since 1988. The unit of observation is the hospitali-
zation rather than the individual patient, so multiple hospitalizations for
the same person are unique observations in the NIS and cannot be linked
at the individual level to provide longitudinal information about care.
In some states, linkage for multiple hospitalizations and across HCUP
databases is available, although these data have not been commonly
used to estimate cancer burden. Although millions of cancer survivors
can be identified in the NIS by diagnosis and procedure codes, informa-
tion about date of diagnosis, stage, additional cancers, pre-​hospitaliza-
tion comorbidity, and other factors that influence patient eligibility for
specific treatments is not available. Further, information about cancer
survivors treated outside the hospital inpatient setting is unavailable in
the NIS. The NIS has been mainly used to estimate the use and costs of
surgery among hospitalized cancer survivors (Newton and Ewer, 2010;
Seifeldin and Hantsch, 1999). Because information about the date of
cancer diagnosis is not available, the estimates from the NIS are prev-
alence estimates. Although the number of hospital days can be used to
identify patient time in the hospital, these data have rarely been used for
estimating any types of costs other than direct medical costs.
Linked SEER-​Medicare Data
The linked SEER-​Medicare data are made available by the National
Cancer Institute and contain longitudinal information about medical
care and associated payments received before, during, and after cancer
diagnosis for Medicare beneficiaries (Warren et al., 2002). Information
about cancer diagnoses is available for the years that each geographi-
cally defined registry has been part of the SEER program, starting in
1973. Medicare claims since 1991 are available for two cohorts of ben-
eficiaries included in the SEER-​Medicare data: cancer survivors and a
sample of Medicare beneficiaries residing in the SEER areas who do
not have cancer. Because more than 95% of individuals over the age
of 65 in the United States are enrolled in the Medicare program, and
SEER registries currently cover approximately 26% of the US popu-
lation, these data contain information about cancer care for a large
 17
The Economic Burden of Cancer in the United States 177
portion of the elderly in the United States. More than 3 million cancer
survivors can be identified from SEER-​Medicare with detailed infor-
mation about cancer stage, grade, and histology for each diagnosis.
Identification of incident cancer patients and patients with multiple
cancers are additional strengths of the linkage of health insurance pro-
gram data with cancer registry data.
As with other health insurance program data (also known as admin-
istrative data), Medicare claims do not contain any information about
individuals without health insurance or the utilization and costs of spe-
cific services covered by other insurance programs or those services paid
entirely out of pocket. Medicare payments represent approximately 51%–​
65% of all direct medical care costs in the elderly (Crystal et al., 2000;
Guy et  al., 2013), with the remaining costs covered by other insurers
or by out-​of-​pocket payments. These linked SEER-​Medicare data have
been used extensively to estimate the incidence and prevalence costs of
medical care associated with cancer in the elderly (Mariotto et al., 2011;
Warren et al., 2008). Additionally, the costs associated with patient time
have been estimated from patients’ medical service frequencies (e.g.,
hospital length of stay, physician visits, chemotherapy), combined with
average service-​specific time estimates (Yabroff et al., 2007). Notably,
the linked SEER-​Medicare data cannot be used to estimate costs associ-
ated with cancer care in the working-​age population under the age of 65
(who are only eligible for Medicare in limited situations), and informa-
tion about employment and health status is unavailable.
Medical Expenditure Panel Survey
The Medical Expenditure Panel Survey (MEPS) is an annual nation-
ally representative household survey conducted by the Agency for
Healthcare Research and Quality (AHRQ) (Cohen et al., 2009). The
MEPS was first fielded in 1996 and consists of three surveys:  the
Household Component (HC), the Medical Provider Component, and
the Insurance Component. The MEPS-​ HC collects demographic,
health status, access to medical care, employment, and healthcare uti-
lization and expenditure data for adults of all ages, with all insurance
types (Table 10–3). The MEPS also collects these data for individuals
without health insurance.
The MEPS-​HC uses an overlapping panel design, in which each
panel consists of individuals who are interviewed in person five times
(or rounds) over approximately 2.5  years. Data from two panels are
combined to produce estimates for each calendar year, and each panel
separately produces longitudinal estimates. Through panel 11 in 2007,
cancer survivors were only identified in the MEPS if they received care
for cancer, or missed work or school or spent a day in bed because of
cancer, during the survey period (“treated prevalence”). Only very small
numbers of cancer survivors were identified in a given year during this
period, although multiple years of the MEPS have been combined to
assess economic burden (Howard et al., 2004; Short et al., 2011).
Starting in panel 12 and in 2008, a new question was added for
adults aged 18 years and older about whether a doctor or other health
professional ever told the person that he or she had cancer or a malig-
nancy of any kind. Rather than only identifying the subset of cancer
survivors undergoing cancer treatment at the time of the survey, this
change now results in the identification of all individuals with a history
of cancer, consistent with definitions of cancer survivorship used to
estimate cancer prevalence in the United States (de Moor et al., 2013;
Mariotto et al., 2011). Notably, the question about a cancer diagnosis
is asked for all adults in the family, making the MEPS one of the only
data sources to identify cancer history for the family, and these data
can be used to assess the effects of cancer on a spouse (Litzelman and
Yabroff, 2015). Details about cancer diagnosis, including stage, tumor
characteristics, and other prognostic information, are unavailable.
Several studies have combined multiple years of the MEPS to describe
healthcare utilization and expenditures in cancer survivors receiving
cancer care compared with individuals without cancer (Bernard et al.,
2011; Finkelstein et al., 2009; Guy et al., 2013, 2014; Howard et al.,
2004; Short et al., 2011). These MEPS data have also been used to esti-
mate the costs associated with patient time from medical service fre-
quencies (e.g., hospital length of stay, physician visits, chemotherapy),
combined with average service-​specific time estimates (Yabroff et al.,
2014). Because date of diagnosis is not available, cost estimates from
the MEPS are prevalence cost estimates.
In 2011, the MEPS Experiences with Cancer survey was a self-​
administered questionnaire of adult cancer survivors, containing ques-
tions on financial hardship related to cancer, its treatment, and lasting
and late effects of treatment, such as having to borrow money or go
into debt, being unable to cover medical care costs, worry about pay-
ing medical bills, and other financial sacrifices (Yabroff et al., 2012). It
also included a number of questions related to productivity for cancer
survivors and their caregivers. An updated MEPS Experiences with
Cancer survey of adult cancer survivors is being fielded in 2016.
Medicare Current Beneficiary Survey
The Medicare Current Beneficiary Survey (MCBS) is a longitudinal,
nationally representative survey of Medicare beneficiaries in the United
States conducted by the Centers for Medicare & Medicaid Services.
The MCBS collects information about expenditures and sources of
payment for all services used by Medicare beneficiaries, including
copayments, deductibles, and non-​covered services. In addition, demo-
graphics, health status, access to medical care, and physical functioning
are collected about individuals with all types of health insurance. The
survey is conducted over a 4-​year period, with multiple interviews a
year. The MCBS Cost and Use files link Medicare claims from the pop-
ulation with fee-​for-​service coverage to the survey. Cancer survivors
can be identified based on their response to the question “Have you ever
been told by a doctor or other health professional that you had cancer or
a malignancy of any kind?” or with claims algorithms using diagnosis
codes. The survey can be used to supplement the claims data to explore
out-​of-​pocket spending or use of strategies to reduce the costs of medi-
cations (Davidoff et al., 2013; Nekhlyudov et al., 2011). Cost estimates
from the MCBS are prevalence cost estimates.
Nationally representative surveys such as the MEPS or the MCBS
are limited by small numbers of patients who are newly diagnosed or
diagnosed with cancers associated with short survival (e.g., lung) or
low incidence (e.g., testicular). Details about cancer diagnosis, includ-
ing stage, clinical characteristics and other prognostic information,
and treatment are generally not available. Because questions are not
specific to burden of illness related to cancer (except in the MEPS
Experiences with Cancer survey), these MEPS and MCBS data have
been previously used to assess employment, insurance coverage, access
to care, and health status in cancer survivors compared with individu-
als without a history of cancer (Davidoff et al., 2013; Dowling et al.,
2010; Guy et al., 2013; Nekhlyudov et al., 2011; Yabroff et al., 2004).
As described earlier and as illustrated in Table 10.3, commonly used
publicly available data sources have different strengths and limitations
for estimating the burden of cancer in the United States. No single
data source contains comprehensive longitudinal information for large
numbers of cancer survivors about multiple healthcare services across
insurance type (including the uninsured) in the elderly or in younger
populations. Further, few data sources contain information about indi-
rect costs, including patient and caregiver time costs and lost produc-
tivity due to morbidity (Lund et al., 2009).
WHAT ARE KEY FACTORS RELATED TO THE
MEASUREMENT OF HEALTHCARE COSTS?
There are several key factors that are critical to the measurement of the
economic burden of cancer, including the perspective of the economic
analyses, consideration of current and future costs, and measurement
of cancer-​attributable costs. These issues are defined and discussed in
following sections.
The Frame of Reference or Perspective
The frame of reference of an economic study is the viewpoint from
which the analyses are conducted. As shown in Table 10–4, examples
of perspectives are those of the patient and family, employers, health-
care insurers or payer, including federal and state programs such as
178
178 PART II:  THE MAGNITUDE OF CANCER
Table 10–4.  Perspectives and Relevant Cost Categories
Cost Category Patient and Family
DIRECT COSTS Medical √ Premiums, copayments
and other out-​of-​pocket
Non-​Medical √ Transportation, housekeeping
INDIRECT COSTS Morbidity √ Reduced productivity, time
seeking medical care
Mortality √ Lost productivity
INTANGIBLE/​PSYCHOSOCIAL COSTS √ √
Medicare and Medicaid, and society. Depending on the perspective
of the analysis, the types of costs included, sources of data, and study
design will vary. While the societal perspective is preferred for pur-
poses of economic analysis for general policy analysis, for specific
purposes, such as the impact of new healthcare legislation, it is often
useful to define a frame of reference that is narrower than all of society
(Gold et al., 1996). For example, while the societal perspective may be
the relevant perspective for policy analysis involving approval of an
innovative cancer control intervention, the perspective of the Medicare
program or a health maintenance organization may be relevant for
assessing the financial impact of such a decision on resource require-
ments required to fund these operations.
Not all social costs will be recognized as costs at various organiza-
tional levels. Time lost from paid work for unpaid caregiving by the rel-
atives of the cancer patient is a cost to society in terms of lost economic
productivity and a cost to the family in terms of lost household income,
but it might represent a savings to the Medicare program in terms of a
shorter length of hospital stay or less provision of formal home-​care ser-
vices. As noted previously, the time spent by cancer patients and family
members related to cancer and its treatment is rarely fully accounted for
among existing studies because these data are not collected systemati-
cally. Excluding patient time costs from analyses comparing alternative
interventions (e.g., cost-​effectiveness analyses) may result in favoring
interventions with large patient-​time cost burdens (Russell, 2009).
Discounting
When costs are distributed over time and the purpose of analysis is
to assess these costs relative to an initial investment, such as a can-
cer screening program to promote early detection, economists use an
adjustment known as discounting. The purpose of discounting is to
adjust the value of costs and benefits (savings) incurred in the future
to their present market value because the same resources, if avail-
able and invested today, would yield a return if placed in a productive
activity. In the United States, the most commonly used value in cur-
rent health economics literature is 3% (in real terms—​that is, adjusted
for inflation). Other industrialized countries have used different dis-
count rates, and there is some discussion about what the appropri-
ate discount rate should be from a social viewpoint. The choice of a
discount rate reflects a value judgment: a low discount rate indicates a
long time horizon, and a high discount rate indicates a short time hori-
zon. All else being equal, the use of a high discount rate would tend
to favor investment in a treatment program where benefits would be
realized more rapidly over investment in a prevention program where
ongoing costs are incurred well in advance of the realization of any
benefits.
Adjusting for Inflation
It is often useful to express the cost of cancer in current-​year dollars.
Because the rate of inflation for the price of healthcare services has
consistently been higher than the rate for the economy as a whole, it
Perspective
Employer Health Insurer/​Payer Society
√ Premiums √ Payments for services √
√
√ Reduced productivity, presentism, √
absenteeism, disability payments,
replacement costs
√
is necessary to use a price index specific to this sector of the economy.
Direct medical cost estimates using multiple years of data (e.g., 2008–​
2011) are typically inflated using a price index to the latest year of data
and reported for that year (e.g., in 2011 US dollars). The healthcare
component of the Consumer Price Index (CPI) is often used for this
purpose. This index, however, refers only to the components of health-
care expenditures paid for directly by consumers. Other prices indices
are used in other settings, such as the Personal Health Care Expenditure
Price Index or indices that are designed to reflect healthcare price infla-
tion as experienced by the Medicare program (Agency for Healthcare
Research and Quality, 2015a). Note that adjustments for inflation and
the discounting of future costs and benefits are distinct and unrelated
issues.
Charges, Reimbursements, Expenditures, and Costs
The economic concept of cost relates to the use of specific resources
in an efficient manner. Direct observation of resource use is rarely
available, however. Reflections of cost are available, such as the
amount billed, charged, or reimbursed for the provision of healthcare
services. The amount billed or charged may not reflect the actual cost
associated with providing healthcare services, however, and may have
little relationship to underlying costs (Finkler, 1982). For example,
some hospitals or other providers may negotiate with health plans
for reduced payments for specific patients. Here, the actual “cost”
of the service may be unrelated to the amount charged to any of
the purchasers. When using claims data, researchers frequently use
payments to reflect costs, rather than charges (Yabroff et al., 2013).
Charges may also be converted into costs using “cost-​to-​charge”
ratios (Agency for Healthcare Research and Quality, 2015b).
Measurement of Costs Attributable to Cancer
There are two general approaches to estimating the costs attributable
to cancer:  estimating costs for specific events assumed to be cancer-​
related, and comparing costs of all care for cancer patients to other
individuals without a cancer history. In the first approach, research-
ers classify specific costs as being due to cancer or not. This approach
can be used in observational studies and is more frequently used in
microsimulation modeling, where treatment scenarios are developed as
a series of probabilistic events for a well-​defined, hypothetical popula-
tion of cancer patients. The cost of medical services and procedures
defined by the scenario can then be estimated using a cost estimate from
another data source. This approach may underestimate the frequency of
services that cancer patients receive for seemingly unrelated care.
In the second approach, researchers measure attributable costs of
cancer care by comparing the costs of all care for cancer patients or
survivors to those of non-​cancer patients or patients without a cancer
history. The difference is a net cost. The comparison can match cancer
patients and individuals without a cancer history by relevant character-
istics, such as age, gender, geographic region, and comorbidity status,
or can control for these characteristics with multivariable analyses.
 179
The Economic Burden of Cancer in the United States 179
This approach is particularly advantageous when using administra-
tive data because it minimizes reliance on diagnostic and procedure
codes for identifying services as cancer-​related or not. In some situ-
ations, such as the estimation of costs associated with lung cancer,
this approach may overstate services as attributable to cancer that are
more common among lung cancer patients. For example, emphysema
is more common among smokers who are also more likely to develop
lung cancer. Costs associated with emphysema care would also be
included in any net cost of lung cancer.
WHAT ARE EMERGING ISSUES IN THE ECONOMIC
BURDEN OF CANCER IN THE UNITED STATES?
In this section, we discuss several emerging issues related to the eco-
nomic burden of cancer in the United States, including precision medi-
cine and financial hardship associated with cancer care.
Precision Medicine
The average cost of newly developed cancer treatments, primarily tar-
geted therapies used in precision medicine, has risen dramatically over
the past decades (Bach, 2009; Schrag, 2004), and many have price tags of
more than $10,000 per month. Advances in the identification of genetic
mutations associated with treatment response allow the tailoring of treat-
ment to individual patients. Limiting the use of expensive therapies to
patients with genetic profiles associated with treatment response has the
potential to reduce the program costs of these treatments. For example,
colorectal cancer patients carrying KRAS mutations do not respond to
treatment with cetuximab or panitumumab (Amado et al., 2008), and by
restricting the use of cetuximab to patients without the KRAS mutations,
the incremental cost-​effectiveness ratio is more favorable (Mittmann
et al., 2009). However, because the goal of precision medicine is to iden-
tify patients most likely to respond to targeted therapies, all potentially
eligible patients must be tested, including those for whom treatment
will not ultimately be indicated. Finally, the increase in median survival
attributed to treatment with many of these targeted therapies, even among
those most likely to respond, is typically only a few additional months
(Fojo et  al., 2014). Currently, little is known about the utilization and
effectiveness of precision medicine therapies in community practice.
Important areas for future research include estimating and projecting
their uptake, patterns of care, and cost; the appropriate use of genetic tests
to personalize therapy; and the impact on patient morbidity and survival.
Financial Hardship Associated with Cancer
The use of precision medicine highlights an increasingly important
issue—​out-​of-​pocket costs and financial hardship to patients and their
families. Because most health insurance plans require some form
of cost-​sharing for oral drug therapy (20% co-​insurance is typical),
patients and their families with health insurance may face bills of
tens of thousands of dollars for a full course of treatment. The costs
of cancer care will present additional challenges to cancer survivors
without health insurance because they may responsible for the entire
treatment cost. Patients may delay treatment or may fail to seek care
because of high patient cost-​sharing or financial hardship (Kent et al.,
2013; Weaver et al., 2010). Treatment adherence is also poorer among
cancer survivors with financial hardship or higher out-​of-​pocket costs
(Dusetzina et al., 2014; Neugut et al., 2011). A national study estimated
that more than 2 million cancer survivors in the United States did not
receive needed medical services because of cost (Weaver et al., 2010).
Because health insurance in the United States is predominantly
employment-​ based in the working-​ age population, its relationship
with the economic burden of cancer survivorship is complex. A can-
cer diagnosis may limit employment opportunities, which in turn may
lead to a loss of health insurance and fewer resources for paying for
medical care, further magnifying financial hardships associated with
cancer. Cancer survivors are at risk of medical debt and bankruptcy
(Banegas et  al., 2016; Ramsey et  al., 2013; Yabroff et  al., 2016), as
well as psychological aspects of financial hardship, including stress,
anxiety, and worry about their financial situation (Meneses et  al.,
2012; Yabroff et al., 2016). Among working-​age cancer survivors, one
in four report ever having any material financial hardship (i.e., medical
debt, bankruptcy, trouble paying medical bills) and one in three report
psychological financial hardship (Yabroff et al., 2016).
Informal caregiving may also influence employment opportunities for
caregivers, potentially limiting a caregiver’s ability to hold a full-​time
position or resulting in higher rates of absenteeism, particularly when
the patient travels long distances for specialized care. Alternatively,
maintaining health insurance coverage may lead cancer survivors or
their employed family caregivers to work longer hours (Bradley et al.,
2002; Hollenbeak et al., 2012) or to continue working (Bradley et al.,
2007)  and delay retirement. Evaluation of financial hardship and
employment and health insurance trajectories in cancer survivors and
their families will be an important area for additional research, particu-
larly in relation to changes in health insurance status that may occur
with ongoing implementation of the Affordable Care Act.
As the prevalence of cancer survivorship increases in the United
States, the economic burden of cancer will increase as well. Thus,
estimating and projecting the economic burden of cancer, including
healthcare expenditures and productivity losses for patients and their
families, are increasingly important issues for healthcare policymak-
ers, healthcare systems, physicians, employers, and society overall.
Efforts to ensure the comprehensiveness and quality of data resources
for estimating the economic burden of cancer, particularly indirect
costs, are ongoing. Emerging areas for future research include evalu-
ating the use, effectiveness, and consequences of targeted therapies,
and financial hardship for patients and their families. This work
will inform efforts by healthcare policymakers, healthcare systems,
and employers to improve the cancer survivorship experience in the
United States.
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182
 183

III
THE CAUSES OF CANCER
 185
11 Tobacco
MICHAEL J. THUN AND NEAL D. FREEDMAN
OVERVIEW
Tobacco is the leading preventable cause of cancer and other non-​com-
municable diseases worldwide. The International Agency for Research
on Cancer (IARC) and the US Surgeon General designate over 20 can-
cer sites or subsites as causally related to active cigarette smoking,
including lung, oral cavity, nasal cavity, and accessory sinuses, naso-​,
oro-​, and hypopharynx, larynx, esophagus (squamous cell carcinoma
and adenocarcinoma), stomach, pancreas, colorectum, liver, kidney
(adeno-​and urothelial carcinomas), ureter, urinary bladder, uterine
cervix, ovary (mucinous), and acute myeloid leukemia. Even this list
may be incomplete, as it does not include sites for which the evidence
is still considered limited, such as advanced prostate cancer and breast
cancer. In addition to cigarettes, all other forms of smoked and conven-
tional smokeless tobacco products, as well as involuntary exposure to
tobacco smoke, cause cancer.
Trends in tobacco use and tobacco-​related diseases are complex.
Despite progress in decreasing smoking prevalence in many countries,
the number of smokers worldwide is projected to increase from 1.3
billion in 2010 to 1.7 billion by 2025, with much of the growth occur-
ring in low-​to middle-​income countries. Population-​based surveys
have only recently begun to monitor patterns of tobacco use in many
countries. In high-​income countries, lung cancer risk has continued to
increase among cigarette smokers for decades after the initial decline
in smoking prevalence, due to birth cohort patterns in age at initiation
of smoking as well as intensity. The histologic distribution of lung
cancers has also changed in many countries, because of changes in
the design and composition of cigarettes. The use of multiple tobacco
products continues to complicate tobacco control, as does the increas-
ing use of novel products such as e-​cigarettes that have created chal-
lenges for regulators and have divided the public health community.
INTRODUCTION
Tobacco use is the largest single recognized cause of cancer and other
non-​communicable diseases worldwide. Prolonged cigarette smoking
is estimated to cause premature death in one of every two smokers (Peto
et al., 1992). Cigarette smoking alone has been estimated to account
for about 30% of all cancer deaths in the United States since the early
1980s (Doll and Peto, 1981; Jacobs et  al., 2015; US Department of
Health and Human Services, 2004); smoking causes even more deaths
from non-​ malignant cardiovascular and respiratory diseases than
from cancer (US Department of Health and Human Services, 2014).
Despite reductions in smoking prevalence and consumption in many
countries, the global burden of cancer and other diseases caused by
tobacco use is increasing rapidly because massive numbers of young
smokers in highly populous low-​and middle-​income countries are
now surviving into the ages where cancer becomes common. Tobacco
use caused an estimated 100 million deaths in the twentieth century
(Peto et  al., 2015). If current smoking patterns persist, the growing
toll is expected to exceed one billion deaths in the twenty-​first century
(Jha et al., 2013).
The history of how tobacco use was transformed from a ceremo-
nial practice in precolonial North and South America into the world’s
largest preventable cause of non-​communicable diseases has been
reviewed extensively elsewhere (Brandt, 2007; Doll, 1998; IARC,
2004; US Department of Health and Human Services, 2014). A major
contributor to this transformation was the rise of manufactured ciga-
rettes, first in high-​and later in middle-​and low-​income countries dur-
ing the twentieth century. The term “tobacco epidemic” refers to the
global dissemination and disease consequences of manufactured ciga-
rettes and cigarette-​like products (Lopez et  al., 1994); these greatly
amplify the endemic problems from other forms of tobacco use.
Patterns of tobacco use have changed markedly over time. The
uptake of manufactured cigarettes began among affluent and middle-​
class men in high-​income countries in the early twentieth century
(Doll, 1998). Successive generations of first men and then women
initiated cigarette smoking at progressively earlier ages and smoked
more intensively, creating strong birth cohort patterns in both smok-
ing and lung cancer, as discussed further later in the chapter. By the
mid-​twentieth century, manufactured cigarettes had largely displaced
the use of other tobacco products in English-​speaking countries, as
shown for the United States in Figure 11–​1 (US Department of Health
and Human Services, 2014). The prevalence of cigarette smoking and
per capita consumption began to decrease in the United States and the
United Kingdom by the mid-​1960s, but continued to increase else-
where as economies recovered after World War II. In high-​income
countries, smokers who did not quit and who represented birth cohorts
with the highest lifetime smoking histories have dominated age-​
standardized lung cancer rates for decades (Pirie et  al., 2013; Thun
et al., 2013).
The design and composition of tobacco products has also changed
over time (US Department of Health and Human Services, 2014). The
introduction of blended and reconstituted tobacco in high-​ income
countries in the mid-​twentieth century changed the bioavailability of
nicotine and the relative concentration of different classes of carcino-
gens in tobacco smoke. The introduction of filters (initially plain cellu-
lose acetate filters and later “ventilated” filters that diluted the smoke)
did not produce the anticipated linear reduction in exposure to carcino-
gens (US Department of Health and Human Services, 2010). Tobacco
products other than cigarettes continue to be widely used, even in high-​
income countries (Table 11–​1). While manufactured cigarettes are by
far the most commonly used tobacco product worldwide, 15%–​35% of
global production involves other products (Tobacco Atlas, 2015). The
emergence of novel nicotine-​delivery products, such as e-​cigarettes, is
further complicating patterns of consumer behavior.
Epidemiologic studies continue to be central in identifying the
adverse health effects of tobacco use and in monitoring the progres-
sion of the tobacco epidemic. Humans, unlike other mammals, use
tobacco voluntarily (Thun and Henley, 2006). Whereas tobacco smoke
is irritating and highly toxic to other species exposed experimentally in
laboratory studies, non-​smokers who experiment with tobacco persist
through the initial noxious effects until they develop physical and psy-
chological dependence on tobacco. Observational (non-​randomized)
studies of smoking continue to be ethical and feasible, whereas ran-
domized clinical trials are not. Epidemiologic studies are better suited
than clinical observations to surmount the long delay between the
initiation of exposure and the onset of tobacco-​related diseases. The
association between active smoking and many diseases is sufficiently
strong that epidemiologic studies provide convincing evidence of
causality despite imprecise quantification of lifetime tobacco expo-
sure (Thun and Henley, 2006). For all of these reasons, epidemio-
logic studies have been essential in identifying the long-​term adverse
185
186

186 PART III:  THE CAUSES OF CANCER

14

12
Pounds of tobacco per capita
10

Snuff
6
Chewing
Pipe/roll your own
4
Cigars
2 Cigarettes

0
1880 1890 1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 2010
Year

Figure 11–​1.  Per capita sale of tobacco products in the United States, 1880–​2011. Source: Surgeon General Report (2014).

effects of tobacco use and the progression of the tobacco epidemic in
populations.
This chapter will discuss (a)  the epidemiology of cigarette smok-
ing and use of other tobacco products; (b)  the composition of ciga-
rette smoke; (c)  aspects of product design and usage that influence
exposure; (d)  tobacco products other than manufactured cigarettes;
(e)  cancers caused by various forms of tobacco use; (f)  the benefits
of cessation; (g) the adverse health effects of involuntary exposure to
tobacco smoke; (h)  emerging tobacco products such as e-​cigarettes
and other products; and (i)  opportunities for prevention and future
research. Readers are referred to the chapter on tobacco in the previ-
ous edition of this text for additional background information (Thun
and Henley, 2006).
GLOBAL PATTERNS OF TOBACCO USE
Geographic Distribution
Figure 11–​ 2 illustrates that, among men, the prevalence of daily
cigarette smoking in 2012 was highest in Eastern Europe, the former
Soviet Union, and Eastern Asia (Ng et al., 2014). In women, the preva-
lence was highest in North America, Northern Europe, and Australia.
The Global Tobacco Surveillance System has greatly expanded col-
lection of nationally representative data in middle-​and low-​income
Table 11–​1. Commonly Used Tobacco Products
Smoked/​Combustible
Cigarettes (Manufactured and hand-​rolled)
Cigars (Large and small)
Pipes
Bidis
Kreteks
Waterpipes (hookah, shisha, narghile)
Chutta
Non-​combusted
Chewing tobacco
Snuff (moist and dry, high and low nitrosamine content)
Betel quid (Pan masala)
Novel tobacco products
E-​cigarettes and other electronic nicotine delivery products (ENDS)
Dissolvable products
countries (Centers for Disease Control and Prevention [CDC], 2016;
Warren et  al., 2009). The two largest surveillance initiatives are the
Global Adult Tobacco Survey (GATS) and the Global Youth Tobacco
Survey (GYTS). GATS is a nationally representative, face-​to-​face
household interview of persons 15 years of age and older, designated
as “adults.” GATS has collected cross-​sectional data on all forms of
tobacco use and cessation on more than three billion individuals in 16
countries (Giovino et al., 2012). The parallel survey of youth, GYTS,
is a school-​based survey designed to provide primarily cross-​sectional,
nationally representative estimates of tobacco use among students, age
13–​15 years, in 168 countries (Warren et al., 2008). The area covered
can be a country, province, city, or any other geographic area. Other
data sources, such as the Demographic and Health Survey, the World
Health Organization (WHO) STEPS instrument, the Canadian Youth
Smoking Survey, and the US National Tobacco Survey are described
elsewhere (National Cancer Institute and Centers for Disease Control
and Prevention, 2014).
Temporal Variation
Per Capita Sales
As indicated in Figure 11–​1, most tobacco use in the United States in
the early twentieth century involved chewing tobacco, pipes, cigars,
and snuff, rather than cigarettes (US Department of Health and Human
Services, 2014). The invention during the 1880s of portable safety
matches and cigarette rolling machines (which could mass-​produce
cigarettes that were considerably less expensive than hand-​rolled prod-
ucts) made it possible to smoke tobacco frequently throughout the day
in diverse settings. These technologies were coupled with novel and
aggressive advertising campaigns that glamorized smoking of par-
ticular brands of cigarettes, beginning with Camel cigarettes in 1913
(Slade, 1993). Free cigarettes were distributed to soldiers during World
Wars I and II and the Korean War.
The data on per capita sales in Figure 11–​1 are based on tax infor-
mation on total sales of tobacco by weight. If these were expressed as
the number of cigarettes sold per capita, they would show a more than
80-​fold increase in the United States from 1900 (when the average was
54 cigarettes per person per year) to 1963 (when the average peaked at
4345 cigarettes per person per year) (CDC, 1999).
Figure 11–​3 shows that the global sale of manufactured cigarettes
increased nearly 500-​fold from 1880 to 2009 (Asma et al., 2014).
Almost six trillion cigarettes were sold worldwide in 2009. While the
rate of increase has slowed, the number of cigarettes sold continues
to increase because of population growth and the persistently high
 187

(a) Age–standardized smoking prevalence among men, 2012

Smoking prevalence deciles, %

0.5 to < 2.6 16.5 to < 19.7
2.6 to < 5.6 19.7 to < 23.4
5.6 to < 9.8 23.4 to < 27.5
9.8 to < 13.3 27.5 to < 34.7
13.3 to < 16.5 34.7 to < 61.1
Deciles of prevalence were calculated
for men and women combined.

(b) Age–standardized smoking prevalence among women, 2012

Smoking prevalence deciles, %

0.5 to < 2.6 16.5 to < 19.7
2.6 to < 5.6 19.7 to < 23.4
5.6 to < 9.8 23.4 to < 27.5
9.8 to < 13.3 27.5 to < 34.7
13.3 to < 16.5 34.7 to < 61.1
Deciles of prevalence were calculated
for men and women combined.

Figure 11–​2.  Global prevalence of daily cigarette smoking among men (a) and women (b), estimated for 2012. Modified from Ng et al., JAMA (2014).

6000

5000

4000
Billions of cigarettes

3000

2000

1000

0
1880 1890 1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 2009
Year

Figure 11–​3.  Trends in global sale of manufactured cigarettes (billions of sticks). Source: Asma et al. (2014).
18
188 PART III:  THE CAUSES OF CANCER
prevalence of cigarette smoking, especially among men in highly pop-
ulous middle-​and low-​income countries. The largest market for manu-
factured cigarettes is in China, where more than 300 million smokers
consume 37% of all cigarettes sold (Tobacco Atlas, 2015).
Sales data derived from tax records provide the earliest objective
record of the uptake of cigarette smoking in a given country. They
indicate that the increase in smoking manufactured cigarettes occurred
first in North America and Northern Europe and then proceeded to
Central, Southern, and Eastern Europe, South America, and Asia.
Harsh economic conditions during and after World War II delayed
the increase in cigarette smoking by men in China until the 1960s,
with much of the initial increase involving light smoking by adult
men (Chen et al., 2015). The sustained decrease in per capita cigarette
sales that began later in the twentieth century has followed approxi-
mately the same progression. The downturn in the United States fol-
lowed publication of the inaugural 1964 Surgeon General Report
on Smoking and Health (US Department of Health Education and
Welfare, 1964). Between 1964 and 2012, per capita sales decreased by
72%, from 4345 cigarettes per adult per year in 1964 to 1196 in 2012.
By comparison, smoking prevalence decreased by 58% in men and
women combined, as discussed below (US Department of Health and
Human Services, 2014).
Sales data provide a useful ecological indicator of the average inten-
sity of smoking at various points in time. Their main limitation is that
they do not indicate who is smoking the cigarettes. Descriptive infor-
mation on differences in smoking behavior between women and men
by age, birth cohort, and other characteristics can be derived only from
population-​based surveys.
Smoking Prevalence
The first national survey of smoking prevalence among adults in the
United States was conducted in 1955, when 57% of men and 28%
of women age 18 years and older reported current cigarette smoking
(Haenszel and Shimkin, 1956). Prevalence was reportedly even higher
in Britain between 1948 and 1952, when nearly 70% of men and more
than 40% of women between the ages of 25 and 59 smoked cigarettes
(Peto et al., 2000). Figure 11–​4 shows the 58% decrease in smoking
prevalence among men and women in the United States from 1965
(42.7%) to 2012 (18.1%). By 2015, the proportion of US adults, age
> 18 years, who currently smoked cigarettes had decreased further to
15.1% (Jamal et al., 2016).
Smoking prevalence and/​or consumption are now decreasing in
the majority of countries worldwide (Ng et  al., 2014). Data on 172
90
80
70
Current smoking prevalence (%)
60
50
40
30
20
10
0
1965 1970
Figure 11–4.  Annual global sale of manufactured cigarettes (billions of sticks), 1880–​2009. Source: Surgeon General Report (2014).
countries collected for the WHO Global Monitoring Framework indi-
cate that male smoking is decreasing in 125 (72%) countries and that
female smoking is decreasing in 156 (88%) (Bilano et  al., 2015).
However, only one in five countries is on track to achieve the 2025
targets specified by WHO. Furthermore, the prevalence of cigarette
smoking was increasing rapidly among men in parts of sub-​Saharan
Africa and among both sexes in the Eastern Mediterranean. The abso-
lute number of smokers is also increasing worldwide because of popu-
lation growth (Ng et al., 2014).
Birth Cohort Patterns
In high-​income countries, the uptake of cigarette smoking has followed
strong birth cohort patterns in terms of prevalence and consumption.
Birth cohort patterns typically reflect exposures or exposure patterns
that are established in early life and then affect behavior and/​or dis-
ease occurrence later in life. The initiation of tobacco use is influenced
by social norms as each birth cohort passes through critical periods
of life, especially adolescence. The trajectory of continued smoking
within a birth cohort is influenced by peer behavior, tobacco market-
ing, and other social and economic conditions that individuals encoun-
ter as they age through different periods of calendar time.
Birth cohort trends in the uptake of cigarette smoking in the United
States have been reconstructed from serial National Health Interview
Surveys (NHIS) (Burns et al., 1997; Harris, 1983; Holford et al., 2014).
Figure 11–​5 shows the birth cohort trends in smoking prevalence for
men and women in the United States born between 1890 and 2000 and
followed through 2010 (Holford et al., 2014). These data are adjusted
for the differential mortality of smokers. Prevalence at first increased
and then decreased in a distinctive wave-​like progression across suc-
cessive 5-​year birth cohorts. The progression in men preceded that in
women by about 15 years. The highest prevalence of daily cigarette
smoking in men occurred around 1950 in the birth cohort 1920–​1925;
the corresponding peak in women occurred in about 1965 in the birth
cohort 1935–​1940.
The birth cohort patterns in Figure 11–​5 are asymmetrical in two
respects. First, the downturn in smoking prevalence begins at progres-
sively younger ages in the birth cohorts from 1890–​1894 to 1950–​
1954 in men and after 1960–​1964 in women. This downturn reflects
increased cessation, due to growing public awareness about the
adverse health effects of smoking, that occurred first among men in the
1950s and later among women (US Department of Health and Human
Services, 2014). The second asymmetry is the partial resurgence in
smoking prevalence that began in the 1970s for women and 1990s for
Males
Females
1975 1980 1985 1990 1995 2000 2005 2010 2015
Year
 189

Tobacco 189
(a) Males
90

80

70
Current smoker prevalence (%)

60

50

40

30

20

1930

1950
1940
1920
1910
1900

1960

0
1890

198

0
10

199
70
19
0
1890 1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 2010
Year

(b) Females
90

80

70
Current smoker prevalence (%)

60

50

40

30

20
1940
1930
1920

1950

1960

10 00
0

0
10

19
197

198

199
19

0
189
0
1890 1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 2010
Year

Figure 11–​5.  Prevalence of current smoking by gender, calendar year, and birth cohort in the United States. Source: Holford TR et al. (2014).

men. The resurgence among women coincided with the introduction
of the Virginia Slims brand of cigarettes and increased initiation of
smoking among young women (O’Keefe and Pollay, 1996; Toll and
Ling, 2005). The upturn among men likely reflects a decrease in ces-
sation rates after 1970, when ventilated cigarettes with progressively
lower “tar” ratings, as measured by machine smoking, were marketed
as having putatively lower health risks (US Department of Health and
Human Services, 2014).
Not all indices of smoking behavior follow exactly the same
birth cohort patterns. Whereas smoking prevalence peaked in birth
cohorts 1915–​ 1919 and 1920–​ 1924 among men and 1935–​ 1938
among women (Figure 11–​5), cigarette consumption among smokers
continued to increase until it peaked in the 1935–​1939 birth cohort of
men and 1940–​1944 birth cohort of women (Holford et al., 2014) (data
not shown). Daily cigarette consumption among smokers continued
to increase for up to 20 years beyond the initial population decrease
in smoking prevalence. The complex birth cohort patterns in smoking
prevalence, intensity, and age at starting give rise to the birth cohort
patterns in lung cancer incidence and mortality observed 20–​50 years
later in the general population, as discussed in Chapter 28.
Not all countries have followed the same temporal sequence in
which the uptake of smoking in women follows 15–​20 years after the
uptake in men. The opposite pattern occurred among Chinese women,
in whom the prevalence of ever smoking decreased over successive
190
190 PART III:  THE CAUSES OF CANCER
30
28
Ever-smoking prevalence (%)
20
10
5 study areas
0
1930
Figure 11–​6.  Prevalence of ever-​smoking among Chinese women in Kadoori Study, by year of birth and locality. Source: Chen Z et al. (2015).
birth cohorts as smoking by women became unfashionable. Figure
11–​6 shows that nearly 30% of Chinese women born in the mid-​1930s
and participating in the Kadoori study smoked at some point in their
life (Chen et al., 2015). This decreased to 2% among those born in
the late 1960s. In contrast, the prevalence of ever smoking increased
among Chinese men, peaking at nearly 80% in rural areas in those
born during the 1950s and early 1960s, before decreasing in later
birth cohorts (Chen et al., 2015).
Patterns of tobacco use continue to change worldwide. For example,
in the United States the prevalence of light and intermittent smoking
has become more common. Over the last 10 years, the proportion of
non-​daily cigarette smokers has increased from 19.2% to 24.3% of
smokers; the proportion of smokers who smoke less than 10 cigarettes
per day increased from 16% to 25%. A growing proportion of smok-
ers, particularly young people, also use cigarettes in combination with
other tobacco products, such as e-​cigarettes or water pipes.
Figure 11–​7 shows the dramatic changes in the tobacco products
being smoked by middle and high school students in the United States
from 2011 to 2015 (Singh T et  al., 2016). The use of e-​cigarettes
increased rapidly throughout the period, and e-​cigarettes became the
most commonly used tobacco product by 2014. The increased use of e-​
cigarettes was accompanied by decreases in all other forms of tobacco
use except waterpipes. About half of the students who reported any
tobacco use used > 2 products.
NATURE OF THE EXPOSURE
Smoked Tobacco Products
Manufactured cigarettes comprise an estimated 84% of global tobacco
consumption. Commonly used smoked and non-​combustible tobacco
products are listed in Table 11–​1 and are discussed later in this chapter.
Composition of Tobacco Smoke
Tobacco smoke is a complex, heterogeneous mixture that contains at
least 5300 (and by some estimates as many as 7000) identified chem-
icals (US Department of Health and Human Services, 2010, 2014).
2 study areas (1 urban, 1 rural) in
Northeast or Southwest China
24
12
8 remaining 6
3
2
1 0 0
1940 1950 1960 1970
Mean birth year
These include at least 70 chemicals designated by the IARC as having
sufficient evidence of carcinogenicity, based on studies of laboratory
animals and/​or humans (IARC, 2012a; US Department of Health and
Human Services, 2014). Comprehensive reviews of the chemical com-
position of tobacco smoke are available elsewhere (IARC, 2004).
At least seven classes of carcinogens are formed by the combustion
of tobacco (Table 11–​2). These include polycyclic aromatic hydro-
carbons (PAHs), heterocyclic compounds, N-​nitrosamines, aromatic
amines, formaldehyde, phenolic compounds, and a variety of free
radicals (IARC, 2004). Others, such as arsenic, cadmium, chromium,
nickel, and polonium 210, are incorporated into the tobacco plant from
soil or phosphate fertilizers. The concentrations of carcinogens such as
tobacco-​specific nitrosamines are increased by fermentation and some
forms of curing. The concentration of nicotine and the rapidity with
which it can be absorbed depends on the selection of tobacco strains
and the pH of the smoke (IARC, 2004; US Department of Health and
Human Services, 2010). The chemical characteristics of the smoke
have not generally been considered in epidemiologic studies of cancer,
largely because the presence and concentration of various constituents
have changed over time and are difficult to reconstruct.
Mainstream Versus Sidestream Smoke
Active smoking generates both mainstream smoke (MS) and side-
stream smoke (SS):  MS is drawn directly from the burning tobacco
into the mouth; SS is released from the smoldering tobacco into the
ambient air, where it mixes with exhaled MS to make up environmental
tobacco smoke (ETS). Involuntary exposure to ETS, also called pas-
sive or secondhand smoking, involves similar chemical constituents,
although the concentrations may differ by several orders of magnitude
(IARC, 2004; US Department of Health and Human Services, 2014).
Nicotine
Nicotine is the principal alkaloid present in tobacco and accounts for
0.05%–​4.00% (by weight) of the tobacco leaf (US Department of
Health and Human Services, 1988). While nicotine itself is not car-
cinogenic, physical dependence on nicotine is the main factor that
 19

Tobacco 191
100

2011
2012
2013
25
2014
2015

20
Percentage of students

15

10

0
Any ≥ 2 types E-cigarettes Cigarettes Cigars Hookahs Smokeless Pipe tobacco Bidis
tobacco
Tobacco product

Figure 11–​7.  Tobacco use in middle and high school students, United States, 2011–​2015. Source: Singh T et al. (2016).

sustains tobacco use (US Department of Health and Human Services, neurotransmitters such as dopamine, serotonin, and γ-​aminobutyric
2014). Nicotine from tobacco binds with the nicotinic receptors for acid. Exposure to exogenous nicotine stimulates the production of
acetylcholine in the central and peripheral nervous systems. In the additional nicotine receptors (Benowitz, 1996).
central nervous system (CNS), the receptors regulate the release of For most users, nicotine addiction from tobacco use represents true
drug dependence (US Department of Health and Human Services,
2010). Withdrawal symptoms among cigarette smokers who attempt
Table 11–​2. Tobacco Smoke Carcinogens Evaluated in the IARC
to quit include anxiety, irritability, weariness, constipation/​diarrhea,
Monographs
insomnia, intense craving, and difficulty concentrating (Balfour and
Number of Fagerstrom, 1996). The severity of these symptoms may equal with-
Chemical Class Carcinogens Representative Carcinogens drawal from opiates, amphetamines, and cocaine. The strength of the
addiction is illustrated by the high failure rate among smokers who
Polycyclic aromatic 15 Benzo(a)pyrene (BaP) attempt to quit. Approximately 70% of current smokers express a
hydrocarbons Dibenz(a,h)anthracene desire to quit, yet fewer than 50% try to stop each year (Centers for
(PAHs) and their Disease Control and Prevention, 2000). Unassisted, about 2.5% of
heterocyclic smokers succeed in quitting permanently on a single quit attempt. The
analogues success rate approximately doubles with appropriate pharmacological
N-​Nitrosamines 8 4-​(Methylnitrosamino)-​1-​(3-​ and/​or behavioral treatment.
pyridyl)-​1-​butanone (NNK)
N'-​Nitrosonornicotine (NNN)
Aromatic amines 12 4-​Aminobiphenyl Factors That Influence Exposure
2-​Naphthylamine
Aldehydes 2 Formaldehyde Cumulative exposure to the carcinogens in tobacco depends on fac-
Acetaldehyde tors that affect the design and manufacture of the product, and social,
Phenols 2 Catechol economic, and biological determinants of usage.
Caffeic acid
Volatile 3 Benzene Bioavailability of Nicotine
hydrocarbons 1,3-​Butadiene Tobacco products vary in their delivery of nicotine in a form that can
Isoprene be rapidly absorbed. Differences in the bioavailability of nicotine
Other organics 12 Ethylene oxide influence both the addictiveness of various products and the surface
Acrylonitrile
area of epithelium or number of cells exposed to harmful constituents
Inorganic 8 Cadmium
compounds Polonium-​210
in tobacco smoke. Cigarettes and moist snuff increase plasma nicotine
concentration almost immediately (Figure 11–​8) and are most addic-
tive, whereas nicotine replacement products generally provide much
There are many other carcinogens in cigarette smoke that have not been evaluated in an
IARC Monograph.
slower nicotine uptake (Benowitz, 1996; US Department of Health
Source: IARC (2004a). and Human Services, 2010). Inhalation of cigarette smoke increases
192
192 PART III:  THE CAUSES OF CANCER
20
Cigarette (nicotine
delivery 1–2 mg)
15
Plasma nicotine concentration (ng/mL)
10
20
Nicotine gum (Polacrilex 4 mg)
15
10
0
0 30 60
Figure 11–​8.  Plasma nicotine uptake from various tobacco products.
plasma nicotine and produces discernible CNS effects in as little as 7
seconds owing to the large surface area of the lungs.
The uptake of nicotine from various tobacco products depends on
the pH of the product. Commercial brands of moist snuff produce a pH
range in saliva from 5.39 (at which less than 3% of the nicotine is free
or un-ionized) to 8.19 (where at least half of the nicotine is un-ionized
and can be rapidly absorbed) (Djordjevic et al., 1994). Nicotine in an
alkaline environment, as produced by pipes, cigars, smokeless tobacco
products, and cigarettes in the first half of the twentieth century is
absorbed through the oral mucosa. Alkaline smoke is too irritating for
most people to inhale. In contrast, protonated nicotine, as delivered by
contemporary cigarettes, is absorbed more rapidly through respiratory
epithelium. Deeper inhalation was made palatable by the development,
selection, and mixing of special tobacco blends and other modifica-
tions. Inhalation not only accelerates the absorption of nicotine, but
also exposes a much larger surface area to the toxic and carcinogenic
compounds in smoke.
Other Aspects of Product Design and Composition
As mentioned, the concentration of toxic and carcinogenic chemicals
in tobacco smoke is influenced by methods of curing and manufactur-
ing, as well as by agricultural practices. For example, the introduction
of reconstituted tobacco in the 1950s allowed manufacturers to use the
ribs and stems from tobacco as well as the leaves (US Department of
Health and Human Services, 2010). This reduced waste and produc-
tion costs and somewhat lowered the concentration of polycyclic aro-
matic hydrocarbons (PAHs), but greatly increased the concentration
of tobacco-​specific nitrosamines (TSNAs) (Hoffmann and Hoffmann,
1997; US Department of Health and Human Services, 2014). Tobacco
that is flue-​cured and has direct contact with the combustion byprod-
ucts from propane gas heaters also has higher concentrations of
TSNAs than air-​cured tobacco (Collishaw, 2016). Fermentation of
tobacco for use in cigars and moist snuff greatly increases the con-
centration of TSNAs (US Department of Health and Human Services,
2010). Brands of moist snuff commonly used in the United States have
TSNA levels far above the limit allowed in other consumer products
(Hoffmann and Hoffmann, 1997).
Cigarettes from different countries differ in their concentration
of nitrosamines, nitrates, nicotine, and other compounds (Ashley
et  al., 2003). Comparative studies of the levels of TSNAs in ciga-
rette tobacco documented that Marlboro cigarettes purchased in 11
of 13 foreign countries had significantly higher TSNA levels than
the locally popular non-​U.S. brands from the same country (Ashley
Tobacco
Oral snuff Nasal spray (1 mg)
Nico Derm CQ patch (21 mg) Nicotrol patch (21 mg)
90 120 0 30 60 90 120 0 30 60 90 120
Time post administration (minutes)
et  al., 2003). Even when measured by machine smoking, the “tar”
and nicotine yields of cigarettes vary by a factor of 3 across WHO
regions (Calafat et  al., 2004). Although epidemiologic studies have
not generally been able to consider measurements of the chemical
composition of smoke in different countries when comparing risk,
the observed variations in TSNA levels provide a promising target
for regulation. As described later in the chapter, urinary markers of
TSNA exposure have been associated with esophageal and lung can-
cer (Yuan et al., 2014).
Ventilated Cigarettes
Cigarettes with ventilated filters were introduced in the United States
in the late 1960s. Unlike plain cellulose acetate filters, these were
designed with ventilation holes that allowed air to enter and dilute the
smoke when the cigarettes were smoked by machines (US Department
of Health and Human Services, 2014). Machine-​measured “tar” and
nicotine ratings from cigarettes with ventilated filters were substan-
tially lower than machine ratings from a similar cigarette with an
unventilated filter or from an unfiltered cigarette. Smokers who used
these products could block the ventilation holes to obtain their accus-
tomed level of intake. Nevertheless, they perceived the smoke to be
less harsh than that from unfiltered or unventilated cigarettes. Cigarette
companies marketed these products to health-​conscious smokers as an
alternative to quitting, using the terms “light,” “ultralight,” “mild,” and
“low tar” to imply lower health risks.
The method of machine smoking was developed by the tobacco
industry during the 1930s and was adopted officially by the Federal
Trade Commission (FTC) in 1969. It became known as the “FTC pro-
tocol” (Institute of Medicine, 2001). Settings were fixed so that the
machine took one 2-​second (35 ml) puff per minute until the ciga-
rette was consumed. Tar and nicotine were extracted from a special
filter through which the machine “smoked” the cigarette. Tar repre-
sents the total particulate matter after removing the nicotine and water
(Institute of Medicine, 2001). As shown in Figure 11–​9, the average
sales-​weighted tar and nicotine yields of US cigarettes decreased dra-
matically according to machine measurements. The average “tar”
yield per cigarette decreased from 38 mg in 1954 to 12 mg in 1998,
while the average nicotine rating decreased from 2.3 mg to 0.9 mg (US
Department of Health and Human Services, 1981, 1989; Kozlowski
et al., 2001). Initially, the reduction was achieved by adding cellulose
acetate filters and using more porous wrapping paper (Hoffmann and
Hoffmann, 1997). Further reductions were achieved after 1970 by the
use of ventilated filters, “puffed tobacco” that reduced the amount
 193
Tobacco 193
4.0
3.5
3.0
2.5
Tar (mg)
2.0
1.5
1.0
0.5
0.0
1950 1955 1960 1965 1970 1975
Year
Figure 11–​9.  Sales-​weighted tar and nicotine values for US cigarettes as measured by a smoking machine using the Federal Trade Commission (FTC) method,
1954–​1998. Note: Values before 1968 are estimated from available data. Courtesy of D. Hoffmann, personal communication. Source: National Cancer Institute
Smoking and Tobacco Control Monograph 13 (2002), p. 2.
per cigarette, and modified wrapping paper that burned more rap-
idly so that the testing machine could take fewer puffs (Kozlowski
et al., 2001).
Epidemiologists who studied the cancer risks from “reduced-​yield”
cigarettes were largely unaware of the changing technologies that
affected the machine measurements. Studies conducted before the
year 2000 equated “high” and “low” tar cigarettes with unfiltered and
filter-​tip cigarettes respectively. It was assumed that a reduction in risk
associated with the addition of a filter would correspond to further
reductions in risk across much lower levels of machine-​measured “tar”
(Harris et  al., 2004). The critical distinction between ventilated and
unventilated filters had not yet been disclosed to the public.
The limitations of the FTC protocol in measuring the risk of venti-
lated cigarettes became apparent by the late twentieth century, when
age-​standardized lung cancer rates continued to increase in smokers,
despite large reductions in machine-​measured yield (Thun et al., 1997;
US Department of Health and Human Services, 1989). Studies of sali-
vary cotinine found little relationship between machine-​measured rat-
ings below 1.0 mg nicotine and actual nicotine uptake (Figure 11–​10)
(Benowitz, 2001; Jarvis et al., 2001). Moreover, an analysis by Harris
and colleagues at the American Cancer Society found no reduction
in lung cancer risk from “light” or “ultralight” cigarettes compared
to “regular” cigarettes with unventilated cellulose acetate filters, but
higher risk from smoking unfiltered cigarettes (Figure 11–​11) (Harris
et al., 2004).
Based on these findings, the FTC rescinded its approval of machine
smoking in 2008 and the Food and Drug Administration (FDA) banned
the use of descriptors such as “light,” “mild,” and “low tar” in the
United States. The tobacco industry has subsequently circumvented
this restriction by introducing color codes that smokers recognize as
equivalent to the banned terms (Connolly and Alpert, 2014).
Tobacco Products Other Than Cigarettes
Combustible
As mentioned, about 15%–​ 35% of global tobacco consumption
involves tobacco products other than manufactured cigarettes (Eriksen
et  al., 2012). These are listed in Table 11–​1. Other smoked tobacco
products include hand-​ rolled cigarettes, cigars, pipes, and a vari-
ety of products smoked widely in Southeast Asia. Hand-​rolled ciga-
rettes made from loose tobacco are used increasingly in the United
3.0
Tar
2.5
Nicotine
2.0
Nicotine (mg)
1.5
1.0
0.5
0.0
1980 1985 1990 1995
States, since they are exempted from the excise taxes on manufactured
cigarettes. For tax purposes, cigars are defined as shredded tobacco
wrapped in tobacco leaf or paper (Department of the Treasury, 2006).
They vary in size from cigarette-​sized cigarillos to cheroots and dou-
ble coronas (Eriksen et  al., 2012). Small filter-​tip cigars are usually
smoked like cigarettes but are less heavily taxed and can be purchased
individually. Their use is increasing in the United States, whereas the
previously widespread use of pipes is decreasing worldwide (Shafey
et al., 2009). Waterpipes (shisha or sheecha) have been used tradition-
ally in Middle-​Eastern countries and in Russia and Vietnam (Giovino
et  al., 2012; IARC, 2004), but are increasingly marketed to young
people in Western countries using flavors of molasses, apple, banana,
vanilla, and other fruits or candies (Tobacco Atlas, 2016).
The most common form of smoked tobacco in India involves bidis,
traditionally hand-​rolled in dried temburni leaf and tied with a string
(Shafey et  al., 2009). Kreteks are clove-​and cocoa-​flavored small
cigars that are produced and sold in Indonesia but also marketed
worldwide (Gandini et al., 2008).
Non-​Combusted Products
An historical overview of the use of smokeless or non-​combusted
tobacco products is provided in IARC Monograph 89 (IARC,
2007)  and more recently in a National Cancer Institute Monograph
(National Cancer Institute and Centers for Disease Control and
Prevention, 2014). Traditional forms of smokeless or “spit” tobacco
used in Western countries include snuff (moist and dry) and chewing
tobacco. In the United States alone, several million people use smoke-
less products (Agaku et  al., 2014; Lee et  al., 2014; Mazurek et  al.,
2014). Moist snuff is the most commonly used product in the United
States (Agaku and Alpert, 2015); snus, a lower nitrosamine form of
moist snuff, is widely used in Nordic countries. Moist snuff consists
of finely ground tobacco with 20%–​55% moisture content, often fla-
vored with mint, wintergreen, or raspberry (Borgerding et al., 2012).
A pinch (called a “dip” or “rub”) is placed between the gum and the
cheek or under the tongue (Shafey et al., 2009). Chewing tobacco is
popular among baseball players, male adolescents, and in both sexes
in some rural populations in the United States. Products may be fla-
vored with sugar, molasses, or licorice, and in the United States are
sold with a range of concentrations of nicotine and other toxicants
that increase as users become habituated. Dual use of cigarettes plus
smokeless tobacco products is most common among young unmar-
ried men (Lee et al., 2014). This form of poly-​tobacco use increased
194

194 PART III:  THE CAUSES OF CANCER

900

800

700

Saliva cotinine (ng/ml)

600

500

400

300

200

100

0
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1
Nicotine yield (mg)

Figure 11–​10.  Range of salivary cotinine among smokers smoking cigarettes within a given FTC rating for nicotine. Source: Jarvis et al. (2001).

among users under age 26 in the United States between 2002 and 2011
(Fix et al., 2014). The predominant form of tobacco used in Sweden
is moist snuff or snus with much lower concentration of nitrosamines
than most products in the United States (Nilsson, 1998).
Betel quid or pan is widely used in Asia and the Western Pacific,
especially by women (Shafey et al., 2009). Betel leaves (Piper betle)
are mixed with tobacco, Areca nut (Areca catechu), lime, wood ash,
or other substances to form a “quid,” “pan,” or “nass” (IARC, 2004).
The mixture is then chewed and/​or retained in the mouth. The use of
smokeless tobacco is estimated to cause more than 100,000 deaths
annually from cancer, with most deaths occurring in Southeast Asia
(Ezzati et al., 2002; Sinha et al., 2016).
Novel Tobacco Products
Electronic Nicotine Delivery Devices (ENDS). Novel
devices that heat tobacco or nicotine but do not produce smoke have
been introduced in recent decades. E-​cigarettes are the most widely
used of the electronic nicotine delivery systems (ENDS). The use
of e-​cigarettes is greatest in the United States and Europe (Arrazola
et al., 2015), but uptake is also occurring in middle-​and low-​income
countries (Palipudi KM et  al., 2015). They were invented by the
Chinese pharmacist Hon Lik in the first decade of the 2000s and are
principally manufactured in China. According to tobacco industry
documents, cigarette manufacturers were working to develop simi-
lar products since the early 1990s to serve as alternatives to nicotine-​
replacement therapy and for use in smoke-​free environments, but only
recently decided to bring these products to market (Dutra et al., 2016).
Users obtain nicotine through vaporization of a liquid solution that
typically includes a carrier compound such as propylene glycol, as
well as various flavorings (Grana et al., 2014). Many of these flavors,
such as “gummy bear” and “jolly rancher” are attractive to youth (US
Department of Health and Human Services, 2016). The products come
in many shapes and sizes, including both disposable and reusable
models, as illustrated in Figure 11–​12. Cross-​sectional studies indicate
that ENDS users are exposed to a number of carcinogens, including
tobacco specific–​nitrosamines and acrolein (Goniewicz et al., 2014),
although at concentrations that are lower and involve fewer carcino-
gens than tobacco smoke.
The ultimate impact of e-​cigarettes and other putative harm reduc-
tion products on health is unknown. Although use of these products
produces lower exposures to toxic and carcinogenic compounds than

2.5 2.5

2.0 2.0
Hazard ratio (95% CI)

Hazard ratio (95% CI)

1.5 1.5

1.0 1.0

0.5 0.5

≤ 35 35–54 ≥ 55 ≤ 7 8–14 15–21 ≥ 21 ≤ 35 35–54 ≥ 55 ≤ 7 8–14 15–21 ≥ 21

Never smoked Quit smoking Tar level (mg) Never smoked Quit smoking Tar level (mg)
regularly at age (years) current smoker regularly at age (years) current smoker

Figure 11–​11.  Hazard ratios for lung cancer in men and women from the CPS-​II cohort by level of machine-​measured “tar” in cigarettes smoked for cur-
rent smokers or by age at cessation for former smokers. Source: Harris et al. (2004).
 195

Tobacco 195

ENDS type Product characteristics

Disposable e-cigarette • For short time use

• Cheap; widely available from gas
stations or super markets
• Convenient, as no refill solution or
cartridge is needed
• Might be a starting point for many users

Rechargeable e-cigarette • Various sizes from cigarette size

to compact flashlight size
• Various colors and style
• Requires battery with a charger
• Requires replacing or refilling
nicotine cartridges

Tank system e-cigarette • High capacity

• Battery operated
• Lasts longer than typical
rechargeable models
• Requires refilling the tank with
nicotine solution
• Often recommended for heavy
smokers by retailers

Personal Vaporizer • Large size and heavy weight

• Battery power output control allows
the user to adjust the output of the
voltage going to the heating element,
which has a direct effect on the
temperature of the heating element
• Usually not recommended by
retailers for beginning users

E-cigar • Looks like an authentic large ciger

• Usually disposable

Figure 11–​12.  E-​cigarettes and other ENDs. Source: ASCO, AACR policy statement: Brandon et al., JCO (2015).

active smoking, marketing practices may detrimentally affect cessa-
tion and initiation patterns in the population. Smokers who continue
to smoke in addition to using e-​cigarettes often use them to delay ces-
sation by circumventing smoke-​free laws. Ultimately, it is unknown
whether e-​cigarettes will be used predominantly by smokers or by
adolescents and young adults who do not otherwise use tobacco, and
whether e-​cigarettes are contributing to the decline in other forms of
tobacco smoking among youth in the United States (Figure 11–​7).
Accurate prevalence data on the use of e-​cigarettes and other ENDs is
only now emerging from the National Health Interview Survey (Figure
11–​13) (Arrazola et al., 2015; QuickStats, 2016). The majority of e-​
cigarette smokers reported continuing to smoke cigarettes, especially
at ages > 25 years. A substantial proportion of e-​cigarette users in the
youngest age group (18–​24  years) had never smoked cigarettes, but
may have used other tobacco products. The percentage who had never
smoked cigarettes became much smaller with age. There is consider-
able variation among countries in awareness and use of e-​cigarettes
(Gravely et al., 2014).
Only a few studies have examined the effects of e-​cigarette use on
cessation of cigarette smoking (Orellana-​Barrios et  al., 2016), with
data from randomized trials being particularly scarce. As described
in the 2016 Surgeon General’s report (US Department of Health and
Human Services, 2016), current knowledge suggests health benefits
for current adult cigarette smokers who use e-​cigarettes as a way to
quit tobacco use completely or perhaps even as a long-​term replace-
ment for cigarette smoking. Much larger randomized clinical trials
are urgently needed, however, to determine whether e-​cigarettes are
effective smoking-​cessation devices. Observational studies are needed
to determine the effects of switching from cigarettes to e-​cigarettes on
disease risk.
As discussed earlier, a substantial proportion of younger e-​cigarette
users have never tried cigarettes or other tobacco products. Over
the last few years, longitudinal studies of tobacco-​use patterns have
been initiated. Published studies so far suggest that youths who use
e-​cigarettes may be more likely to use cigarettes subsequently than
never e-​cigarette users (Barrington-​Trimis et al., 2016; US Department
of Health and Human Services, 2016). Whether these associations per-
sist in future studies and ultimately affect the prevalence of cigarette
smoking in the United States and other countries will be a critical
gauge of the impact of e-​cigarettes on health.
MEASUREMENT OF EXPOSURE
Questionnaire Measures
The best and most thoroughly validated external measures of active
cigarette smoking derive from self-​ reports (Shields, 2002). Most
adults can report whether they have smoked 100 or more cigarettes
in their lifetime and whether they now smoke every day or on some
days, the definition of current smoking (Centers for Disease Control
and Prevention, 1994). A meta-​analysis of 26 studies that evaluated the
validity of self-​reported data on tobacco use found that self-​reported
smoking status predicted biochemical evidence of active smoking
196
196 PART III:  THE CAUSES OF CANCER
100
90
Current cigarette smokers
80 Former cigarette smokers
Never cigarette smokers
70
60
Percentage
50
40
30
20
10
0
Total 18–24 years
Age group
Figure 11–​13. Cigarette smoking status among current adult e-​cigarette users, by age group. Sources: National Health Interview Survey (2016) in
QuickStats (2016).
with 87% sensitivity and 89% specificity (Patrick et  al., 1994; US
Department of Health and Human Services, 2001). The sensitiv-
ity and specificity of self-​reported smoking were higher in studies
of adults than in those of children. Less than 1% of respondents in
the National Health and Nutrition Examination Survey (NHANES)
who denied the use of a nicotine-​containing product had an elevated
serum cotinine level, after adjustment for passive smoking (Yeager and
Krosnick, 2010). Information on tobacco use of comparable quality
can be collected online, by paper questionnaire, or by structured inter-
view (Steffen et al., 2014). Smoking history is considered a more sen-
sitive measure of intermittent smoking than are biochemical indices,
as the half-​life of cotinine is only about 17 hours (Benowitz, 1996).
However, self-​reported data on the number of cigarettes consumed per
day are thought to underestimate actual consumption by at least 20%.
Estimates of per capita consumption based on questionnaire surveys
consistently underestimate consumption based on cigarette sales data
by 20%–​30% (Todd, 1978).
Despite their quantitative limitations, self-​reported data on num-
ber of cigarettes smoked per day, years of smoking, and ages at
initiation and cessation have been sufficient to document etiologic
relationships between smoking and numerous disease endpoints
(IARC, 2004). They may not be sufficient to document relatively
small differences in the pathogenicity of cigarettes, however, given
potentially large unmeasured variations in smoking behavior. Other
measures that might refine estimates of cumulative exposure over a
lifetime could consider the intensity of smoking at different ages, as
well as daily and non-​daily use, birth cohorts, indices of addiction,
the number and duration of failed cessation attempts, and the design
characteristics of the product being smoked. Behavioral character-
istics such as puff volume, the average number of puffs taken per
cigarette, depth of inhalation, and retention time in the lung cannot
be reliably measured by questionnaire. Self-​reported data on depth
of inhalation have not proven to be reliable, and personal monitor-
ing has not yet been widely used.
Exposure assessment is less well developed for non-​ cigarette
tobacco products. For example, few epidemiological studies have
assessed risk in relation to age at initiation and cessation of use of
products other than cigarettes. It is particularly difficult to assess expo-
sures from e-​cigarettes and waterpipes. E-​cigarette users may puff on
25–44 years ≥45 years
a single tank of e-​juice over the course of a day or days. Waterpipe
users often share puffs with others over the course of several hours.
Future studies of non-​cigarette tobacco products should extensively
query usage patterns in order to further delineate the health risks of
these products.
The FDA Center for Tobacco Products (FDA-​ CTP) recently
released a list of 93 harmful and potentially harmful constituents
(HPHC) in tobacco products and tobacco smoke that must be reported
by tobacco manufacturers and importers for their products (Food and
Drug Administration, 2012). This information has not yet been used
in epidemiologic studies, but could conceivably be coupled with bio-
markers of exposure to estimate exposure to specific chemicals.
Exposure to secondhand smoke can be estimated from qualitative
information on questionnaires, supplemented by quantitative assess-
ments based on biomarkers or air measurements (Apelberg et  al.,
2013; Avila-​Tang et al., 2013a, 2013b) Study participants can describe
the smoking status of their spouse, the number of smokers at home,
and the extent of exposure at work or in other settings in the recent past
(see Chapter  17). Cotinine and other biomarkers of tobacco smoke
provide objective evidence of exposure within the past 3–​7 days. Self-​
reported information on exposures in childhood and at various periods
throughout life cannot be validated directly, but can provide qualitative
information about past exposures.
Measures of Addiction
A parameter that has not often been included in epidemiologic stud-
ies but that appears informative is the level of nicotine addiction of
individual smokers. The Fagerstrom index is a widely used index of
addiction in behavioral studies (Fagerstrom, 1978; Fagerstrom et al.,
1996) that measures six correlates of physical dependence. It includes
questions such as: “How soon after you wake up do you smoke your
first cigarette? Do you find it difficult to refrain from smoking in places
where it is forbidden? Do you smoke if you are so ill that you are in
bed most of the day?” Questions in the Fagerstrom index may corre-
late with parameters of tobacco exposure that are difficult to measure
by questionnaire, such as greater puff volume, depth of inhalation, and
retention time in the lung. Including one of more of these questions in
epidemiologic studies might prove to be a useful adjunct to the current
 197
Tobacco 197
assessment of lifetime exposure. For example, a recent study found
that time to first cigarette was associated with lung cancer in and above
standard smoking measures such as smoking duration and cigarettes
smoked per day (Gu et al., 2014).
The common practice of combining information on the intensity
and duration of smoking into a single variable of cumulative exposure
(pack-​years or cigarette-​years) is contraindicated. Analyses of both the
British Doctors’ Study (Doll and Peto, 1978) and the American Cancer
Society Cohorts (Flanders et al., 2003) have shown that the duration
of smoking is a much stronger predictor of lung cancer risk than is
the number of cigarettes smoked per day. Lung cancer risk increases
with the fourth or fifth power of years of smoking but only the second
power of cigarettes per day. Researchers increasingly recommend that
pack-​years no longer be used as an exposure variable (Leffondre et al.,
2002), just as “ever” smoking is no longer considered an optimal cat-
egory of exposure because of changes in risk after cessation.
Biomarkers
Various biomarkers have been used in epidemiologic studies of tobacco
to assess absorption, metabolism, excretion, and biologic activity of
constituents in smoke (IARC, 2004; US Department of Health and
Human Services, 2010).
Biomarkers of Exposure
The most commonly used biomarkers of exposure are those that
reflect nicotine absorption. Cotinine is the main proximate metabo-
lite of nicotine and is considered the biomarker of choice for indicat-
ing exposure to tobacco during the last 2–​7 days (Avila-​Tang et al.,
2013a; Benowitz, 1996). The concentration of cotinine in plasma,
saliva, or urine can reliably differentiate active smoking from ETS
exposure (IARC, 2004). Other biomarkers, such as thiocyanate
in plasma or saliva, carbon monoxide in exhaled alveolar air, and
blood carboxyhemoglobin concentrations, are less sensitive and/​or
less specific as markers of tobacco exposure than cotinine (Institute
of Medicine, 2001). Biomarkers of nicotine metabolism are highly
informative in studies of secondhand smoke, but less useful for quan-
tifying the lifetime history of active smoking because of their short
half-​life.
Other biomarkers reflect the uptake, activation, and excretion of
carcinogens in tobacco smoke. These are discussed extensively else-
where (IARC, 2012a; US Department of Health and Human Services,
2010). Studies that measure metabolites of tobacco-​specific nitrosa-
mines in urine and other bodily fluids (Hecht et al., 2016) document
the absorption and metabolic activation of two powerful carcino-
gens, 4-​(methylnitrosamino)-​1-​(3-​pyridyl)-​1-​butanone (NNK) and
N'-​nitrosonornicotine (NNN) following active or passive exposure to
tobacco smoke or smokeless products (Hecht et al., 2008).
All of these biomarkers of exposure reflect recent time periods
rather than lifetime exposure. They also cannot typically distinguish
between forms of tobacco, challenging interpretation in populations
where dual or poly use is common. Biomarkers are useful, however,
for validating questionnaire information on recent smoking, for docu-
menting the absorption of carcinogens from active and passive smok-
ing, and for excluding active smokers from studies of secondhand
smoke. However, they do not improve measurably on questionnaire
data in epidemiologic studies of smoking and cancer. Serum cotinine
has been shown to predict lung cancer risk among smokers (Boffetta
et al., 2006), but there is no evidence that it is more predictive than
questionnaire-​based measures of smoking. Cotinine and carbon mon-
oxide levels reflect smoke exposure within the last few days, and thio-
cyanate (from hydrogen cyanide) within the past few weeks (Jarvis
et al., 1987).
Several studies suggest that measurement of urinary levels of the
tobacco-​specific carcinogens NNN and NNK and their metabolites
may improve on estimates of carcinogen exposure from active or pas-
sive smoking when combined with cotinine and self-​reported smok-
ing (Goniewitz et al., 2011; Vardavas et al., 2013; Yuan et al., 2014).
However, these studies have been conducted in only a few populations
so far. Further studies in other populations with a range of tobacco use
patterns are merited.
Biomarkers of Genotoxicity
DNA adducts provide direct evidence that carcinogenic constituents
of tobacco smoke interact with circulating lymphocytes and with tis-
sues affected by smoking-​related cancers (lung, oral cavity, urinary
bladder, and uterine cervix). Cigarette smoking increases the muta-
genicity of urine, the activation of certain enzymes in body tissue, and
the presence of DNA adducts from tobacco-​specific nitrosamines or
4-​aminobiphenyl in lymphocytes, hemoglobin, and tumor tissue (US
Department of Health and Human Services, 2010). Adducts bound to
cellular macromolecules persist longer than nicotine metabolites after
abstinence from tobacco use. The number of chromosomal aberra-
tions in cultured lymphocytes and the extent of lipid peroxidation have
been shown to correlate with the number of cigarettes smoked per day
(Shields, 2002).
Smoking produces multiple distinctive mutational signatures in
tumors that are correlated with aspects of cigarette smoking behav-
ior (Alexandrov et al., 2016). The most widely recognized are the
G→T transversions in TP53 found in adenocarcinomas and squamous
cell carcinomas of the lung in smokers (Alexandrov et al., 2016; US
Department of Health and Human Services, 2010). Thirty percent of
the TP53 mutations in lung tumors of smokers involve G→T transver-
sions, whereas only 10% of the mutations in lung tumors obtained
from non-​smokers are of this type. TP53 mutations in smokers occur
preferentially at hotspots where DNA adducts from exposure to poly-
cyclic aromatic hydrocarbons (PAH) are formed and incompletely
repaired (US Department of Health and Human Services, 2010). They
are found in pre-​neoplastic lesions as well as lung cancer in smokers,
indicating that they represent early somatic events (US Department of
Health and Human Services, 2010).
Other studies have shown clear associations between cigarette smok-
ing and methylation status at numerous genomic regions (Joehanes
et al., 2016). These and future molecular studies may provide further
insights into the mechanisms by which tobacco causes various types of
cancer, may refine associations with particular subtypes of cancer, and
may suggest new treatment modalities.
CANCERS CAUSED BY ACTIVE CIGARETTE SMOKING
Cancer Sites with “Sufficient Evidence”
Active cigarette smoking causes more than 20 different cancer sites
or subsites, according to designations by the IARC and the US
Surgeon General (IARC, 2012a; US Department of Health and Human
Services, 2014). These include cancers of the lung (all histologic sub-
types), oral cavity, nasal cavity and accessory sinuses, naso-​, oro-​, and
hypopharynx, larynx, esophagus (including both squamous cell car-
cinoma and adenocarcinoma), stomach, pancreas, colorectum, liver,
kidney (including adeno-​and urothelial carcinomas), ureter, urinary
bladder, uterine cervix, ovary (mucinous), and acute myeloid leuke-
mia. Even this list may be incomplete, as it does not include sites such
as breast cancer or advanced prostate cancer for which the Surgeon
General has designated the evidence as “suggestive but not conclu-
sive” (US Department of Health and Human Services, 2014).
Table 11–​3 shows the relative risk (RR) estimates for the associ-
ation between current cigarette smoking and cancer sites that are
formally designated as smoking-​related by both the IARC and the
Surgeon General (IARC, 2012a; US Department of Health and Human
Services, 2014). It also shows the year when each site was classified
as causally related to smoking, and the estimated attributable fraction
(AF) of deaths from active cigarette smoking in the United States.
The number of cancer sites and/​or subsites classified as causally
related to smoking has increased since the earliest studies of smok-
ing and cancer (Doll, 1998; US Department of Health and Human
Services, 2014). Larger studies with longer follow-​up have identi-
fied relationships with cancers that are less common or less strongly
associated with smoking than cancers of the lung, larynx, oral cavity,
198

198 PART III:  THE CAUSES OF CANCER

and esophagus. The identification of oncogenic infectious agents has
allowed studies to control for confounding by these pathogens with
regard to cancers of the liver, stomach, and uterine cervix (IARC,
2004; US Department of Health and Human Services, 2014). Changes
in cigarette design have strengthened the association between smok-
ing and adenocarcinoma of the lung (US Department of Health and
Human Services, 2014). Studies of tumor subsites have revealed causal
relationships with mucinous ovarian cancer and with both adenocarci-
noma and squamous cell carcinoma of the esophagus. The recognition
of additional smoking-​related cancers may also reflect the aging of
birth cohorts with the heaviest lifetime exposure, especially in women
(Carter et al., 2015; Pirie et al., 2013; Thun et al., 2013). Undiscovered
causal relationships may still exist with rare cancers, uncommon sub-
types, or molecularly defined subgroups (Carter et al., 2015).
Cigarette Smoking and Respiratory Tract Cancers
The respiratory epithelium is heavily exposed to cigarette smoke.
Cancers of the lung and larynx were the first to be designated as
causally related to active smoking in men (US Department of Health
Education and Welfare, 1964). The associations between active ciga-
rette smoking and cancers of the lung and larynx are the strongest of
all sites—​an estimated 77% of laryngeal cancer and 80% of lung can-
cers in the United States are attributed smoking (Siegel et al., 2015).
Nasal Cavity and Paranasal Sinuses.  The evidence linking
active cigarette smoking to cancers of the nasal cavity and paranasal
sinuses was designated as causal by the IARC in 2004 (IARC, 2004).
Sinonasal cancers are rare; thus the evidence comes mainly from case-​
control studies. The nasal cavity and paranasal sinuses are exposed to
mainstream tobacco smoke only during exhalation and only for a sub-
set of smokers. Evidence for causality includes the presence of dose–​
response relationships in most studies, the decrease in relative risk
observed with time since quitting, the absence of likely confounders,
and the stronger relationship observed for squamous cell cancers than
for adenocarcinomas (IARC, 2004). Active cigarette smoking approxi-
mately doubles the incidence of nasal cavity squamous cell carcino-
mas in case-​control studies conducted in North America, Europe,
Japan, and China (IARC, 2004; US Department of Health and Human
Services, 2004). Prospective studies of these sites are few, although
consistent associations were observed in the large NIH-​AARP cohort
(Freedman et al., 2016).
Larynx.  Cancer of the larynx is more strongly associated with active
cigarette smoking than any other cancer except lung (Table 11–​3)
(Chapter 27). Smoking was designated “a significant factor in cau-
sation” of laryngeal cancer among men in 1964 (US Department of
Health Education and Welfare, 1964) and among women in 1980 (US
Department of Health and Human Services, 1980). The association
between active cigarette smoking and death from laryngeal cancer
appears to have strengthened in women but not men in the United
States since the 1960s. The relative risk estimates for current ver-
sus never cigarette smoking were 14.6 in men and 13.0 in women in
Cancer Prevention Study I, a large American Cancer Society cohort
followed from 1959 to 1966 (Hammond, 1966). The corresponding
relative risk estimates from a pooled analysis of five contemporary US
cohorts was 13.9 (CI: 8.3, 23.3) in men and 103.8 (CI: 24.2, 445.5) in
women (Carter et al., 2015). The wide confidence interval for women
in the contemporary cohorts reflects the low risk of death from laryn-
geal cancer among female never smokers (only two deaths from this
cancer observed in female never smokers). It is important to note that,
although the relative risks of cigarette smoking for laryngeal cancer
tend to be higher in women than in men, the absolute number of smok-
ing-​attributable deaths from laryngeal cancer annually in the United
States is far higher in men (2125) than in women (730), reflecting the
particularly low incidence of laryngeal cancer in non-​smoking women
(Siegel et al., 2015). Variations in the strength of the association by
tumor subsite, gender, age, type of tobacco, and time since cessation
are discussed further in Chapter 27. Siegel et al. estimate that 77% of
deaths from laryngeal cancer in the United States are attributable to
cigarette smoking (Siegel et al., 2015). The combination of tobacco
smoking and heavy alcohol consumption creates much higher risk of
laryngeal as well as other aerodigestive tract cancers than does smok-
ing alone (Hashibe et al., 2009), as discussed below.
Trachea, Bronchus, and Lung. Cigarette smoking is more
strongly associated with lung cancer than with any other cancer site
(Table 11–​3). All histologic subtypes of lung cancer are now strongly
associated with cigarette smoking, whereas during the 1950s, adeno-
carcinoma was reported to be minimally associated (Chapter 28) (Doll
et al., 1957; Kreyberg, 1962; Wynder and Hoffmann, 1994). A recent
US Surgeon General Report attributed this increase to changes in the
design and composition of cigarettes (US Department of Health and
Human Services, 2014). The Report identified the two most plausible
explanations for the increased association with adenocarcinoma of the
lung as the increase in TSNA concentrations in smoke from recon-
stituted tobacco and the shift in inhalation patterns due to ventilated
cigarettes. The evidence for any specific explanation was characterized
as suggestive rather than definite.
The association between active cigarette smoking and death from
lung cancer has strengthened over the last 50 years in the United States

Table 11–​3. Smoking-​Attributable Mortality from Cancer, 2010–​2014

Attributable Deaths
Relative Risk for Current
vs. Never Smoking % No.
Year Formally
Cancer Type Classified Men Women Men Women Men Women

Lip, oral cavity, pharynx 1964/​1971* 5.7 5.6 48.7 43.0 2955 1077
Esophagus 1982 3.9 5.1 52.3 44.4 6011 1296
Stomach 2004 1.9 1.7 25.6 10.8 1656 476
Colorectum 2014 1.4 1.6 11.2 8.0 2976 1992
Liver 2014 2.3 1.8 28.1 14.1 4085 975
Pancreas 1982 1.6 1.9 9.9 14.2 1870 2626
Larynx 1964 13.9 103.8 72.1 93.4 2125 730
Trachea, lung, bronchus 1964/​1968* 25.3 22.9 83.2 76.4 72,164 53,635
Cervix uteri 2004 N.A.-​ 3.5 N.A.-​ 22.2 -​-​-​ 862
Urinary bladder 1979 3.9 3.9 46.5 40.9 4920 1804
Kidney, other urinary tract 1982 1.8 1.2 22.3 7.2 1904 350
Acute myeloid leukemia 2004 1.9 1.1 23.2 3.4 1181 136

Source: Modified from US Surgeon General report 2014; Carter et al., NEJM 2015; Siegel et al. (JAMA Internal Medicine, 2015).
*Lip cancer was classified as causal in 1964, other oropharyngeal cancers in 1971. Lung cancer was classified as causal in men in 1964 and in women in 1968.
 19
Tobacco 199
and the United Kingdom, following birth cohort patterns in smoking
(Pirie et al., 2013; Thun et al., 2013). In men, the relative risk for death
from lung cancer in current versus never smokers increased from
approximately 12 in the 1960s to about 24 in the 1980s and then pla-
teaued (Thun et al., 2013). The corresponding relative risk for female
smokers increased from less than 3 in the 1960s to almost 26 in the
contemporary cohorts (2000–​2010). In both sexes, the relative risk
estimates for long-​term smokers of 40+ cigarettes per day approached
50. Projections based on age and birth cohort patterns suggest that
the average risk will continue to increase among older female smok-
ers in the United States for several decades (Thun et al., 2013; Pirie
et al., 2013).
Active cigarette smoking is estimated to account for approxi-
mately 80% (CI:  79.2, 81.1) percent of lung cancer deaths in the
US general population (Siegel et al., 2015), and 96% among current
smokers, based on updated hazard ratio estimates (Thun et al., 2013).
Incidence and mortality rates and the relative risk estimates associ-
ated with smoking have been shown to vary by ethnicity, with the
highest rates in the United States found among blacks (Torre et al.,
2016). Several factors are thought to contribute to these dispari-
ties, as reviewed in Thun and Henley (2006). Menthol cigarettes are
smoked more commonly by black smokers than other racial or ethnic
groups, but epidemiological studies have not found that these confer
higher risk for lung cancer than non-​menthol cigarettes (Blot et al.,
2011; Brooks et al., 2003; Rostron, 2012). The association between
current cigarette smoking and lung cancer is considerably weaker
in Japan and China; it is not yet clear whether this reflects the more
recent uptake of manufactured cigarettes in these countries than in
the West, less intensive smoking, or, in the case of Japan, the use of
charcoal filters.
Cigarette Smoking and Gastrointestinal Cancers
Cigarette smoking is causally associated with cancer at all sites in the
gastrointestinal tract except the salivary glands and possibly the small
intestine (IARC, 2012a). It is also causally associated with cancer of
the pancreas and liver. Among the gastrointestinal tract cancers, the
association with smoking becomes progressively weaker from the oral
cavity to the colorectum (Table 11–​3). The interaction between smok-
ing and alcohol is also strongest for squamous cell cancers of the upper
aerodigestive tract (Hashibe, 2010).
Oral Cavity, Oropharynx, Lip, and Salivary Glands.  Active
cigarette smoking was first designated as causally related to cancers of
the oral cavity and pharynx by the US Surgeon General in 1982 (US
Department of Health and Human Services, 1982) and by the IARC
in 1986 (IARC, 1986). Historically, many studies have combined can-
cers of the oral cavity with those of the oropharynx, even though these
are now recognized to have distinctive etiologic and clinical features.
More recently, a pooled analysis of over 13,000 cases and 18,000 con-
trols reported similar relative risk estimates for ever smoking with oral
cavity cancer (RR 2.87; 95% CI: 2.60, 3.18) and oropharyngeal cancer
(RR 3.01; 95% CI: 2.71, 3.35) (Wyss et al., 2013). Unlike other sites,
cancers of the salivary gland have not been shown to be associated
with cigarette smoking.
The etiology of cancers of the oral cavity and oropharynx differ
substantially with regard to human papillomavirus (HPV) infection.
Whereas HPV is a strong risk factor for cancers of the oropharynx and
base of the tongue, it is minimally associated with cancers of the oral
cavity. Studies have not yet fully elucidated whether cigarette smok-
ing interacts with HPV infection for cancers of the oropharynx. Active
cigarette smoking is estimated to account for almost half (47.0%;
CI: 38.6, 55.5) of deaths from cancers of the oral cavity and pharynx
in the United States (Siegel et al., 2015). This attributable fraction esti-
mate has not decreased, despite decreases in smoking prevalence and a
large increase in HPV-​related oropharyngeal cancers (see Chapter 29)
(Chaturvedi et al., 2008, 2013). The high fraction of cases attributed to
smoking may increasingly represent an interaction between smoking
and HPV, rather than smoking alone. Future studies of oral cavity and
oropharyngeal cancers should separate them into etiologically relevant
subsites.
Nasopharynx.  Active smoking was first classified as causally
related to nasopharyngeal cancer by the IARC in 2004 (IARC, 2004).
A meta-​analysis of 28 case-​control studies and four prospective cohort
studies published between 1979 and 2011 reported a meta-​relative risk
estimate of 1.60 (95% CI: 1.38, 1.87) for ever versus never smoking,
with higher risks associated with greater intensity and longer duration
of smoking (Xue et al., 2013). Other studies and heterogeneity by cell
type and geographic population are discussed further in Chapter 26.
Esophagus.  Active cigarette smoking was designated as a major
cause of esophageal cancer by the US Surgeon General in 1982
and by the IARC in 1986 (IARC, 1986; US Department of Health
and Human Services, 1982). Historically, only cancers of the lung
and larynx were more strongly associated with active smoking than
esophageal cancer (Vineis et al., 2004). Active cigarette smoking is
causally related to both esophageal squamous cell carcinoma and
adenocarcinoma, the two main histologic subtypes (IARC, 2004).
The association with squamous cell carcinoma is stronger (RR 5.63;
95% CI: 2.7, 11.7) than that with adenocarcinoma (RR 2.77; 95%
CI: 1.4, 5.6) in a pooled analysis of smokers with > 60 pack-​years
in the Beacon Consortium (Lubin et al., 2012). Alcohol consump-
tion strongly potentiates the relationship of smoking to esophageal
squamous cell carcinoma but not adenocarcinoma (see Chapter 30).
The overall association between cigarette smoking and esophageal
cancer appears to have decreased in high-​income countries, coinci-
dent with the shift in cell type toward a larger proportion of adeno-
carcinoma. Whereas the relative risk estimates in Cancer Prevention
Study I  during follow-​up from 1959 to 1966 were 6.76 for men
and 7.75 for women (Hammond, 1966), they had decreased to 3.9
(CI: 3.0, 5.0) and 5.1 (CI: 3.5, 7.4) in men and women, respectively,
in a pooled analysis of five large contemporary cohorts followed
from 2000 to 2010 (Carter et al., 2015). Active cigarette smoking is
estimated to account for about half (50.7%, range 44.8% to 56.5%)
of deaths from esophageal cancer in the United States (Siegel et al.,
2015). Greater detail about the association between cigarette smok-
ing and esophageal cancer is provided in Chapter 30.
Stomach.  The IARC and the US Surgeon General first desig-
nated the evidence linking active smoking to stomach cancer as
causal in 2004 (IARC, 2004; US Department of Health and Human
Services, 2014). The relative risk estimates for current versus never
smokers average approximately 1.6 for men and women combined
in more than 20 cohort studies and nearly 40 case-​control studies
(IARC, 2004). As described in Chapter  31, the relationship is not
confounded by infection with Helicobacter pylori. However, case-​
control studies stratified on H.  pylori seropositivity have reported
stronger associations in persons who are seropositive for H. pylori
than in uninfected individuals (Brenner et al., 2002; Jedrychowski
et al., 1993, 1999; Siman et al., 2001; Wu et al., 2003; Zaridze et al.,
2000). Levels of DNA methylation also increase with pack-​years
of smoking only among H.  pylori–​infected individuals (Shimazu
et  al., 2015). Cigarette smoking increases the risk of cancers
throughout the stomach, including cardia and non-​cardia (IARC,
2004; Ladeiras-​Lopes et  al., 2008). No studies have yet examined
associations between smoking and four recently identified molec-
ularly defined subtypes of gastric cancer (Cancer Genome Atlas
Research, 2014a). Siegel et al. estimate that 19.6% (13.8%–​26.8%)
of deaths from stomach cancer among men and women combined
in the United States are attributable to cigarette smoking (Siegel
et al., 2015).
Colorectum.  Smoking was not associated with colorectal cancer
in large cohort mortality studies conducted in the mid-​twentieth cen-
tury (Doll and Hill, 1964; Hammond, 1966; Kahn, 1966; Weir and
Dunn, 1970). Beginning in the 1980s, studies consistently reported
associations between smoking and colorectal adenomatous polyps
20
200 PART III:  THE CAUSES OF CANCER
(IARC, 2004). In the mid-​1990s, Giovannucci and colleagues reported
increased frequency of adenomatous polyps and colorectal can-
cer among smokers in the Harvard Nurses and Health Professionals
cohorts (Giovannucci et  al., 1994a, 1994b). They hypothesized that
smoking affected an early stage of colorectal neoplasia, and that a long
induction period might be needed to observe an association with inci-
dence or mortality rates.
The relationship between active smoking and large bowel cancer
was designated causal by the IARC in 2012 (IARC, 2012a) and by the
US Surgeon General in 2014 (US Department of Health and Human
Services, 2014). The association between cigarette smoking and colo-
rectal cancer is weaker than that for most other smoking-​related can-
cers (Table 11–​3); it is also weaker for cancer of the colon (RR = 1.2;
95% CI: 1.1, 1.3) than rectum (RR = 1.6; 95% CI:1.3, 1.8) (Botteri
et  al., 2008). The IARC based its conclusion on the consistent rela-
tionship between smoking and adenomatous colorectal polyps and the
results of four meta-​analyses that controlled for multiple covariates
(Botteri et al., 2008; Huxley et al., 2009; Liang et al., 2009; Tsoi et al.,
2009). The 2014 US Surgeon General report reviewed 19 high-​quality
prospective studies of smoking in relation to incident colorectal cancer,
9 prospective cohort studies of cancer mortality, and 16 case-​control
studies, published during 2002–​2009, plus the meta-​analyses men-
tioned earlier (US Department of Health and Human Services, 2014).
Nearly all studies reported the strongest associations with adenoma-
tous polyps and colorectal cancer in current smokers and intermediate
associations in former smokers. The associations are stronger among
smokers with early age at initiation and longer duration of smoking.
Intriguingly, several studies have suggested stronger associations
between cigarette smoking and the subset of colorectal tumors with
microsatellite instability (MSI) and CIMP-​or BRAF-​positive tumors
(Campbell et al., 2009; Chia et al., 2006; Limsui et al., 2010; Poynter
et al., 2009). These findings may point to the carcinogenic mechanism
underlying the association. Such relationships, as well as the impor-
tance of early life exposure, are discussed in Chapter 36.
Pancreas.  As described in Chapter  32, the association between
active cigarette smoking and pancreatic cancer was designated as
causal by the US Surgeon General in 1982 (US Department of Health
and Human Services, 1982) and by the IARC in 1986 (IARC, 1986).
A recent pooled analysis of five cohorts in the United States reported
relative risk estimates of 1.6 in men and 1.9 in women for current
versus never cigarette smokers (Carter et  al., 2015). Relative risk is
lower for former than for current smokers and decreases with earlier
age at cessation (Iodice et al., 2008; Lynch et al., 2009). As noted in
Chapter 32, the decrease in pancreatic incidence and mortality rates
that occurred among US whites in the late twentieth century, following
reductions in smoking, reversed after the year 2000, following large
increases in the prevalence of obesity and type 2 diabetes. Recent esti-
mates indicate that active smoking accounts for 10%–​14% of pancre-
atic cancer in the United States (Siegel et al., 2015; US Department
of Health and Human Services, 2014). Further information about the
association of active smoking with pancreatic cancer, including poten-
tial molecular mechanisms, can be found in Chapter 32.
Liver.  The IARC designated the relationship between active smok-
ing and liver cancer as causal in 2004 (IARC, 2004), as did the US
Surgeon General in 2014 (US Department of Health and Human
Services, 2014). The latter reviewed 113 studies published through
2012, with particular attention to potential confounding by viral hepa-
titis and alcohol consumption (US Department of Health and Human
Services, 2014). Meta-​analyses found comparable associations in 31
studies that allowed comparisons between current and never smok-
ers (mRR = 1.7; CI: 1.5, 1.9) and in a subset of nine case-​control and
four cohort studies in which subjects had no evidence of viral hepatitis
(mRR = 1.8; CI: 1.2, 2.7). Other supporting evidence for causality is
discussed in Chapter 33.
Active smoking has been suggested to interact with other liver can-
cer risk factors, including viral hepatitis and consumption of alco-
hol (Chuang et al., 2010; Hassan et al., 2008; Kuper H et al., 2000;
Kuper HE et al., 2000; Marrero et al., 2005), raising concerns about
the future burden of liver cancer in low-​and middle-​income countries
with continued high prevalence of viral hepatitis and increasing smok-
ing prevalence.
Cigarette Smoking and Urinary Tract Cancers
Active cigarette smoking is a well-​established risk factor for cancers
throughout the urinary tract, including the kidney (parenchyma and
pelvis), ureter, and bladder. The association of these sites with cig-
arette smoking has long been classified as causal (IARC, 1986; US
Department of Health and Human Services, 2004). Current smoking
is more strongly associated with urothelial (formerly known as tran-
sitional) carcinomas of the renal pelvis (RR > 3) than with tumors of
the renal parenchyma (RR about 1.3), as discussed in the following
and in Chapter 51.
Renal Adenocarcinoma. Active cigarette smoking has been
designated a cause of renal cell carcinoma by both the IARC and the
US Surgeon General (IARC, 2012a; US Department of Health and
Human Services, 2014). Relative risk estimates from a recent meta-​
analysis indicate that, compared to never smokers, risk is approxi-
mately 36% higher in current smokers and 16% higher among former
smokers (Cumberbatch et al., 2016).
The classification of renal cell tumors has evolved substantially over
the last 30 years to incorporate genetic and molecular tumor charac-
teristics (Chapter 51). The current classification scheme recognizes 15
distinct entities and 4 subtypes (Srigley et al., 2013). Most of the avail-
able data on cigarette smoking pertain to clear cell tumors, which com-
prise over 75% of renal cell carcinomas. Relatively few studies have
examined associations by histological subtype. These report associa-
tions with clear cell and papillary type, but not with the rarer chromo-
phobe type (Patel et al., 2015; Purdue et al., 2013). Larger studies are
needed to characterize variations in the association between smoking
and histologic and molecular subtypes of renal cell cancer.
Renal Pelvis and Ureter. Active cigarette smoking is firmly
established as the major cause of urothelial cancers of the renal pel-
vis and ureter. Relative risk estimates exceed 3.0 in most studies
(McLaughlin et al., 1992), including the large prospective NIH-​AARP
cohort (Freedman et al., 2016). The estimates of attributable fraction
are 50% or higher in many parts of the world.
Urinary Bladder.  The association between active cigarette smok-
ing and cancer of the urinary bladder was first designated as causal by
the IARC in 1986 (IARC, 1986) and by the US Surgeon General in
1979 (US Department of Health and Human Services, 1979). Cigarette
smoking is the leading cause of bladder cancer in most countries (see
Chapter 52). As is the case for lung and laryngeal cancers, the asso-
ciation between smoking and bladder cancer has increased over the
last few decades. The relative risk in current compared to never smok-
ers increased from about 3 during the 1990s to approximately 4–​5 in
the last decade (Baris et al., 2009; Freedman et al., 2011; Purdue and
Silverman, 2016). The relative risk and attributable fraction estimates
have historically been higher among men than women (IARC, 2004),
but have converged over time in the United States. The attributable
fraction was estimated to be approximately 50% in both men and
women in the NIH-​AARP cohort (Freedman et al., 2011).
Metabolites of heterocyclic aromatic amines, polycyclic aromatic
hydrocarbons, and other carcinogens in tobacco are excreted in urine
(IARC, 2004; US Department of Health and Human Services, 2010).
Studies have investigated interactions between cigarette smoking and
inherited variants in metabolizing genes and have documented differ-
ences in risk associated with loci that affect N-​acetyltransferase (NAT2)
activity (Garcia-​Closas et al., 2013; Kilfoy et al., 2010). These stud-
ies, in combination with functional genomic analyses, have provided
important clues to bladder carcinogenesis (Chapter 52). Emerging data
on the somatic mutations in bladder cancer from The Cancer Genome
Atlas (TCGA) and similar projects (Cancer Genome Atlas Research,
 201
Tobacco 201
2014b) indicate that there are distinct molecularly defined subtypes of
bladder cancer. Future studies that examine associations between ciga-
rette smoking and molecularly defined subtypes will likely provide
further insights into carcinogenic mechanisms.
Cigarette Smoking and Reproductive Tract Cancers
The evidence that cigarette smoking causes cervical cancer and muci-
nous carcinoma of the ovary is designated as “sufficient” and is dis-
cussed here. The evidence that active smoking causes cancers of the
breast, vulva and vagina, and aggressive prostate cancer, or reduces
the risk of endometrial cancer, are considered “suggestive” and are
discussed later.
Uterine Cervix.  Cancer of the uterine cervix is consistently associ-
ated with cigarette smoking. Not until HPV infection was identified as a
necessary cause of cervical cancer, however, were concerns about con-
founding by sexually transmitted diseases addressed directly (IARC,
1995)  (Chapter  48). Later studies investigated cigarette smoking as
a cofactor for cervical cancer in HPV-​positive women and observed
consistent associations with both invasive squamous cell cancer and
carcinoma in situ (Castellsague and Munoz, 2003; International
Collaboration of Epidemiological Studies of Cervical Cancer et  al.,
2006). The relative risk for squamous cell carcinoma increases in cur-
rent compared to never smokers with the number of cigarettes smoked
per day and with younger age at starting smoking. No association is
observed between smoking and adenocarcinoma of the cervix, how-
ever. The IARC and the US Surgeon General designated the overall
relationship between active cigarette smoking and cervical cancer as
causal in 2004 (IARC, 2004; US Department of Health and Human
Services, 2004).
Ovary.  Well over 30 epidemiologic studies have investigated the
association of active cigarette smoking with ovarian cancer (IARC,
2012a). Most reported no overall association, although at least four
studies have reported a positive association between active cigarette
smoking and mucinous ovarian cancer (Collaborative Group on
Epidemiological Studies of Ovarian Cancer et al., 2012; Faber et al.,
2013; Gram et al., 2012; Wentzensen et al., 2016). Smoking has not
been associated with serous or endometrioid subtypes of ovarian can-
cer; an inverse association has been reported for clear cell tumors
(Wentzensen et al, 2016). Etiologic heterogeneity among subtypes of
ovarian cancer has also been observed for other established risk factors
besides smoking (Wentzensen et al., 2016).
Cigarette Smoking and Hematopoietic Cancers
As part of the 2001 WHO classification of hematopoietic and lym-
phoid neoplasms, “the leukemias” were classified into two major
groupings:  myeloid neoplasms (including acute myeloid leukemia,
myelodysplastic syndromes, and myeloproliferative neoplasms)
(Chapter 38) and lymphoid neoplasms, including lymphoid leukemias
(circulating phase) and lymphomas (solid phase) (Chapter 40).
Active cigarette smoking has consistently been associated with
increased risk of acute myeloid leukemia (AML), as discussed here,
but not other hematological or lymphoid malignancies, discussed later
in the chapter.
Myeloid Leukemia. The association between active cigarette
smoking and increased risk of AML was designated as causal by
both the US Surgeon General and the IARC in 2004. The relative
risk for current versus never smoking was 1.40 (95% CI: 1.22,1.60)
in a recent meta-​analysis of 23 studies and 7746 cases (Fircanis et al.,
2014). Accumulating evidence also suggests that there is also a posi-
tive association between smoking and the preleukemic myelodysplas-
tic syndromes. For example, the relative risk for current versus never
smoking was 1.81 (95% CI: 1.24, 2.66) in a 2013 meta-​analysis of 14
studies and 2588 cases, with evidence for a dose-​response relationship
(Tong et al., 2013).
Fewer studies have examined associations with other myeloid neo-
plasms, and the results have been mixed (Chapter 38). Existing stud-
ies have been limited, however, by the uncommon nature of many
types and subtypes of myeloid neoplasms and changing classification
schemes over time.
Cancer Sites with Suggestive or Limited Evidence
Breast
The question of whether a causal relationship exists between breast
cancer and exposure to tobacco smoke has been controversial for
over 20 years (Chapter 45). The 2014 US Surgeon General Report
comprehensively reviewed 15 cohort and 34 case-​control studies pub-
lished between 2000 and 2012 (US Department of Health and Human
Services, 2014), as well as studies previously considered by the IARC
(IARC, 2004, 2012a) and the US Surgeon General (US Department of
Health and Human Services, 2004). The 2014 Report devoted more
than 160 pages of tables and text to this issue. Based on the data then
available, it concluded that the evidence regarding active smoking as
a cause of breast cancer was “suggestive but not sufficient to infer a
causal relationship” (US Department of Health and Human Services,
2014). There was concern about the potential for residual confound-
ing by alcohol consumption and screening and inconsistencies regard-
ing the timing of exposure. An additional eight large cohort studies
and meta-​analyses have been published on smoking and breast can-
cer since the Surgeon General Report (Bjerkaas et al., 2013; Catsburg
et al., 2015; Dossus et al., 2014; Gaudet et al., 2013; Gram et al., 2015,
2016; Nyante et al., 2014; Rosenberg et al., 2013). These consistently
showed a 10%–​20% higher risk of breast cancer in women who are
current compared to never smokers and a somewhat stronger associa-
tion in women who initiated smoking before first birth. Given the sub-
stantial public health importance of the issue, the evidence should be
periodically reviewed by expert panels to identify and resolve residual
controversies.
Advanced Stage Prostate Cancer
Many studies have investigated associations between active cigarette
smoking and prostate cancer (Chapter 53). The relationship is compli-
cated by potential differences in PSA screening and healthcare utilization
among smokers and non-​smokers. For incident cancer, a large meta-​
analysis of more than 50,000 incident cases found an inverse association
comparing current to never smokers (RR = 0.90; 95% CI: 0.85, 0.96).
This association was limited to studies completed after 1995, however,
when PSA screening became widely adopted (Islami et al., 2014).
In contrast, studies of advanced stage or aggressive prostate can-
cer have tended to find positive associations with smoking (Zu and
Giovannucci, 2009), as have studies of prostate cancer mortality.
Current cigarette smoking was associated with increased mortality
from prostate cancer in a meta-​analysis of nearly 12,000 prostate
cancer deaths (RR:  1.24; 95% CI:  1.18, 1.31), with evidence for
a dose-​response relationship (Islami et  al., 2014). There remains
uncertainly about whether this association is causal, however. In
2014, the US Surgeon General comprehensively reviewed the evi-
dence and concluded that the available data were suggestive of no
causal relationship with incident prostate cancer but higher risk
of prostate cancer death (US Department of Health and Human
Services, 2014). Future epidemiologic and mechanistic research is
certainly warranted.
Vulva and Vagina
Cancers of the vulva and vagina are rare, but active cigarette smoking
is associated with increased risk of both sites in the limited number
of studies on this issue (Chen et al., 1999; Daling et al., 1992, 2002;
Hussain et  al., 2008; Madeleine et  al., 1997). A  strong interaction
between cigarette smoking and HPV 16 on the risk of vulvar cancer
was reported by Madeleine et al. (1997). More work is needed to char-
acterize the combined effect of smoking and HPV infection on these
cancers with respect to the timing of exposure (Chapter 49).
20
202 PART III:  THE CAUSES OF CANCER
Anus
Cancer of the anus, a malignancy with squamous or transitional cell
histology, has been repeatedly associated with cigarette smoking,
although confounding by HPV has not been excluded (Chapter  37).
Future studies with careful control of confounding are needed to
resolve the issue.
Biliary Tract
Studies have investigated associations between active smoking and
cancers of the biliary tract, including gallbladder, extrahepatic bile
duct, and ampulla of Vater (Chapter  34). Neither the IARC nor the
US Surgeon General has classified biliary tract cancer as being caus-
ally related to tobacco smoking. However, a recent meta-​analysis of
11 studies reported an association between ever smoking and gallblad-
der cancer (summary RR = 1.45; 95% CI: 1.11, 1.89) (Wenbin et al.,
2013). A separate meta-​analysis also found evidence for an associa-
tion with extrahepatic bile duct cancers (summary RR  =  1.23; 95%
CI: 1.01, 1.50) (Ye et al., 2013).
Keratinocyte Carcinomas
Keratinocyte cancers are the most common malignancies in humans.
These tumors, which include basal and squamous cell carcinomas,
arise from keratinocytes or their precursor cells (Chapter 58). Results
from case-​control and cohort studies generally suggest an associa-
tion between active cigarette smoking and squamous cell carcinomas.
A meta-​analysis in 2012 observed a relative risk of 1.54 (95% CI: 1.03,
2.31) comparing current to never smokers (Leonardi-​Bee et al., 2012).
In contrast, active smoking does not appear to increase risk of basal
cell carcinoma (0.89; 95% CI: 0.77, 1.03).
Cancer Sites Inversely Associated with Cigarette
Smoking
Endometrium
The incidence of endometrial cancer is inversely associated with
active cigarette smoking (IARC, 2004; US Department of Health
and Human Services, 2004). The relationship varies by smoking
status; risk was 30%–​40% lower in current smokers and 9%–​12%
lower among former compared to never smokers in an analysis of
the National Institutes of Health-​AARP Diet and Health Study (Felix
et al., 2014). The association is also stronger in postmenopausal than
premenopausal women (Zhou et al., 2008), but has not been exam-
ined in relation to tumor subtypes or molecular markers. A number of
mechanisms have been hypothesized, including effects of smoking on
circulating hormone levels (discussed in Chapter 47 for endometrial
cancer and in Chapter  45 for breast cancer, as well as in the 2014
US Surgeon General’s report) (US Department of Health and Human
Services, 2014).
Thyroid
Data from both case-​control and cohort studies suggest an inverse
association between active cigarette smoking and thyroid cancer
(Chapter 44). For example, the relative risks for current versus never
smoking was 0.68 (95% CI: 0.55, 0.85) in a pooled analysis of five
prospective US cohort studies (Wiersinga, 2013). The mechanisms
that underlie this association are unclear.
Melanoma
Both case-​control and cohort studies have examined the association
between active cigarette smoking and melanoma (Chapter 57). Most
studies have reported inverse associations. A  2015 meta-​analysis of
23 studies observed pooled relative risks of 0.70 (95% CI: 0.63, 0.78)
for current smoking and 0.90 (95% CI: 0.85, 0.95) for former smok-
ing (Li et al., 2015). The mechanisms underlying this association are
unclear. Non-​causal explanations, including confounding by sunlight
and other risk factors, selection bias, competing risks, and publica-
tion bias, have been suggested (Freedman et al., 2003; Li et al., 2015;
Thompson et al., 2013).
Cancer Sites with Limited Evidence or No Association
Small Intestine
Relatively few studies have examined active smoking in relation to
cancers of the small intestine, due to the rarity and heterogeneity of
these cancers. However, recent studies do not suggest an association
with either adenocarcinoma or carcinoid tumors, which make up the
two main histological types of small intestinal cancers (Chapter 35).
Testes
There is limited published evidence on cigarette smoking and cancer
of the testes (Brown et  al., 1987; Gallagher et  al., 1995; Henderson
et al., 1979), although three relatively recent studies have found asso-
ciations with marijuana smoking (Daling et  al., 2009; Lacson et  al.,
2012; Trabert et al., 2011) (Chapter 54).
Penis
Several case-​control studies have examined the association of active
cigarette smoking with penile cancer (Chapter 55); however, the results
to date are inconsistent, and confounding by HPV status is a concern.
Non-​Hodgkin Lymphoma
Numerous studies have investigated associations of active smoking
with non-​Hodgkin lymphomas (NHL), a heterogeneous group of over
40 lymphoid neoplasms (Chapter 40). Overall, there appears to be no
association, although associations with certain subtypes have been
noted (Morton et al., 2014).
Hodgkin Lymphoma
Active cigarette smoking is not generally considered to be a risk fac-
tor for Hodgkin lymphoma. However, results from a pooled analysis
from 12 case-​control studies in the InterLymph consortium (Kamper-​
Jorgensen et  al., 2013), as well as separate meta-​analyses, provide
evidence for a positive association (Castillo et al., 2011; Sergentanis
et al., 2013), at least for some subtypes (Chapter 39).
Multiple Myeloma
There is no evidence that smoking causes multiple myeloma
(Chapter 41).
Nervous System
Most studies have found no association with smoking and glioma or
other tumors of the nervous system (Chapter 56).
Soft Tissue Sarcomas
The data regarding cigarette smoking and soft-​tissue sarcoma are lim-
ited and mixed (Franceschi and Serraino, 1992; Serraino et al., 1991;
Zahm et al., 1992) (Chapter 43).
Fraction of Cancer Deaths Attributed
to Cigarette Smoking
Estimates of the fraction of all cancer deaths attributable to tobacco
use have changed little over the past 30–​40  years. In 1981, Doll
and Peto estimated that 30% (acceptable range 25%–​40%) of cancer
deaths in the United States could be attributed to tobacco smok-
ing (Doll and Peto, 1981). This estimate has persisted, despite
reductions in smoking prevalence and consumption, partly because
additional cancer sites have been designated as causally related to
smoking (US Department of Health and Human Services, 2014),
and partly because of the delayed effect of birth cohort patterns of
smoking on cancer risk. Jacobs et  al. recently estimated that the
population attributable fraction (PAF) for deaths from all cancers
combined was 28.7% when estimated conservatively, including only
deaths from the 12 cancers currently formally designated as caus-
ally related to smoking by the US Surgeon General, but that the PAF
was 31.7% when estimated more comprehensively, including excess
deaths from all cancers (Jacobs et al., 2015). The PAF also varies by
 203
Tobacco 203
state and region, reflecting the levels of tobacco use and control. In
a recent state-​wide analysis, the PAF estimates for active smoking
ranged from 16.6% in Utah to 34% in Kentucky (Lortet-​Tieulent
et  al., 2016). Although substantial, these estimates do not include
involuntary exposure to tobacco smoke or other types of tobacco
use such as cigars, pipes, or smokeless tobacco (Jacobs et  al.,
2015). The attributable fraction is smaller for incident cancers than
for deaths from cancer, due to the large contribution of breast and
prostate cancer to incident cases. Parkin has estimated that smoking
caused 60,000 new cancer cases in the United Kingdom in 2010
(19.4% of all new cases) (Parkin, 2011). The only global estimate
of smoking-​attributable cancer is by Jha, who estimated that 31% of
cancer deaths worldwide in men, and 6% in women, were attribut-
able to smoking (Jha, 2009).
CANCER RISKS FROM OTHER TOBACCO PRODUCTS
Both the IARC and the US Surgeon General have concluded that all
forms of tobacco use are carcinogenic. However, the evidence based
on combustible products other than cigarettes and on non-​combustible
tobacco products in relation to cancer is less extensive than that for
cigarettes (IARC, 2012b).
Other Combustible Products
Pipes and Cigars
Pipes and cigars are the main non-​cigarette smoked tobacco products
in high-​and many middle-​income countries. Pipe smoking was desig-
nated causally related to lip cancer in 1964 (US Department of Health
Education and Welfare, 1964). Exclusive pipe smoking was associ-
ated with increased mortality rates from four cancer sites among men
in an analysis of the CPS-​II cohort by Henley et al. (2004). Compared
to never smokers, men who currently smoked pipes but reported no
history of using other tobacco products had increased mortality from
cancer of the oral cavity/​pharynx (RR = 3.90; 95% CI: 2.15, 7.08),
larynx (RR = 13.1; 95% CI: 5.2, 33.1, lung (RR = 5.00; 95% CI: 4.16,
6.01), and esophagus (RR  =  2.44; 95% CI:  1.51, 3.95), as well as
coronary heart disease, stroke, and chronic obstructive pulmonary
disease (Henley et al., 2004). The risks were generally smaller than
those associated with cigarette smoking and similar to or larger than
those associated with cigar smoking.
A separate analysis of men who currently and exclusively smoked
cigars in CPS-​II reported increased death rates from cancers of the
lung (RR = 5.1; 95% CI: 4.0, 6.6), oral cavity/​pharynx (RR = 4.0; 95%
CI: 1.5, 10.3), larynx (RR = 10.3; 95% CI: 2.6,41.0), and esophagus
(RR  =  1.8; 95% CI:  0.9, 3.7) compared to never smokers (Shapiro
et al., 2000).
Both cigar and pipe smokers had increased incidence of head
and neck cancer in the International Head and Neck Cancer
Epidemiology (INHANCE) Consortium (Wyss et  al., 2013). The
risk of head and neck cancer was elevated for those who reported
exclusive cigar smoking (odds ratio  =  3.49; 95% CI:  2.58, 4.73)
or exclusive pipe smoking (odds ratio = 3.71; 95% CI: 2.59, 5.33)
compared to never smokers. The associations with cancers of the
head and neck and esophagus are predominantly with squamous cell
carcinoma rather than adenocarcinoma (Chang et al., 2015; National
Cancer Institute, 1998).
The INHANCE study separately examined the association of pipe
and cigar smoking with oral cavity cancer, based on approximately
4100 cases. The odds ratio (OR) estimates for oral cavity cancer were
2.51 (95% CI: 1.68, 3.75) for exclusive pipe smoking and 2.83 (95%
CI: 1.91, 4.17) for cigar smoking, compared to the risk of never smok-
ers (Wyss et al., 2013).
Bidis
As mentioned earlier, bidis are local tobacco products composed of
coarse and uncured tobacco, generally smoked without filters by men
in India (IARC, 2012a). Epidemiologic studies of bidi smoking and
cancer were reviewed by the IARC (IARC, 2012a). Additional cohort
and case control studies from India have reported associations between
bidi smoking and cancers of the oral cavity (Jayalekshmi et al., 2011;
Pednekar et  al., 2011), hypopharynx and larynx (Jayalekshmi et  al.,
2013; Pednekar et al., 2011), lung (Pednekar et al., 2011), esophagus,
and stomach (Jayalekshmi et al., 2015).
Kreteks, Waterpipes, and Chuttas
Kreteks, waterpipes, and chuttas are other smoked tobacco products
for which the long-​term effects on health are not well characterized.
Kreteks are clove-​flavored cigarettes, manufactured and widely con-
sumed in Indonesia (Palipudi K et al., 2015). They contain eugenol,
a natural compound found in high concentration in clove buds, which
has an anesthetic effect (Tobacco Atlas, 2015). Waterpipes, also known
as “hookah,” “narghile,” and “shisha,” are commonly smoked in North
Africa, the Mediterranean, and parts of Asia. They have recently
been popularized among students in high-​income countries. A meta-​
analyses of 13 case-​control studies suggest increased risks for water-
pipe use with cancers of the lung, esophagus, and possibly other sites
(Montazeri et al., 2017). However, most existing studies have method-
ological limitations, and high-​quality studies with standardized expo-
sure measurements are needed.
Chuttas are coarse cheroots, infrequently smoked in South India
with the lighted end inside the mouth (reverse smoking). They have
been associated with carcinomas of the hard palate in a case series
(Reddy, 1974).
SMOKELESS TOBACCO PRODUCTS
More than 300 million adults in 70 countries use smokeless tobacco
(National Cancer Institute and Centers for Disease Control and
Prevention, 2014). The IARC has determined that smokeless
tobacco is causally related to cancers of the esophagus, oral cav-
ity, and pancreas (IARC, 2012a). The majority of consumers (89%)
are in Southeast Asia, where these products are inexpensive, socially
acceptable, and readily available. In most countries, usage is more
common in men than women. In some countries, however (e.g.,
Bangladesh, Thailand, Cambodia, Malaysia, Vietnam, and some
African countries), use by adult women is similar to or greater than
that by adult men.
The chemical composition and levels of free nicotine vary widely
among these products. The concentrations of tobacco-​specific carcino-
gens (TSNAs) such as NNN and NNK can vary by several orders of
magnitude (National Cancer Institute and Centers for Disease Control
and Prevention, 2014). Products that are widely used in low-​and
middle-​income countries are usually handmade or produced by cottage
industries, and are consequently less standardized than manufactured
smoked or smokeless tobacco products. Studies of these products in
relation to cancer are complicated by their diversity and the frequent
use of more than one product. They involve exposure to complex and
varying mixtures of ingredients that may include other plant materi-
als, such as areca nut and tonka bean, in addition to tobacco (National
Cancer Institute and Centers for Disease Control and Prevention, 2014).
Betel Quid
Betel quid is commonly chewed in India and throughout much of
Southeast Asia and the Western Pacific. As mentioned earlier, it con-
tains a mixture of areca nut, betel leaf (Piper betle), and other ingredi-
ents, and can be made with or without tobacco. IARC Working Groups
have classified betel quid with tobacco as a Group 1 human carcino-
gen, based on cancers of the oral cavity (IARC, 2004) and squamous
carcinoma of the esophagus (IARC, 2012a). Areca nut is also classi-
fied as carcinogenic to humans. A  Taiwanese cohort study reported
associations between betel-​quid chewing and laryngeal cancer (Lee
et al., 2011), with consumption of > 20 quids daily associated with an
adjusted hazard ratio of 1.7 (CI: 1.2, 2.6).
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204 PART III:  THE CAUSES OF CANCER
Moist Snuff and Chewing Tobacco
In high-​income countries, the most commonly used traditional product
is moist snuff, followed by chewing tobacco. Fermentation and aging
are used to modify the taste of both moist and dry snuff, but these
increase the concentration of TSNA. The IARC has designated moist
snuff as carcinogenic to humans, based on cancers of the oral cavity
and pancreas (IARC, 2007). In high-​income countries, moist snuff is
increasingly sold in teabag-​like sachets that reduce the need to spit.
A  moist snuff, low-​nitrosamine product called snus is manufactured
and widely used in Scandinavia. The levels of TSNA are much higher
in commercial brands of moist snuff sold in the United States and in
products sold in low-​and middle-​income countries than in snus. Until
recently, tobacco control and regulatory efforts have focused primarily
on cigarettes, and have paid less attention to the marketing practices
and chemical composition of smokeless products. The situation is fur-
ther complicated in low-​and middle-​income countries by the unorga-
nized nature of a large business sector, which impedes product control
and regulation (National Cancer Institute and Centers for Disease
Control and Prevention, 2014).
Novel Smokeless Tobacco Products
As mentioned previously, tobacco manufacturers have introduced
novel smokeless tobacco products using innovations such as por-
tion pouches, dissolvable tobacco, unique flavorings (such as fruit
and candy flavors), electronic nicotine delivery systems (ENDS) and
varying nicotine levels, which may make products more attractive to
consumers, including those who have not previously used tobacco
products (National Cancer Institute and Centers for Disease Control
and Prevention, 2014). Among these, e-​cigarettes are by far the most
popular. E-​cigarettes are overtly marketed to smokers as a source of
nicotine in settings where they cannot smoke, and are informally posi-
tioned as cessation devices. They also are sold in a remarkable variety
of flavors, many of which appeal to youth.
The health effects of e-​cigarettes are at this point unclear. With their
recent introduction to the marketplace, e-​cigarettes may have long-​
term effects that will not be fully apparent for many years. In addition
to directly affecting health, they can indirectly affect disease risks by
modifying the use of other tobacco products. For example, adolescents
may choose e-​cigarettes as an alternative to cigarette smoking, or they
may become addicted to nicotine from e-​cigarettes and then prog-
ress to cigarette smoking. Cigarette smokers may use e-​cigarettes to
facilitate quitting, or alternatively may use ENDS to supplement their
nicotine intake in settings where they cannot smoke. Any product that
facilitates continued smoking instead of quitting will increase disease
risks. Even smokers who continue to smoke just a few cigarettes a day
have measurably higher risks of cancer and other chronic diseases than
those who quit (Inoue-​Choi et al., 2016).
INTERACTIONS WITH OTHER EXPOSURES
Alcohol
The combined effect of tobacco use and alcohol consumption has
been examined extensively for cancers of the oral cavity, pharynx, lar-
ynx, and esophagus and to a lesser extent for cancers of the liver and
pancreas (IARC, 2004). In the larger studies, cancer risk consistently
increased more rapidly with the combination of smoking and heavy
drinking than with either exposure alone. Case-​control studies that
evaluated statistical interaction formally demonstrated a greater than
multiplicative relationship with joint exposure.
Infectious Agents
Tobacco use is an established cofactor with human papillomavirus
infection for anogenital cancers (Chapter 24). There is intriguing, albeit
limited, evidence that tobacco use combined with certain infectious
agents may foster transformation of premalignant abnormalities into
invasive cancer of the liver, stomach, uterine cervix, and/​or lung. The
evidence currently available regarding possible interactions between
tobacco use and diet is limited.
Occupational Exposures
There are well established interactions between tobacco smoking and
several occupational exposures with respect to lung cancer. These
include asbestos and radon (National Research Council Committee
on Health Risks of Exposure to Radon, 1998). In general, the statis-
tical interaction between smoking and radon appears submultiplica-
tive, but without strong evidence against multiplicative interaction
(IARC, 2004).
INVOLUNTARY EXPOSURE TO TOBACCO SMOKE
Lung Cancer
Many authoritative scientific groups have concluded that involuntary
exposure to tobacco smoke causes lung cancer and coronary heart
disease in humans (Australian National Health and Medical Research
Council, 1987; IARC, 1986, 2004, 2012a; National Research Council,
1986; US Environmental Protection Agency, 1992; US Department of
Health and Human Services, 1986, 2006, 2014). The association has
long been judged to be causal based on its biologic plausibility, replica-
tion in multiple different settings by different investigators using a vari-
ety of study designs, and supportive clinical information. Biomarker
studies indicate that non-​ smokers exposed to secondhand smoke
absorb, metabolize, and excrete toxic constituents of tobacco smoke
(US Department of Health and Human Services, 2006). In fact, passive
smokers appear to have greater excretion of a metabolite of a tobacco-​
specific carcinogen than active smokers (Vogel et al., 2011). Studies of
genotoxicity document a greater prevalence of DNA adducts and strand
breaks in non-​ smokers exposed to secondhand smoke (Husgafvel-​
Pursiainen, 2004). The most recent comprehensive review by IARC
(2012a) cited more than 50 epidemiologic studies and meta-​analyses
published internationally since the first studies in Japan and Greece
reported increased lung cancer risk in non-​smoking women married to
cigarette smokers (Hirayama, 1981; Trichopoulos et al., 1981). Despite
this evidence, the tobacco industry has long sought to maintain the
appearance of controversy, as discussed in Chapter 17.
Breast Cancer
In contrast to the evidence on secondhand smoke and lung cancer,
reviews of breast cancer in relation to involuntary exposure have
reached different conclusions (California Environmental Protection
Agency, 1997; IARC, 2004, 2012a; Johnson, 2005; Miller et al., 2007;
US Department of Health and Human Services, 2006). The IARC
and the US Surgeon General have variously described the evidence
as “inconsistent” (IARC, 2004)  or as “suggestive but not sufficient”
to infer causality, whereas reviews by the California Environmental
Protection Agency in (California Environmental Protection Agency,
2005) and by a panel of researchers convened in Canada (Collishaw
NE et  al., 2009)  designated the evidence for secondhand tobacco
smoke as “consistent with a causal association in younger primarily
premenopausal women.”
Much of the supportive evidence comes from case-​control studies
that have attempted to collect full “lifetime exposure histories” of sec-
ondhand smoke (Collishaw NE et al., 2009). These studies observed
the strongest associations with breast cancer and were considered by
Collishaw et  al. to have the most complete information on lifetime
exposure to secondhand tobacco smoke from all sources. An important
limitation of these studies, however, is that they are also most suscep-
tible to recall bias, especially for exposures many years in the past,
during an era when exposure to secondhand smoke was ubiquitous
(IARC, 2012a).
 205
Tobacco 205
According to the IARC, the strongest support for the hypothesis comes
from a cohort study in Japan (Hanaoka et al., 2005), which reported sig-
nificantly increased risk (RR 2.6; 95% CI: 1.3, 5.2) of premenopausal
breast cancer in women who previously reported having ever lived with a
regular smoker or ever being exposed to secondhand tobacco smoke for
at least 1 hour per day in settings outside the home. The referent group
in this analysis included only nine unexposed cases, however. A weak
association between secondhand tobacco smoke exposure and premeno-
pausal breast cancer was also reported in the California Teachers cohort,
when menopausal status was defined by age at diagnosis rather than age
at entry into the study (Reynolds et al., 2006).
The absence of a strong and convincing relationship between breast
cancer and active smoking weakens the case for a causal relationship
with secondhand smoke, given that the level of exposure is orders of
magnitude lower. Theories have been advanced to explain why sec-
ondhand tobacco smoke might have a stronger effect on breast cancer
than active smoking (California Environmental Protection Agency,
1997; Collishaw NE et  al., 2009; Johnson, 2005), these assume the
existence of a bidirectional effect of tobacco smoke on breast cancer
risk, for which there is no direct evidence (IARC, 2012a).
Other Cancer Sites
The IARC 2012 review also comprehensively considered the epide-
miologic evidence regarding involuntary smoking and cancers of the
upper aerodigestive tract, gastrointestinal and genitourinary systems,
brain, leukemias, lymphomas, and childhood cancers. The evidence
regarding these sites remains inadequate.
OPPORTUNITIES FOR PREVENTION
Well-​established “best practices” in tobacco control are discussed
in Chapter 62.1. The implementation of these can effectively reduce
tobacco use and prevent the devastating effects of tobacco on health
(US Department of Health and Human Services, 2014). Long-​term
progress depends on the systematic application of primary prevention
measures that can reduce the initiation of tobacco use by young people
and end the pandemic during the second half of the twenty-​first cen-
tury. In the near term, substantial reductions in smoking-​attributable
cancers and other diseases can be achieved by providing counseling
and treatment to facilitate cessation among the 36.5 million Americans
and others who currently smoke (Jamal et al., 2016).
Increasing the Age at Initiation
A growing public health emphasis has been placed on increasing the
minimum age of tobacco purchase to age 21 (Winickoff et al., 2014).
As described earlier, most cigarette smokers in economically devel-
oped countries begin smoking in their teenage years. Earlier age at
initiation has been associated with increased addiction to nicotine and
greater risk of nearly all smoking-​related diseases. Furthermore, the
main source of cigarettes for minors is from others under the age of
21 (DiFranza and Coleman, 2001). Adolescent brains have also been
shown to be particularly sensitive to the addictive properties of nico-
tine (US Department of Health and Human Services, 2012). For these
and other reasons, modeling studies, including those in a compre-
hensive 2015 report by the Institute of Medicine, estimate that rais-
ing the cigarette smoking age to 21 years could substantially decrease
the prevalence of cigarette smoking in the population (Institute of
Medicine, 2015). At the time of this writing, at least 200 local and
two state governments have implemented “tobacco 21” policies, and
emerging data suggest that these may indeed affect teenage smoking
prevalence (Kessel Schneider et al., 2016).
Tobacco Cessation
Many of the adverse effects of tobacco use can be prevented or
reversed by cessation (IARC, 2004, 2012a). Paradoxically, the benefits
of cessation appear more quickly than does the increase in cancer risk
after initiation, presumably because quitting removes late-​stage pro-
moting effects of smoking on carcinogenesis. The benefits of stopping
smoking or other forms of tobacco use are best seen by comparing
risk among smokers who quit at various ages with the risk of those
who continue to smoke (Figure 11–​11). Smoking cessation at any age
avoids much of the future risk seen with continued smoking. The rel-
ative and absolute benefits are greatest when cessation occurs at an
early age, but are substantial even when stopping occurs by age 50
or 60 (Peto et al., 2000). The relative risks among persons who quit
smoking compared with those who continue are progressively smaller
the earlier the age of cessation and the longer the time that has elapsed
since cessation. Only in smokers who quit at younger ages does the
relative risk of death from these cancers approach unity when com-
pared with that of persons who have never smoked.
Analyses of cessation are more informative when based on the age
at cessation than time since quitting, since the relative and absolute
benefits vary by age, and individual smokers can more easily relate
their personal situation to age at quitting. It is also more informative to
compare smokers who have quit smoking to those who continue than
to compare them with lifelong non-​smokers. Smokers have the option
to quit smoking but not to become lifelong non-​smokers.
FUTURE RESEARCH DIRECTIONS
Despite progress in reducing cigarette smoking in many high-​and
middle-​income countries and the immense literature that already exists
on the harmful health effects of tobacco use, continuing research is
needed to strengthen global tobacco control efforts and address unre-
solved etiologic and mechanistic questions. The significant expansion
of efforts to collect nationally representative surveillance data (CDC,
2016), especially in low-​and middle-​income countries, creates opportu-
nities to monitor patterns of tobacco use in countries where the number
of smokers is expected to increase most rapidly over the next decade.
Studies that track the implementation of “best practices” for compre-
hensive tobacco control, as mandated by the Framework Convention on
Tobacco Control (FCTC) (WHO, 2003), are essential in countries at all
levels of economic development. Other types of application research,
such as comparative effectiveness studies, can be used to tailor inter-
ventions to specific populations and social contexts. Descriptive studies
can characterize the temporal and geographic relationships between the
implementation of tobacco control measures and changes in knowl-
edge, attitudes, beliefs, and behaviors in populations. Assessment of
key indicators, such as tobacco use by medical providers and average
age at initiation, are especially informative in this regard.
The introduction of novel tobacco products, such as e-​cigarettes,
creates both challenges and opportunities for research. For example,
much larger randomized clinical trials are urgently needed to deter-
mine whether e-​cigarettes are effective for smoking cessation, and, if
so, to compare their efficacy to that of established cessation treatments.
More studies are needed to characterize the impact of e-​cigarettes on
nicotine dependence, intermediate endpoints, and patterns of tobacco
usage in populations. Longitudinal studies are needed to determine
whether e-​cigarettes as currently marketed deter the uptake of ciga-
rette smoking in young people or simply addict them to nicotine.
Continued surveillance research is needed to monitor the shifting
patterns of tobacco use, trends in dual or poly use, and increased con-
sumption of roll-​your-​own cigarettes and small filter-​tip cigars to cir-
cumvent the excise taxes on cigarettes. Research on marketing must
increasingly monitor point-​of-​sale promotions (discounts, single ciga-
rettes) designed to counter tobacco control policies.
Important etiologic questions remain unresolved as well, such as
whether active cigarette smoking is causally related to breast cancer
and aggressive prostate cancer. Larger studies that incorporate detailed
information on known risk factors for these cancers and screening
are needed to resolve these controversies. It is hypothesized, but not
firmly established, that the initiation of smoking between menarche
and the time of first childbirth confers increased susceptibility to pre-
menopausal breast cancer, and that tobacco smoke has a bidirectional
206
206 PART III:  THE CAUSES OF CANCER
effect on the metabolism of steroidal sex hormones (US Department of
Health and Human Services, 2014). The availability of more accurate
high-​throughput measurement of sex hormones and their metabolites
(Chapter 22) could be used to test the latter hypothesis. Similarly, mea-
surements of harmful and potentially harmful constituents (HPHCs)
among users of different classes of tobacco products have the potential
to refine our understanding of tobacco carcinogenesis and may con-
tribute to regulation.
Studies based on histologic or molecular characteristics have already
demonstrated associations with cigarette smoking for some tumor sub-
types but not others. Broader efforts are needed to identify molecular
subtypes associated with tobacco use across a range of cancer sites.
Advances in molecular and genomic technologies create opportunities
to study the effects of tobacco exposure on the genome and transcrip-
tome (methylation, mutational patterns, mosaicism, mRNA expres-
sion). Already cigarette smoking has been demonstrated to cause
wholesale genomic and epigenetic changes in users. Studies to assess
whether smoking affects later stage molecular events in prostate can-
cer could provide mechanistic information to assess the causality of its
relationship with advanced disease.
Finally, there is a continuing need to assess the usage and disease
consequences of multiple types of tobacco products, including bio-
markers of exposure, measures of addictiveness, and transition to
manufactured cigarettes.
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 213
12 Alcohol and Cancer Risk
SUSAN M. GAPSTUR AND PHILIP JOHN BROOKS
OVERVIEW
Alcoholic beverages have been consumed by humans for thousands of
years. Currently, the alcoholic beverages most frequently consumed are
spirits, beer, and wine, respectively. Worldwide, an estimated 47.7% of
men and 28.9% of women aged 15 years or older report drinking alco-
hol, and approximately 16.0% of drinkers engage in heavy, episodic
(binge) drinking. In 2010, alcoholic beverage consumption caused an
estimated 3.3  million deaths worldwide, and contributed to injuries,
violence, liver cirrhosis, social disruption, and at least seven differ-
ent types of cancer. The International Agency for Research on Cancer
(IARC) classifies exposure to both ethanol in alcoholic beverages and
acetaldehyde, the primary metabolite of ethanol, as carcinogenic to
humans (Group 1) based on “sufficient” evidence that alcoholic bev-
erage consumption is causally related to cancers of the oral cavity,
pharynx, larynx, esophagus, liver, colorectum, and female breast. The
World Cancer Research Fund/​American Institute of Cancer Research
Continuous Update Project (WCRF/​AICR CUP) characterized the
evidence as “limited” that heavy alcohol consumption increases pan-
creatic cancer risk. The IARC also notes lack of carcinogenicity of
alcohol consumption with non-​ Hodgkin lymphoma and renal cell
carcinoma, and for other cancers the evidence is inconclusive. The
biologic mechanisms by which alcohol and its primary metabolite
acetaldehyde affect cancer risk appear to vary across anatomic sites.
Broadly, these mechanisms involve DNA and protein damage from
acetaldehyde and oxidative stress, nutritional malabsorption, and met-
abolic effects, and for breast cancer, increased estrogen levels. In addi-
tion, carcinogenic contaminants can be introduced during alcoholic
beverage production. While there are known harmful effects of alcohol
consumption, relative to no consumption, light to moderate consump-
tion has been associated with reduced risk of coronary heart disease,
although recent Mendelian randomization studies have challenged this
finding. The World Health Organization (WHO) has increased global
surveillance of alcohol consumption and encourages national efforts to
apply evidence-​based policies to reduce consumption.
INTRODUCTION
Alcoholic beverages have been consumed for religious, social, and
cultural reasons for thousands of years. Archaeological evidence indi-
cates that honey, rice, and hawthorn fruit or grapes were fermented
to produce alcohol as early as 7000–​6600 bc in China’s Yellow River
Valley (McGovern et  al., 2004). Today, the most common commer-
cially produced alcoholic beverages are spirits distilled from grains,
sugars, fruits or vegetables, beer from barley, and wine from grapes
(World Health Organization, 2014). In some developing countries,
locally or home-​produced alcoholic beverages from, for example, fer-
mented apples (cider) or honey-​water (mead) are important contribu-
tors to daily consumption (World Health Organization, 2014).
The principal form of alcohol found in alcoholic beverages is ethanol
(ethyl alcohol), which is produced by the fermentation of sugars and
starches by yeast. Ethanol is a central nervous system depressant that
motivates recreational use of alcohol, and engenders a sense of excite-
ment, sociability, pleasure, and intoxication. At progressively higher
blood levels, it impairs sensory and motor function, cognition, and judg-
ment; severe intoxication can produce stupefaction, unconsciousness,
and death. The WHO estimates that 5.9% of all deaths (7.4% of males
and 4% of females) and 5.1% of disease worldwide is attributed to
alcohol, and has identified 60 common alcohol-​related conditions and
more than 200 conditions in which alcohol consumption is recog-
nized as a component cause (World Health Organization, 2014). The
adverse effects of harmful drinking include, for example, intentional
and unintentional injuries, violence, acute alcohol poisoning, liver cir-
rhosis, social disruption, impoverishment, neuropsychiatric disorders,
gastrointestinal and cardiovascular problems, fetal alcohol syndrome,
preterm complications, diabetes mellitus, exacerbation of certain infec-
tious diseases, and seven types of cancer (IARC, 2012).
Acetaldehyde is the primary metabolite of ethanol from alcoholic
beverage consumption; preformed acetaldehyde can be measured
in alcoholic beverages. The cytotoxic, mutagenic, and carcinogenic
effects of acetaldehyde, including formation of DNA adducts and inhi-
bition of DNA repair, have been shown in eukaryotic cells and animal
models (Seitz and Stickel, 2010). Acetaldehyde related to alcohol con-
sumption has been classified as carcinogenic to humans (IARC, 2012).
METABOLISM OF ALCOHOL AND ACETALDEHYDE
After ingestion, alcohol undergoes “first pass metabolism” (FPM) in the
upper aerodigestive tract (UADT) and liver, which reduces the amount
of alcohol in circulation relative to the amount consumed. FPM begins
in the oral cavity, where both human cells and microorganisms in saliva
oxidize alcohol to acetaldehyde. An estimated 5%–​14% of the oral dose
of alcohol undergoes FPM (Ammon et al., 1996), with a slightly lower
percent when gastric emptying is rapid or the amount consumed is high.
Alcohol that does not undergo FPM is distributed throughout the body;
the majority (about 90%) of absorbed alcohol is metabolized in the
liver. The enzymes involved in the metabolism of alcohol are expressed
in many tissues throughout the human body, albeit at varying levels in
different cell types (IARC, 2010), and thus play a role in the toxicity
and/​or carcinogenicity of alcohol in specific tissues.
In humans, the metabolism of alcohol primarily involves a two-​step
process in which ethanol is first oxidized to acetaldehyde by the enzyme
alcohol dehydrogenase (ADH), and then acetaldehyde is oxidized to
acetate (acetic acid) by the enzyme aldehyde dehydrogenase (ALDH).
The activity of these enzymes profoundly influences the ability of a
drinker to metabolize alcohol and detoxify acetaldehyde. The human
genome contains multiple ADH and ALDH genes that are expressed in
different tissues. The ADH1A, ADH1B, and ADH1C genes encode the
ADH1 α, β, and γ protein subunits, respectively. These different sub-
unit proteins form dimers that are the active form of the ADH enzyme,
and are expressed at high levels in the liver. In contrast, the ADH7
protein is expressed in the stomach and the gastrointestinal tract, and
is thought to play a role in FPM in these tissues (Crabb et al., 2004).
The ADH and ALDH genes encode proteins that combine to form
the functional enzymes and are polymorphic in humans; the preva-
lence of functional variants varies among different geographic popula-
tions (Figure 12–1). Mendelian randomization studies have examined
the role of ADH and ALDH gene polymorphisms on alcohol avoidance
and consumption, and have informed studies of alcohol-​associated
chronic diseases (Holmes et al., 2014). As discussed later in the chap-
ter, the *2 allele of ADH1B and the *2 allele of ALDH2 are particularly
relevant to alcohol-​related carcinogenesis.
213
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214 PART III:  THE CAUSES OF CANCER

The ADH1B*2 allele, which is common in Asian and Ashkenazi
Jewish populations, encodes the β2 subunit that forms an enzyme
with roughly 40-​ fold greater activity at generating acetaldehyde
from ethanol than the β1 subunit, which is encoded by the ADH1B*1
allele. ADH1B*1 is commonly found in European and some African
populations. The ADH1B*3 allele, which commonly occurs in Native
American and other African populations, encodes a subunit of the
enzyme with low affinity for ethanol (Crabb et al., 2004).
In humans, ALDH enzymes are coded by 19 different genes
(Koppaka et  al., 2012). Based on their affinity for acetaldehyde, the
ALDH isoforms that are thought to play a role in ethanol-​derived acet-
aldehyde metabolism include ALDH1A1, ALDH1B1 and ALDH2.
Other ALDH enzymes have low affinity for acetaldehyde and are
unlikely to play a significant role in acetaldehyde metabolism under
normal physiologic conditions.
A polymorphism of ALDH2 (rs671) is of particular relevance for
understanding the relationship of alcohol consumption to acetaldehyde
production and cancer risk. Whereas the ALDH2*1 allele produces a
protein with normal catalytic activity, the ALDH2*2 allele encodes the
amino acid LYS instead of GLU at position 487, resulting in a cata-
lytically inactive enzyme subunit. The ALDH2*2 allele is found pre-
dominantly in East Asians (Japanese, Chinese, and Koreans) (Goedde
and Agarwal, 1987). When individuals carrying the ALDH2*2 allele
drink alcohol, they experience a variety of aversive effects, including
nausea, headache, and facial flushing, resulting from elevated acetal-
dehyde concentrations in the body. Individuals who are homozygous
for the ALDH2*2 allele have essentially undetectable ALDH2 activity,
and they generally cannot tolerate alcohol due to severe acetaldehyde
toxicity. Paradoxically, heterozygotes for the ALDH2*2 allele have an
enzyme activity roughly 1% of that of ALDH2*1 homozygotes, far
less than the 50% value typically expected. The ALDH2 enzyme is
a functional tetramer, and the low enzyme activity among heterozy-
gotes suggests that the presence of even one inactive subunit may be
sufficient to prevent enzyme activity (Crabb et  al., 2004). However,
individuals who are heterozygous for the ALDH2*2 allele can become
tolerant to the side effects of alcohol and can become heavy drinkers,
with significantly elevated risk of alcohol-​related esophageal cancer
(Yokoyama et al., 1996).
In addition to the enzymes in human cells, other important contribu-
tors to alcohol metabolism are microbes (particularly bacteria) resi-
dent in the human body. Some of these bacteria express ADHs. The
microbial metabolism of alcohol to acetaldehyde can result in locally
high concentrations of extracellular acetaldehyde in the oral cavity and
intestine (Homann et  al., 2000), which are thought to contribute to
alcohol-​related carcinogenesis in those tissues.
Aside from ADH and ALDH, another enzyme that metabolizes alco-
hol and affects alcohol-​related carcinogenesis is the ethanol-​inducible
cytochrome P4502E1 (CYP2E1) (Cederbaum, 2012). While both ADH
and CYP2E1 convert alcohol to acetaldehyde, there are several important
differences between these two enzymes. Whereas the level of CYP2E1
protein increases in the presence of high concentrations of circulating
alcohol, the level of ADH is generally not affected. This alcohol-​related
increase in CYP2E1 occurs because ethanol is both a substrate for the
enzyme and, when present, stabilizes the enzyme against degradation.
Alcohol metabolism by CYP2E1 significantly increases at alcohol con-
centrations above ≈ 20 mM (Asai et al., 1996; Salaspuro and Lieber,
1978). For comparison, the legal blood alcohol limit for driving in many
countries is 0.08%, which corresponds to an alcohol concentration of
approximately 17 mM. CYP2E1 oxidation of ethanol can generate
reactive oxygen species that react with cellular lipids to form highly
mutagenic DNA adducts (Linhart et al., 2014). Thus, at high blood con-
centrations, a qualitatively different type of alcohol metabolism takes
places in human cells, resulting in an additional mechanism of genotox-
icity separate from that involving acetaldehyde (Figure 12–2).
EXPOSURE ASSESSMENT
Ethanol Content in Alcoholic Beverages
The content (concentration) of pure ethanol in alcoholic beverages
is usually expressed either as percent of volume (% vol.), or “proof”

Ethanol Acetaldehyde Acetate

ADH ALDH

Cell death/hyper-regeneration
Mutagenesis
carcinogenesis
Acetaldehyde-DNA adducts

O O O OH

N NH N NH N N

N N N
N N CH3 N NH N N CH3
HO HO HO
O O O H
H3C
O
OH OH OH

N2-ethylidenedeoxyguanosine Crotonaldehyde-propanodeoxyguanosine adducts

Figure 12–​1.  Alcohol and acetaldehyde metabolism, acetaldehyde–​DNA adducts. Top: schematic diagram of enzymatic pathway of alcohol and acet-
aldehyde metabolism. As noted in the text, ALDH2 is the primary ALDH involved in the metabolism of acetaldehyde derived from alcohol metabo-
lism. Other ALDHs may be involved in the acetaldehyde metabolism in certain tissues. Bottom panel: Structures of acetaldehyde-​related DNA adducts.
Crotonaldehyde-​derived adducts can exist in either of two forms, ring-​opened (left) and ring-​closed (right). The ring-​opened forms can result in DNA
intrastrand crosslinks. ADH: alcohol dehydrogenase; ALDH: aldehyde dehydrogenase.
 215

Alcohol and Cancer Risk 215

Ethanol Acetaldehyde
CYP2E1

O2
Reactive oxygen H2O
species

Lipid peroxidation Ethenobase-DNA Mutagenesis

products adducts carcinogenesis

N N O

N N N N N
N N
N N O N N
HO HO
O HO O
O

OH OH
OH

1,N6 etheno-deoxyadenosine 3,N4-etheno-deoxycytidine 1,N2-ethenodeoxyguanosine

Figure 12–​2.  Alcohol metabolism by CYP2E1 and ethenobase DNA adducts. Top: schematic diagram of alcohol metabolism by cytochrome P450 2E1
(CYP2E1). CYP2E1 utilizes molecular oxygen to oxidize ethanol to acetaldehyde, generating H2O in the process. CYP2E1 can also generate reactive
oxygen species, including superoxide radical and hydrogen peroxide, which can further react with cellular lipids, resulting in lipid peroxidation and etheno-​
base DNA adducts. The bottom panel shows the molecular structures of three ethenobase DNA adducts.

(which in the United States is twice the percent of alcohol by volume
[e.g., 80 proof is 40% vol.]). The ethanol content is typically lowest
(4%–​5% vol.) in commercially produced beer, intermediate (about
12% vol.) in wine, and highest (about 40% vol.) in distilled spirits.
However, the concentration of ethanol in each beverage type varies
widely (IARC, 2010). In beer, the ethanol content ranges from 2.3%
vol. to over 10% vol., with home-​or locally produced beverages such
as sorghum beer having lower content. The ethanol content in wine
ranges from 8% to 15% vol., and in spirits ranges from 20% vol.
(aperitifs) to well over 40% vol. (e.g., 80% vol. in certain kinds of
absinthe).
The absolute amount of pure ethanol contained in a serving of
alcoholic beverage is estimated by multiplying the standard volume
of an alcoholic drink by its alcohol content. The amount is expressed
either as mL or as grams of pure ethanol (1 mL of ethanol = 0.79 g).
The volume of a standard alcohol drink in the United States is gen-
erally 12 ounces of beer, 5 ounces of wine, or 1.5 ounces of distilled
spirits (Centers for Disease Control and Prevention, 2016). Thus,
for example, a 12 oz. serving of beer with an ethanol content of
5% vol. contains about 14 grams of ethanol (i.e., 355 mL × 0.05 ×
0.79 g/​mL).
Acetaldehyde Content in Alcoholic Beverages
Although most exposure to acetaldehyde from consuming alcoholic
beverages results from ethanol metabolism, high concentrations
of preformed acetaldehyde are present in alcoholic beverages that
are commonly consumed in many countries (IARC, 2012). Average
levels vary from 9 mg/​L in beer, 34 mg/​L in wine, 66 mg/​L in spir-
its, and 90 mg/​L in unrecorded alcohol (Lachenmeier et  al., 2012).
Concentrations are especially high in distilled beverages from Brazil,
the People’s Republic of China, Guatemala, Mexico, and the Russian
Federation, as well as in fortified wines such as calvados and spirits
distilled from fruit in Europe.
Surveillance and Epidemiologic Assessment
of Alcohol Consumption
For both surveillance and epidemiologic studies, the assessment of
alcohol intake takes into account the volume and ethanol content of
beverage(s) consumed. Intake is expressed as the average amount
of pure ethanol (in g) consumed per person per unit time.
At the population level, surveillance data of alcohol consumption typi-
cally reflect annual consumption of pure ethanol per capita, including
both recorded data and estimates of unrecorded data. WHO estimates
average annual per capita consumption for ages 15+ years to include
older adolescents as well as adults (World Health Organization, 2014).
Estimates of recorded consumption derive from official statistics on
production, trade, taxes, and/​or sales. However, estimates of unrecorded
consumption, which comprises nearly 25% of all alcohol consumed, may
include formal or informal accounts of domestic production, illegal sales,
smuggling and cross-​border shopping, and in some parts of the world a
substantial fraction of alcohol consumption is unrecorded (World Health
Organization, 2014). This is particularly important when estimating
consumption in the poorest regions of Africa, Asia, and South America,
and where drinking is prohibited by religion. For example, although the
total level of consumption is very low in Islamic countries in the Eastern
Mediterranean Region, the proportion contributed by unrecorded con-
sumption is high (i.e., more than 50% of consumption). Consumption by
tourists is excluded from these estimates where possible.
In large epidemiologic studies of cancer risk, individual alcoholic
beverage consumption is often self-​reported on food frequency ques-
tionnaires (FFQ). An FFQ queries study participants on the average
frequency of consumption (number of days per week or month), the
usual quantity consumed (number of drinks), and the types of alco-
holic beverages (e.g., spirits, can/​bottle of beer, glass of red or white
wine) consumed during a specified time period (usually the previous
year). Intake is then characterized in terms of either average consump-
tion of ethanol by weight (expressed as grams [g]‌per day) or the aver-
age number of alcoholic beverages consumed per day or per week.
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216 PART III:  THE CAUSES OF CANCER
The validity of self-​reported information on alcohol consumption
has been questioned because of poor recall, inaccurate estimation of the
number of drinks consumed on drinking days, inability to report aver-
age intake according to standard drink sizes (Stockwell et al., 2004),
and variable drinking patterns (Boniface et al., 2014). To address some
of these concerns, several large epidemiologic studies compared alco-
hol intake data estimated from daily diaries or multiple 24-​hour recalls
to alcohol intake data obtained from FFQs, and found the correlations
to be high (range from 0.7 to 0.9) (Giovannucci et  al., 1991; Kaaks
and Riboli, 1997). These findings suggest that the self-​reported data on
usual alcohol consumption are reasonably consistent across different
methods of collection. However, this comparison does not address all
issues of underreporting, such as differences between actual drink size
consumed and standard drink sizes. While misreporting does not influ-
ence the conclusion that alcohol is a human carcinogen, it can affect the
quantitative estimates of the cancer risk associated with a given amount
of consumption. Therefore, methods have been developed to correct
estimates of relative risk (Rosner, 1995), and population-​attributable
risk for errors in the measurement of alcohol consumption (Shield
et al., 2013).
Another source of error occurs when weekly alcohol consumption
is divided by seven to estimate the number of drinks consumed per
day. As discussed elsewhere (Brooks and Zakhari, 2013), consum-
ing seven drinks per week might not correspond to consuming one
drink per day. An individual who drinks three to four drinks on each
weekend night, but nothing during the rest of the week, might report
seven drinks per week. However, this pattern of consumption could
produce a blood alcohol level sufficient to induce CYP2E1, which
would not be induced by actual consumption of one drink per day.
As noted earlier, the induction of CYP2E1 has distinct biological and
genotoxic consequences, with mechanistic implications for alcohol-​
related carcinogenesis.
GLOBAL PATTERNS OF ALCOHOL CONSUMPTION
The Global Information System on Alcohol and Health provides infor-
mation on 180 alcohol-​related indicators for 194 WHO member states
and two associate members. This information is used for the WHO
Global Status Report on Alcohol and Health and is a valuable resource
for worldwide, regional, and country-​specific estimates of total alco-
hol consumption (both recorded and unrecorded) (World Health
Organization, 2014). Summaries of international statistics on alcohol
consumption have been reported for the six WHO regions:  Region
for the Americas (AMR), South-​East Asia Region (SEAR), European
Region (EUR), Eastern Mediterranean Region (EMR), African Region
(AFR) and Western Pacific Region (WPR). These region-​specific sum-
maries provide a useful comparison of alcohol consumption across
the world.
Types of Alcoholic Beverages Consumed
Globally, distilled spirits comprise 50.1% of total recorded alcohol
consumption, beer accounts for 38.8%, wine for 8.0%, and other
commercially produced alcoholic beverages for the remainder.
Consumption patterns vary regionally, however. Wine consumption
accounts for one-​fourth (25.7%) of total consumption in the WHO
EUR and one-​ninth (11.7%) of total consumption in the WHO AMR.
Beer accounts for over-​half (55.3%) of the consumption of alcoholic
beverages in the WHO AMR.
Prevalence of Current Alcohol Drinkers and
Abstainers
Worldwide, an estimated 38.3% of the population aged 15+ years
report current alcohol consumption. However, there are substantial
differences in the prevalence of current drinkers by WHO region. The
lowest prevalence of current drinkers is in the EMR (5.4%) and the
highest prevalence is in the EUR (66.5%), followed closely by the
AMR (61.5%). Interestingly, only 14.7% of the world’s population
aged 15+ years lives in the EUR, but residents of this region account
for more than 25.7% of global consumption.
Males are 1.6 times more likely to be current alcohol drinkers than
females (47.7% vs. 28.9%, respectively). This gender difference varies
regionally, and is greater in the SEAR (i.e., 21.7% of males vs. 5% of
females) than in the EUR or AMR, where the ratio of male to female
current drinkers is 1.2 and 1.3, respectively. In the EUR, 73.4% of
males and 59.9% of females are current drinkers.
Worldwide, 61.7% of the population aged 15+ years did not drink
alcohol in the past 12 months; about half of the population report life-
long abstinence. There is wide variation in the prevalence of absten-
tion across WHO Regions, but females are more likely to be abstainers
than males.
Per Capita Amount of Alcohol Consumed
In 2010, the global average annual consumption per capita of pure
ethanol among persons aged 15+ years was estimated to be about 6.2
liters, or about 13.5 g/​day per capita. The average annual per capita
consumption was highest in the EUR with 10.9 liters and the lowest in
the EMR with 0.7 liters.
Since only a subset of the population consumes alcohol, the
worldwide average annual alcohol consumption per capita is
considerably higher when the estimate is restricted to drinkers.
The average for those who drink alcohol is 17.2 liters per year,
with a range of 11.3 liters in the EMR to 23.1 liters in the SEAR.
Worldwide, men who drink alcohol consume more than twice as
much than women; the average annual per capita consumption
among male drinkers (aged 15+ years) was 21.2 liters and among
female drinkers was 8.9 liters of pure ethanol. The sex difference
in average annual alcohol consumption among drinkers varies con-
siderably across WHO regions; in the SEAR annual consumption is
3.2 times greater among male than among female drinkers, and in
the AFR annual consumption is 1.7 times greater among male than
among female drinkers.
Prevalence of Heavy Episodic Drinking
Globally, approximately 7.5% of the total population aged 15+ years
and 16.0% of drinkers aged 15+ years engage in heavy episodic drink-
ing (i.e., defined as 60 or more g of pure ethanol on at least one occa-
sion at least monthly).
Trends in Consumption
In some parts of the world, alcohol consumption increased from 2005
to 2010, whereas in other parts of the world, consumption decreased or
remained stable. For example, the prevalence of current alcohol drink-
ing in those aged 15+ years increased from 58.3% to 61.5% in the
AMR, from 3.5% to 5.4% in the EMR, and from 10.7% to 13.5% in
the SEAR. Conversely, from 2005 to 2010 the prevalence of current
drinking decreased in the EUR from 68.8% to 66.4%, and in the WPR
from 56.3% to 45.8%, but remained stable in the AFR at approximately
29%. Worldwide the total average annual per capita alcohol consump-
tion remained stable between 2005 and 2010 at approximately 6.1 and
6.2 liters, respectively. However, there was a slight decrease in con-
sumption in the EUR from 12.2 to 10.9 liters and an increase in con-
sumption in the SEAR from 2.2 to 3.4 liters. Some of the differences
in the prevalence of current drinkers and in the average annual amount
consumed per capita are due to changes over time in the available data
and methods to estimate consumption, and therefore these differences
should be interpreted cautiously.
Per capita alcohol consumption among those aged 15+ years is
expected to increase slightly through 2025. In particular, without
effective policies to prevent an increase, the highest increase in aver-
age annual per capita consumption is expected to occur in the WPR
(i.e., from 6.8 liters to 8.3 liters).
 217
Alcohol and Cancer Risk 217
Patterns of Consumption by the Economic Wealth
of a Country
The economic wealth of a country correlates with the prevalence of
current drinking, the amount consumed, and the prevalence of heavy
episodic drinking. The prevalence of current drinking is 18.3% in
low-​income countries, 19.6% in middle-​income countries, 45% in
upper middle-​income countries, and 69.5% in high-​income countries.
Similarly, average annual per capita alcohol consumption in the total
population aged 15+ years ranged from 3.1 liters in low-​income coun-
tries to 9.6 liters in high-​income countries. Furthermore, the preva-
lence of heavy episodic drinking among those who drink alcohol is
11.6% in low-​income countries to 22.3% in high-​income countries.
TYPES OF CANCER CAUSED BY ALCOHOL
CONSUMPTION
The consumption of alcoholic beverages was first classified as carci-
nogenic to humans in 1987 by the International Agency for Research
on Cancer (IARC, 1988). At that time, the evidence for causality was
deemed to be “sufficient” for oral cavity, pharynx, larynx, esophagus,
and liver cancer. Although results of some studies had shown that
alcohol consumption was also positively associated with the risk of
colorectal and female breast cancer, the evidence for these sites was
considered inconclusive. Importantly, no conclusions were made
about the carcinogenic agent in alcoholic beverages (e.g., ethanol or
other constituents of alcoholic beverages) at that time.
Another expert Working Group (which included both authors of this
chapter) convened by the IARC in 2007 reviewed the epidemiologic
and other evidence on the associations of alcoholic beverage con-
sumption and cancer at 27 anatomic sites (IARC, 2010). This Working
Group concluded that “ethanol in alcoholic beverages” is carcinogenic
to humans (Group  1). The Group found no consistent evidence that
the effects of alcoholic beverage consumption on cancer differed by
beverage type, and deemed the evidence that ethanol causes cancer
in experimental animals to be sufficient. They reaffirmed that alcohol
consumption causes cancers of the liver and UADT, including the oral
cavity, pharynx, larynx, and esophagus. Moreover, they expanded the
list of cancers caused by alcohol consumption to include colorectal
and female breast.
The 2007 Working Group also concluded that both non-​Hodgkin
lymphoma and kidney cancer were not caused by alcohol consump-
tion. However, the evidence linking alcohol consumption to other can-
cer sites was considered inconclusive. For example, no conclusions
were drawn concerning lung or stomach cancer due to potential con-
founding by tobacco smoking and diet.
In 2009, a Working Group convened by the IARC again reviewed
the evidence regarding alcohol consumption and updated and con-
firmed the conclusions of previous Working Groups (IARC, 2012).
The evidence that heavy alcohol intake was associated with a small
increase in pancreatic cancer risk was considered limited. For the first
time, the 2009 Working Group concluded that both ethanol and acetal-
dehyde associated with the consumption of alcoholic beverages were
carcinogenic to humans for cancers of the UADT.
As described later in the chapter, the carcinogenic effects of ethanol
found in alcoholic beverages and the primary metabolite of ethanol,
acetaldehyde, vary by cancer type. Broadly, these mechanisms involve
DNA and protein damage from acetaldehyde and oxidative stress,
alterations in DNA repair, cell death and hyper-​regeneration, nutri-
tional malabsorption, changes in DNA methylation, and metabolic
effects, and for breast cancer, increased estrogen levels (Seitz and
Stickel, 2007). In addition, carcinogenic contaminants can be intro-
duced during alcoholic beverage production.
Upper Aerodigestive Tract
Alcoholic beverage consumption is a known cause of cancers of the
UADT, including the oral cavity, pharynx, larynx, and esophagus
(IARC, 1988). The causal relationship is strongest for squamous cell
carcinomas (IARC, 2012). Compared to alcohol non-​drinkers, people
who consume about 50 g of ethanol per day have about a 2-​to 3-​
fold higher risk of UADT cancers (IARC, 2010). It is worth noting
that acetaldehyde, which can be formed during FPM in the oral cavity,
has a boiling point of 25ºC, which is well below body temperature.
This raises the possibility that acetaldehyde vapor may play a role in
alcohol-​related UADT cancers. Experimental studies in animals have
shown that chronic exposure to acetaldehyde vapor increases UADT
metaplasia (Woutersen et al., 1986).
A significant confounder or effect modifier of the association
between alcoholic beverage consumption and UADT cancer risk is
smoking. Smoking causes multiple types of cancer, and alcohol drink-
ers, particularly heavy drinkers, are more likely to be smokers than
non-​drinkers. Controlling for smoking in statistical models only partly
separates the risk due to alcohol consumption from that due to smoking.
A more thorough approach is to study the relationship between alcohol
and cancer in lifelong non-​smokers. Several early studies showed a
significant positive association between alcohol intake and risk, even
in never smokers (IARC, 2010). A meta-​analysis of 15 studies found
alcoholic beverage consumption (4 or more drinks per day) was most
strongly associated with increased risk of pharynx cancer, but was also
associated with oropharynx, larynx, and esophageal squamous cell
carcinoma among those who did not use tobacco (Zeka et al., 2003).
In a pooled analysis of case-​control studies, heavy alcohol consump-
tion (3 or more drinks per day) was associated with an increased risk
of cancers of the oropharynx/​hypopharynx and larynx in never users of
tobacco (Hashibe et al., 2007). There is extensive evidence of a strong
synergistic effect of tobacco smoking and alcohol consumption on the
risk of UADT cancer, even at moderate amounts of consumption. In
most epidemiologic studies, the interaction is greater than multipli-
cative (IARC, 2012). In a large prospective study of British women,
alcohol consumption was most strongly associated with increased risk
of UADT cancers among current smokers, less strongly among former
smokers, and not at all among never smokers (Allen et al., 2009). One
of the two proposed mechanisms by which alcohol consumption might
potentiate the carcinogenicity of tobacco smoking depends on dose.
CYP2E1, which is induced by heavy alcohol consumption, can acti-
vate procarcinogens in cigarette smoke (Cederbaum, 2012). However,
since the interaction between smoking and alcohol consumption has
been observed even at low levels of alcohol consumption, where the
induction of CYP2E1 is unlikely, alcohol might also act as a “solvent,”
enhancing the hydrophobic diffusion of carcinogens present in ciga-
rette smoke into epithelial tissues (Squier et al., 1986).
Much of the evidence that acetaldehyde associated with alcoholic
beverage consumption is a cause of UADT cancer comes from a
series of epidemiologic studies by Yokoyama and colleagues showing
increased risk of esophageal squamous cell carcinoma (ESCC) among
ALDH2*2 heterozygous-​alcoholics (Yokoyama et al., 2006). As noted
earlier, the adverse effects of alcohol in ALDH2*2 homozygous indi-
viduals are so severe that they are generally unable to consume signifi-
cant amounts of alcohol. However, some ALDH2*2 heterozygotes are
able to overcome the adverse effects of acetaldehyde related to alcohol
drinking, and become heavy drinkers. When matched for alcohol con-
sumption and smoking, ALDH2*2 heterozygotes have a significantly
elevated risk of ESCC compared to those with fully active ALDH2
(reviewed by Brooks et al., 2009).
Using a Mendelian randomization approach, a meta-​analysis of
studies examining ALDH2 genotype and esophageal cancer risk dem-
onstrated a reduced risk for ALDH2*2 homozygous individuals (odds
ratio [OR]  =  0.36; 95% confidence interval [CI]:  0.16, 0.80) and a
higher risk among ALDH2*2 heterozygotes (OR = 3.19; 95% CI: 1.86,
5.47), compared with ALDH2*1 fully active homozygotes (Lewis and
Smith, 2005). The lower risk of esophageal cancer in ALDH2*2 homo-
zygotes likely reflects their avoidance of alcohol. When stratified by
alcohol drinking status, ALDH2*2 heterozygosity was not associated
with risk of esophageal cancer in non-​drinkers, but there was a 2.5-​fold
higher risk among moderate drinkers and a 7-​fold higher risk among
heavy drinkers. Similarly, in a meta-​analysis of studies of ALDH2
genotype and head and neck cancer risk, there was a reduced risk for
ALDH2*2 homozygous individuals (OR = 0.53; 95% CI: 0.28, 1.00)
218
218 PART III:  THE CAUSES OF CANCER
and a higher risk among ALDH2*2 heterozygotes (OR = 1.83; 95%
CI: 1.21, 2.77) as compared with fully active ALDH2*1 homozygotes;
the association with ALDH2*2 heterozygosity also varied accord-
ing to the level of alcohol consumption, with no association among
never drinkers and 3.6-​fold higher risk among heavy drinkers (Boccia
et al., 2009). Taken together, these studies support the evidence that
alcoholic beverage consumption can increase risk of UADT cancers
through the carcinogenic effects of acetaldehyde.
Liver
The association between alcohol consumption, particularly heavy alco-
hol consumption, and liver cancer (i.e., hepatocellular carcinoma) is well
established (Turati et al., 2014). This association has been observed in
studies of individuals infected with hepatitis viruses (HV) B or C, and in
unaffected individuals without cirrhosis. A meta-​analysis of 19 prospec-
tive studies that excluded cohorts of alcoholics, patients with cirrhosis,
and individuals with HBV or HCV infection showed that consumption
of 3 or more drinks per day was associated with a 16% increased risk
compared to non-​drinkers, although at this level there was considerable
heterogeneity among studies (p = 0.002) (Turati et al., 2014). The pooled
relative risk for heavy consumption of 6 or more drinks per day was 1.22
(95% CI: 1.10, 1.35) with no evidence of heterogeneity among studies
(p = 0.8). However, because most liver cancers occur in the context of
cirrhosis, which can motivate individuals to reduce their alcohol con-
sumption, estimates of the dose–​response relationship between alcohol
consumption and liver cancer should be interpreted cautiously. Findings
from several studies suggest possible synergistic effects of alcohol with
other established risk factors for hepatocellular carcinoma, including
HBV and HCV infection (Hassan et al., 2002; Yuan et al., 2004), obesity
(Loomba et al., 2010, 2013; Marrero et al., 2005), and smoking (Kuper
et al., 2000; Marrero et al., 2005). More research from prospective stud-
ies is needed to confirm these findings.
Most liver cancers occur in the context of viral hepatitis, fibrosis,
and/​or cirrhosis (El-​Serag and Rudolph, 2007). Chronic heavy alco-
hol consumption often leads to fibrosis and ultimately cirrhosis, and
alcohol-​related liver cancer in the absence of these conditions is rare
(Seitz and Stickel, 2007). Alcohol-​related liver disease not only causes
cell death and regeneration, but also results in chronic inflammation
(Wang et al., 2012), which can itself generate mutagens and damage
DNA (Son et  al., 2008)  beyond the effects of alcohol metabolism.
More specifically, inflammation and oxidative stress resulting from
elevated levels of CYP2E1 can increase levels of etheno DNA-​base
adducts, some of which are highly mutagenic (Pandya and Moriya,
1996). Elevated levels of etheno DNA-​base adducts have been docu-
mented in tissue biopsies from patients with alcoholic liver disease
(Frank et al., 2004; Wang et al., 2009).
Although the liver is the major site of alcohol metabolism, acetalde-
hyde has not been implicated in liver carcinogenesis. Alcoholics defi-
cient in ALDH2 activity have little or no increase in liver cancer risk
(IARC, 2010), despite their dramatically higher risk of UADT cancers.
This difference in the effect of acetaldehyde on the liver compared
to the UADT may be due, at least in part, to the much lower prolif-
eration rates of hepatocytes compared to epithelial cells in the aerodi-
gestive (and gastrointestinal) tract. In the absence of DNA synthesis
and cell replication, mutations resulting from DNA damage are not
transmitted to daughter cells, and there is more time for DNA repair
to occur. Proliferating cells also have higher levels of polyamines,
which can react with acetaldehyde and lead to mutagenic DNA dam-
age (Theruvathu et al., 2005).
Colorectum
The IARC first concluded that alcoholic beverage consumption caused
colorectal cancer in 2007 (IARC, 2010). The evidence at that time was
based partly on a pooled analysis of eight cohort studies (Cho et  al.,
2004) and a meta-​analysis of 16 prospective studies (Moskal et  al.,
2007). These analyses showed that regular consumption of about 50 g
of ethanol per day was associated with an approximately 40% higher
risk of colorectal cancer compared to non-​ drinkers; however, there
was uncertainty regarding the nature of the dose–​response relation-
ship (IARC, 2010). A systematic literature review by the WCRF/​AICR
CUP designated the evidence for a causal association between ethanol
from alcoholic consumption and colorectal cancer risk as convincing in
men and probably convincing in women (World Cancer Research Fund
International, 2011). More specifically, the CUP meta-​analyses of pro-
spective studies showed that a 10 g per day increase in ethanol was asso-
ciated with a 10% increased risk of colorectal and rectal cancers, and an
8% increased risk of colon cancer. The association was stronger among
men than women for both colorectal and colon cancers. The risk of
colorectal cancer increased by 11% among men and 7% among women
per 10 g per day increase in ethanol. Reasons for the gender difference
are unclear, but may relate to differences in the gut microbiome, or hor-
mone-​related differences in alcohol metabolism (Park et al., 2006).
It is unclear whether tobacco use—​an established cause of colorec-
tal cancer—​modifies the association between alcohol consumption
and colorectal cancer risk. In the pooled analysis of eight prospective
studies mentioned in the preceding paragraph (Cho et al., 2004), the
association between alcohol consumption and colorectal cancer risk
was statistically significant among past and current smokers, but not
among never smokers; however, the test for interaction was not sta-
tistically significant (p > 0.2). Similarly, in the European Prospective
Investigation into Cancer and Nutrition, alcohol consumption was
more strongly associated with colorectal cancer risk among smokers
than among non-​smokers, but again there was no evidence of a statisti-
cally significant interaction (p = 0.41) (Ferrari et al., 2007). Another
study showed a marginally significant interaction between smoking
and alcohol consumption for colon cancer (p = 0.051) but not for rectal
cancer (p > 0.19) (Tsong et al., 2007). It is plausible that the combined
exposure to smoking and alcohol could modify their separate effects
on colorectal cancer risk. As noted previously for UADT cancers, alco-
hol might function as a solvent, enhancing the penetration of other
carcinogenic molecules into mucosal epithelium (Squier et al., 1986).
There is compelling evidence for a causal relationship between
acetaldehyde derived from alcohol metabolism and colorectal cancer.
Experiments in animals have shown that alcohol metabolism by colonic
bacteria leads to very high (up to mM) concentrations of acetaldehyde
(Jokelainen et  al., 1996; Visapaa et  al., 1998). Although no similar
measurements have been made in humans, it is not unreasonable to
assume that acetaldehyde levels in the human colon could reach the
same concentrations after alcohol consumption, at least in some indi-
viduals. Variation between individuals might be substantial, depending
upon the composition of the colonic microbiome. The mechanisms by
which acetaldehyde affects the risk of colorectal cancer are not com-
pletely understood. Plausible mechanisms could include DNA adducts
from acetaldehyde, and increased cell division in regenerating tissue.
Other mechanisms have also been considered (Seitz and Stickel, 2007).
While there is some evidence that ALDH2-​deficient individuals are
at increased risk of alcohol-​associated colorectal cancer, more data are
needed to confirm this finding (IARC, 2010). It is notable that ALDH2
is maximally active at low acetaldehyde concentrations. If the levels of
colonic acetaldehyde after alcohol consumption are roughly comparable
in humans and animals, the role of ALDH2 compared to other ALDHs
expressed in the colon would be limited. Thus, the lack of a large difference
in colon cancer risk between ALDH2-​proficient and ALDH2-​deficient
alcohol drinkers does not exclude the possibility that acetaldehyde might
contribute to alcohol-​related colorectal carcinogenesis.
Other mechanisms that could potentially mediate the effects of
alcohol on colorectal carcinogenesis include oxidative stress, altered
DNA methylation, and nutritional deficiencies, such as reduced lev-
els of folic and retinoic acid as a result of heavy drinking (Seitz
et al., 2005).
Breast
Based on a large body of evidence, the 2007 IARC Working Group
concluded for the first time that alcohol consumption is a cause of
breast cancer in humans (IARC, 2010). Included in the IARC review
 219
Alcohol and Cancer Risk 219
was a large pooled analysis of 53 epidemiologic studies with more than
58,000 women with breast cancer. In that analysis, there was a linear
dose–​response association with a 7.1% (95% CI: 5.5, 8.7) increase in
breast cancer risk per 10 g per day increase in ethanol consumption
(Hamajima et al., 2002). Subsequently, at least 13 additional prospec-
tive studies were published. Based on the total evidence, a 2009 IARC
Working Group confirmed the causal relationship between alcohol and
breast cancer risk (IARC, 2012).
In general, most factors do not appear to modify the relationship
between alcohol and breast cancer risk. In the aforementioned pooled
analysis of 53 case-​control and prospective studies, there was no evi-
dence of effect modification by age at diagnosis, parity, age at first
birth, breastfeeding, race, country, education, mother or sister with
breast cancer, age at menarche, height, weight, body mass index, ever
use of hormonal contraceptives, ever use of hormone replacement
therapy, or menopausal status (Hamajima et al., 2002). The possible
exception to these null findings is smoking. A  recently published
pooled analysis of data from 14 prospective studies with over 934,000
participants and 36,060 invasive breast cancer cases showed a statisti-
cally significant interaction between alcohol and smoking status (p-​
heterogeneity = 0.03) (Gaudet et al., 2016).
The mechanism(s) underlying the association between alcohol and
breast cancer risk are not completely understood. Alcohol consump-
tion typically begins in late adolescence and continues throughout life,
and thus it is difficult to isolate the biologically relevant time period of
exposure (Brooks and Zakhari, 2013).
One proposed mechanism involves the genotoxicity of acetalde-
hyde in breast cells. ADH enzymes produced by human breast epi-
thelial cells metabolize alcohol, even at low concentrations (Triano
et al., 2003), suggesting that acetaldehyde is generated at relatively
low levels of consumption. An important unanswered question is
whether those cells also express ALDH2, which would metabolize
the resulting acetaldehyde. ALDH2 protein is detectable in human
breast tissue (Sutton et al., 2010), but the cellular localization has
not been reported.
Binge drinking can raise blood alcohol levels into the range at which
CYP2E1 is induced, resulting in mutagenic DNA damage from free
radicals and lipid peroxidation. As noted earlier, this mechanism does
not involve acetaldehyde. Relatively few epidemiologic studies have
examined binge drinking in relation to breast cancer risk. In the Danish
Nurse Cohort Study, binge drinking during the weekend was associ-
ated with increased breast cancer risk (relative risk [RR] = 1.49; 95%
CI: 1.04, 2.13 for 10–​15 drinks; and RR = 2.51; 95% CI: 1.37, 4.59
for 16–​21 drinks) compared to drinking 1–​3 drinks during the latest
weekend (Morch et al., 2007). In the US Nurses’ Health Study, binge
drinking, but not the frequency of drinking, was positively associated
with breast cancer risk after adjustment for cumulative alcohol intake
(Chen et al., 2011).
Binge drinking may be particularly deleterious for younger
women, who are most likely to binge drink. Breast epithelium is
thought to be most susceptible to possible carcinogens between
menarche and first full-​term pregnancy, a period of time when breast
cells proliferate rapidly but have not yet terminally differentiated.
It is well established that a longer duration between menarche and
age at first full-​term pregnancy is associated with a higher risk of
breast cancer (Li et  al., 2008). The association between alcohol
consumption between menarche and first pregnancy was examined
in the Nurses’ Health Study (Liu et al., 2013). In analyses adjust-
ing for consumption after first pregnancy, a 10 g per day increase
in cumulative average ethanol consumption between menarche
and first pregnancy was associated with an 11% increase in risk of
breast cancer (RR = 1.11; 95% CI: 1.00, 1.23). This association was
comparable to the association with cumulative average consumption
after first pregnancy (RR = 1.09; 95% CI: 0.96, 1.23 per 10 g per day
increase). Notably, the association between alcohol consumption
between menarche and first pregnancy and risk of breast cancer was
limited to women with 10 or more years’ duration of consumption
(RR = 1.21; 95% CI: 1.08, 1.36 per 10 g per day increase). Similarly,
cumulative average ethanol consumption between menarche and
first pregnancy, but not consumption after full-​term pregnancy, was
associated with higher risk of benign breast disease, another estab-
lished breast cancer risk factor.
Alcohol consumption also increases circulating estrogen levels,
which are positively associated with breast cancer risk in both pre-
menopausal (Endogenous et al., 2013) and postmenopausal women
(Key et  al., 2002). In a controlled feeding study among premeno-
pausal women, consumption of 30 g/​day of ethanol for three men-
strual cycles increased plasma estradiol and estrone levels by 28%
and 21%, respectively (Reichman et al., 1993). Similarly, in a ran-
domly assigned cross-​over alcohol feeding study among postmeno-
pausal women, both 15 and 30 g/​day of ethanol increased serum
estrone sulfate and dehydroepiandrosterone concentrations com-
pared to placebo, but did not affect other sex hormones, including
estradiol and testosterone (Dorgan et al., 2001). In a pooled analysis
of 13 prospective studies of postmenopausal women, alcohol con-
sumption was positively associated with both estrogens and andro-
gens, and inversely associated with sex hormone–​binding globulin
(Endogenous et  al., 2011). Further evidence that alcohol might
act through a hormonal mechanism is provided by epidemiologic
studies showing a stronger association between alcohol consump-
tion and risk of hormone-​receptor-​positive breast cancer than with
hormone-​receptor-​negative breast cancer. In a 2008 meta-​analysis
of three prospective cohort studies and 16 case-​control studies, the
summary relative risk for the highest versus the lowest categories of
alcohol consumption were 1.27 (95% CI: 1.17, 1.38) for estrogen-​
receptor-​positive (ER+) breast cancer and 1.14 (95% CI: 1.03, 1.26)
for estrogen-​receptor-​negative (ER–​) breast cancer (Suzuki et  al.,
2008). When further stratified on ER and progesterone-​receptor
(PR) status, high versus low alcohol consumption was associated
with statistically significantly elevated risks of both ER+/​PR+ (RR
= 1.22; 95% CI: 1.11, 1.34) and ER+/​PR–​(RR = 1.28; 95% CI: 1.07,
1.53) breast cancer but not with ER–​/​PR–​breast cancer (RR = 1.10;
95% CI: 0.98, 1.24). Overall, the 2010 IARC Working Group could
not conclude that the association between alcohol consumption and
breast cancer risk differed by hormonal status (IARC, 2012).
An argument against a significant role for estrogen in alcohol-​
related breast cancer is the absence of an association between alcohol
consumption and risk of endometrial (Friberg et  al., 2010)  or ovar-
ian cancer (Genkinger et  al., 2006), two other cancer sites strongly
related to hormones. Based on evidence from WCRF/​AICR CUP sys-
tematic literature reviews, the relative risk per 10 g per day increase
in ethanol consumption was 1.01 (95% CI: 0.97, 1.06) for endometrial
cancer (World Cancer Research Fund International, 2013), and 1.01
(95% CI: 0.96, 1.06) for ovarian cancer (World Cancer Research Fund
International, 2014a).
Finally, moderate alcohol consumption has been hypothesized
to increase risk of breast cancer by increasing breast density. Breast
density reflects fibroglandular breast tissue that appears radiologically
dense on mammograms, and is consistently, strongly, and positively
associated with breast cancer risk (Boyd et  al., 1998). However, as
reviewed by Liu et  al. (2015), the association between alcohol con-
sumption and breast density is inconsistent among epidemiologic
studies.
Pancreas
Although the 2009 IARC Working Group cited accumulating evi-
dence that high alcohol intake (i.e., ≥ 30 g per day) was associated
with a small increased risk for cancer of the pancreas, the evidence
was considered “limited.” The available studies had insufficient
statistical power to examine the association for heavy consump-
tion (e.g., 3 or more drinks per day), or to eliminate potential con-
founding by cigarette smoking (IARC, 2012). Subsequently, the
association between alcohol intake and pancreatic cancer mortality
was examined in the American Cancer Society’s Cancer Prevention
Study-​II (CPS-​II), a large prospective study of over 1  million US
adults. Based on 24 years of follow-​up and almost 7,000 pancreatic
cancer deaths, alcohol consumption of 3 or more drinks per day was
associated with an increased risk of death from pancreatic cancer in
20

220 PART III:  THE CAUSES OF CANCER

lifelong never smokers (RR  =  1.36; 95% CI:  1.13, 1.62) (Gapstur In a large meta-​analysis of 15 prospective studies, moderate, but
et  al., 2011). These results were included in a 2012 WCRF/​AICR not heavy, alcohol consumption was associated with a reduced risk of
CUP systematic literature review, which characterized the evidence type 2 diabetes (Koppes et al., 2005). This finding might be relevant
for a causal association between heavy alcohol consumption and to the inverse relationship between alcohol consumption and kidney
risk of pancreatic cancer as limited (World Cancer Research Fund cancer. Type 2 diabetes was associated with higher risk of kidney
International, 2012). cancer in a large well-​designed prospective study that updates dia-
A causal relationship between heavy alcohol consumption and betes status during follow-​up (Joh et al., 2011). Alternatively, alco-
pancreatic cancer is biologically plausible, since alcohol causes hol has diuretic effects that could reduce the exposure of renal cells
chronic alcoholic pancreatitis (Dufour and Adamson, 2003), an to carcinogens.
established risk factor for pancreatic cancer. Go et al. (2005) hypoth-
esized that oxidative and non-​oxidative metabolism of alcohol in the
pancreas causes inflammation and promotes carcinogenesis through ESTIMATES OF ATTRIBUTABLE FRACTIONS
activation of nuclear transcription factors, increased production of
reactive oxygen species, and dysregulation of cell proliferation and Estimates of the percent of cancer deaths attributable to alco-
apoptosis. hol consumption have been remarkably stable over the past four
decades. Rothman et al. estimated that 3% of all cancer deaths in the
United States in 1974 could be attributed to alcohol consumption
Non-​Hodgkin Lymphoma (Rothman, 1980); Doll and Peto estimated that between 2% and 4%
of US cancer deaths in the late 1970s could be attributed to alcohol
The 2007 IARC Working Group concluded that for non-​Hodgkin
consumption (Doll and Peto, 1981). A recent comprehensive analy-
lymphoma (NHL), there was evidence for lack of carcinogenicity
sis by Nelson and colleagues (Nelson et  al., 2013)  estimated the
for alcohol consumption (IARC, 2010). This conclusion is sup-
population attributable fractions (PAFs) of alcohol-​related deaths
ported by a substantial body of evidence from more recent prospec-
for all cancers and for seven cancer sites (oral cavity, pharynx, lar-
tive studies showing statistically significant inverse, dose–​response
ynx, esophagus, liver, colorectum, and female breast) designated as
relationships with all NHL subtypes combined (Allen et al., 2009;
causally related to alcohol consumption by the IARC (IARC, 2010,
Chang et al., 2010; Chiu et al., 1999; Gapstur et al., 2012; Kanda
2012). These estimates were based on two different methods to esti-
et al., 2010; Klatsky et al., 2009; Lim et al., 2006, 2007; Troy et al.,
mate the prevalence of alcohol consumption and on data from two
2010). Notably, these prospective studies show no clear differences
different population-​based surveys (i.e., the 2009 Behavioral Risk
in the associations of alcohol consumption with specific histologic
Factor Surveillance System survey and the 2009–​2010 National
subtypes of NHL.
Alcohol Survey). They also considered alcohol sales data. Overall,
The inverse association between alcohol consumption and NHL
the different methods showed similar estimates of the attributable
might be an artifact of reverse causation, in which the disease influ-
fraction ranging from 3.2% to 3.7% (i.e., 18,178 to 21,284) for all
ences the exposure. Common symptoms of lymphoma include
US cancer deaths in 2009. In sex-​specific analyses, the proportion
enlarged lymph nodes, extreme fatigue, unexplained fever, weight
of all US cancer deaths due to alcohol ranged from 2.4% (6970)
loss, and night sweats. These symptoms, as well as several chronic
to 4.0% (11,820) among US men, and from 2.7% (7266) to 4.8%
diseases associated with lymphoma, might lead to pre-​diagnostic
(13,094) among women.
reductions in alcohol consumption, which could result in an appar-
Rehm and Shield have estimated that worldwide about 4.2% (i.e.,
ent inverse association with NHL risk. The possibility of reverse
337,400) of all cancer deaths could be attributed to alcohol consump-
causation is supported by findings from one prospective study that
tion in 2010 (Rehm and Shield, 2014). Deaths from cancers of the
found no difference in risk for current drinking but a higher risk for
nasopharynx, oropharynx, oral cavity, larynx, and esophagus are at
former drinking when compared to consistent non-​drinkers (Chang
least twice as likely to be alcohol-​related than deaths from cancers of
et  al., 2010). However, two other prospective studies found no
the liver, colorectum, or female breast. For all cancers combined, the
association with former alcohol consumption (Gapstur et al., 2012;
estimates of attributable proportion are higher among men (5.4%) than
Klatsky et al., 2009).
among women (2.7%). This also is true for most individual cancer
Limited experimental data suggest that alcohol consumption
sites, and especially for UADT cancers. Among men, 23.5% of deaths
might inhibit the development of NHL. Alcohol drinking has mul-
from laryngeal cancer and 37.0% of deaths from oral cavity cancer
tiple effects on the human immune system, both positive and nega-
were attributed to alcohol consumption, whereas among women only
tive (Hagner et  al., 2009; Romeo et  al., 2007). Empirical evidence
7.9% of laryngeal cancer deaths and 12.6% of nasopharynx cancer
that alcohol might inhibit the development of human lymphomas
deaths were attributed to alcohol consumption. Rehm and Shield also
comes from a human lymphoma xenograft mouse model, in which
reported rates of alcohol-​attributed cancer deaths by WHO Global
chronic exposure to 5%–​10% alcohol in water (an amount shown to
Burden of Disease regions. The highest alcohol-​ attributed cancer
lead to 0.05 to 0.15 g/​dL alcohol in circulation) decreased lymphoma
death rate (per 100,000) was in Eastern Europe (8.7), followed closely
growth; this effect was partially due to an inhibition of mTOR sig-
by East Asia (7.5) and Central Europe (7.2). These rates largely affect
naling (Hagner et  al., 2009). Similarly, ethanol was also shown to
men in those regions. The lowest alcohol-​attributed cancer death rates
inhibit mTOR signaling in another human lymphoma cell line in vitro
(per 100,000) were in North Africa/​Middle East (0.6), Andean Latin
(Mazan-​Mamczarz et  al., 2015). Multiple lines of evidence support
America (1.7) and parts of Sub-​Saharan Africa. Interestingly, men in
the development of mTOR pathway inhibitors for the treatment of
Andean Latin America have lower alcohol-​attributed deaths rates than
lymphoma (Arita et al., 2013).
women (1.4 vs. 2.0, respectively).

Kidney ALCOHOL CONSUMPTION AND PROGNOSIS AMONG

The 2007 IARC Working Group found a lack of evidence that
alcohol was carcinogenic for kidney cancer (IARC, 2010). Indeed,
there is some evidence that consumption of alcoholic drinks may be
inversely associated with kidney cancer. A 2015 WCRF/​AICR CUP
systematic literature review showed that a 10 g per day increase
of ethanol was associated with an 8% reduction in risk of kid-
ney cancer (RR  =  0.92; 95% CI:  0.86, 0.97); this association was
observed up to 30 g per day of ethanol (World Cancer Research
Fund International, 2015).
CANCER SURVIVORS
In 2012, there were over 32.6  million people worldwide alive who
have lived at least 5 years after being diagnosed with cancer, other than
non-​melanoma skin cancer (Jemal et  al., 2014). Many cancer survi-
vors are highly motivated to learn about and make healthful behavioral
changes to reduce their risk of recurrence and/​or disease progression.
The most recent American Cancer Society Nutrition and Physical
Activity Guidelines for Cancer Survivors advise cancer patients
 21
Alcohol and Cancer Risk 221
undergoing chemotherapy or radiation therapy to avoid or minimize
alcohol consumption during treatment, because alcohol might affect
chemotherapeutic clearance and worsen toxicity, compromise healing,
or exacerbate treatment associated side effects such as oral mucositis
(Rock et  al., 2012). However, whether alcohol consumption affects
long-​term cancer survival is not completely understood. Issues to be
considered include the following: (1) the correlation between alcohol
consumption before and after diagnosis; (2)  the stage of disease at
diagnosis (because consumption is more likely to influence early-​than
late-​stage disease); (3) confounding by smoking (which is highly cor-
related with alcohol consumption); and (4) assessment of all-​cause ver-
sus site-​specific cancer mortality (since alcohol consumption has been
associated with a reduced risk of cardiovascular disease mortality).
A WCRF/​ AICR CUP systematic literature review of 18 total
studies published through June 2012 examined association of both
pre-​and post-​diagnostic alcohol consumption with total-​and breast
cancer–​specific mortality, as well as risk of second primary breast
cancer among breast cancer survivors (World Cancer Research Fund
International, 2014b). Results showed no associations of pre-​diagnos-
tic alcohol intake with total mortality (RR = 1.00; 95% CI: 0.99, 1.00
per 1 drink/​week increase), or breast cancer–​specific mortality (RR
= 1.00; 95% CI: 0.97, 1.02 per 1 drink/​week). Similarly, there was
no evidence of associations between post-​diagnosis alcohol consump-
tion assessed less than 12 months after diagnosis, or 12 months or
more after diagnosis and total-​or breast cancer–​specific mortality. No
study examined the association between pre-​diagnostic alcohol con-
sumption and risk of second primary breast cancer. In the two stud-
ies that examined the association between consumption less than 12
months after diagnosis and subsequent risk of second primary breast
cancer, one reported no association and the other reported increased
risk (RR = 1.7). In the CUP meta-​analysis, five studies that investi-
gated the association between alcohol consumption during the period
12 or more months after diagnosis and risk of second primary breast
cancer showed a nearly statistically significant increased risk (RR =
1.19; 95% CI: 0.96, 1.47); however, the association was not dose-​
related. Since that review, a large pooled analysis including more than
9300 stage I–​III breast cancer survivors also showed no associations of
post-​diagnostic regular alcohol intake with risk of recurrence or with
total mortality overall (Kwan et al., 2013). However, postmenopausal
women who regularly consumed at least 6 g/​day of ethanol had a statis-
tically significant higher risk of recurrence (RR = 1.19; 95% CI: 1.01,
1.40) compared to non-​drinkers; no association was observed among
premenopausal women (RR = 0.91; 95% CI: 0.72, 1.16). Overall, there
is no clear evidence that alcohol consumption influences breast cancer
prognosis.
At least nine epidemiologic studies have examined the influence
of alcoholic beverage consumption on outcomes after a diagnosis of
colorectal cancer (Asghari-​Jafarabadi et al., 2009; Fung et al., 2014;
Park et al., 2006; Patel et al., 2014; Pelser et al., 2014; Phipps et al.,
2011, 2016; Walter et  al., 2016; Zell et  al., 2007). The results were
inconsistent in studies that examined pre-​diagnostic consumption in
relation to mortality; some studies found that light-​to-​moderate, but
not heavy, alcohol consumption was associated with lower risk of
mortality from all causes and colorectal cancer (Pelser et  al., 2014;
Phipps et al., 2011, 2016; Walter et al., 2016; Zell et al., 2007). Others
studies showed no association (Asghari-​Jafarabadi et al., 2009; Park
et al., 2006). In a study of 175 stage I rectal cancer patients, alcohol
drinking at the time of diagnosis was associated with a 2.4-​fold higher
risk (p = 0.01) of local recurrence compared to never/​former drinkers
(Patel et al., 2014). However, in the Nurses’ Health Study there was no
association between post-​diagnostic alcohol consumption and colorec-
tal cancer mortality (Fung et al., 2014). In some studies, stage I–​IV
colon and rectal cancer patients were included, potentially obscuring
an effect on early-​stage cancers.
There is a high prevalence of tobacco and heavy alcohol use among
head and neck cancer patients (Hashibe et  al., 2009). Research has
shown that continued alcohol consumption after diagnosis is associ-
ated with higher risk of both second primary cancers and mortality
from head and neck cancers. In a study of nearly 1200 patients with
early-​stage head and neck squamous cell carcinoma enrolled in a
chemoprevention trial, there was a statistically significant 30% (95%
CI: 1.0, 1.7) higher risk of second primary cancer among those who
continued to drink alcohol after diagnosis (Do et al., 2003). In another
chemoprevention trial of 264 patients with early-​stage cancer of the
oral cavity, pharynx, and larynx randomized to β-​carotene, there was a
dose–​response increase in total mortality for both pre-​diagnostic alco-
hol consumption and continuous alcohol consumption after diagno-
sis; the RR of death from any cause during follow-​up was 2.72 (95%
CI: 1.20, 6.14) times higher in those who continued to drink after diag-
nosis compared to non-​drinkers after diagnosis (Mayne et al., 2009).
OPPORTUNITIES FOR ALCOHOL PREVENTION
AND CONTROL
Strategies to reduce the harmful use of alcoholic beverages include
measures to increase awareness and reduce consumption at both
the population and individual level. In 2010, the 63rd World Health
Assembly of the WHO endorsed a Global Strategy to Reduce the
Harmful Use of Alcohol (World Health Organization, 2010). This
strategy was designed to support and complement public health poli-
cies in WHO member states, to provide guidance for local, regional,
and global action, and to set priorities for global action. The five objec-
tives of the WHO Global strategy are shown in Box 12–1. These objec-
tives parallel population-​level interventions to reduce tobacco use; in
particular, increases in excise taxes to decreases sales are among the
most effective strategies (Eriksen et al., 2015). There is substantial evi-
dence that increasing the price of alcohol through excise taxes reduces
both consumption (Wagenaar et  al., 2009)  and adverse health out-
comes caused by alcohol, including motor vehicle crashes, violence,
and cirrhosis (Elder et al., 2010; Wagenaar et al., 2010).
Despite the evidence that alcohol causes multiple types of cancer,
fewer than half of the US Comprehensive Cancer Control Plans devel-
oped by the states and funded by the US Centers for Disease Control
and Prevention (CDC) specify goals, objectives, or strategies for
alcohol control (Henley et al., 2014). In particular, efforts are needed
to increase awareness of the long-​term impact of alcohol drinking,
including binge drinking, on breast cancer risk in women. A  survey
of drinking patterns in the United States found that the prevalence of
binge drinking increased more than twice as rapidly among women
than men from 2005 to 2012 (Dwyer-​Lindgren et al., 2015). Effective
population-​ wide education campaigns are needed to target young
women who drink alcohol and encourage them to limit consumption
and avoid binge drinking.
At the individual level, the treatment of alcohol-​related disorders
includes mutual support groups, treatments with medications, behav-
ioral therapies, and/​or combinations of these strategies. In the United
States, the National Institute on Alcohol Abuse and Alcoholism list
Box 12–​1  OBJECTIVES OF THE WHO GLOBAL STRATEGY
1. Raise global awareness of the magnitude and nature of the health,
social, and economic problems caused by harmful use of alcohol,
and increase commitment by governments to act to address the
harmful alcohol use.
2. Strengthen knowledge base on the magnitude and determinants of
alcohol-​related harm and on effective interventions to reduce and
prevent such harm.
3. Increase technical support to, and enhance capacity of, member
states for preventing the harmful use of alcohol and managing
alcohol-​use disorders and associated health conditions.
4. Strengthen partnerships and better coordination among
stakeholders and increase mobilization of resources required for
appropriate and concerted action to prevent the harmful use of
alcohol.
5. Improve systems for monitoring and surveillance at different levels,
and more effective dissemination and application of information
for advocacy, policy development, and evaluation.
2
222 PART III:  THE CAUSES OF CANCER
numerous educational resources for healthcare professionals for use in
diagnosing and treating excessive alcohol intake (National Institute on
Alcohol Abuse and Alcoholism, 2016).
Despite the known adverse effects of alcohol consumption in the
etiology of cancer, several organizations and consensus panels (AHA,
2015; AICR, 2011; Kushi et  al., 2012)  have concluded that low to
moderate alcohol consumption can be part of a healthful dietary pat-
tern because of the apparent benefits of moderate alcohol consumption
on coronary heart disease (Rimm et al., 1999). However, this conclu-
sion was recently challenged by the results of a recent Mendelian
randomization study of a non-​synonymous single nucleotide polymor-
phism in ADH1B in relation to cardiovascular disease risk factors, and
risk of coronary heart disease and stroke (Holmes et al., 2014). In that
study, carriers of the genetic variant associated with non-​drinking and
lower self-​reported alcohol consumption also had lower systolic blood
pressure, circulating interleukin-​6 concentration, waist circumference,
body mass index, risk of coronary heart disease (OR  =  0.90; 95%
CI: 0.84, 0.96), and risk of ischemic stroke (OR = 0.83; 95% CI: 0.72,
0.95). The authors concluded that reductions of alcohol consumption,
even for light to moderate drinkers, may be beneficial for cardiovas-
cular health.
FUTURE RESEARCH
Extensive evidence demonstrates the causal relationships of ethanol
in alcoholic beverages and its primary metabolite, acetaldehyde, to at
least seven different cancer sites in humans. More research is needed,
however, to better understand the associations with other cancer sites
for which the evidence in considered insufficient, for example gastric
and lung cancer. For gastric cancer this might require studying the
separate and joint effects of Helicobacter pylori infection and alcohol
consumption. For lung cancer, large studies of lifelong non-​smokers
will be necessary.
In addition, a better understanding of the mechanistic basis of alco-
hol-​related cancers in different target tissues is needed to help clarify
the causal relationship, particularly for cancers where the current evi-
dence is considered inconclusive by the IARC. Technologic advance-
ments in whole-​ genome or exome sequencing, which can detect
signatures of carcinogens and carcinogenic mechanisms (Alexandrov
and Stratton, 2014), will support these research efforts. Similarly,
exploring etiologic heterogeneity based on the molecular phenotype
of tumors—​beyond traditional markers such as ER status—​will help to
clarify the causal role of alcoholic beverage consumption in the etiol-
ogy of many cancer sites (Ogino et al., 2013).
Further research also is needed to examine whether quitting drink-
ing can reverse the increased risk associated with alcohol consumption
for alcohol-​related cancers. There is some evidence that quitting drink-
ing appears to reduce the elevated risk of oral cavity and pharynx can-
cer (IARC, 2010), but less is known for other cancer sites. In addition,
testing interventions and messages that discourage drinking, especially
binge drinking among young women, could be useful for developing
individual and population strategies to reduce the harmful use of alcohol.
References
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 27
13 Ionizing Radiation
AMY BERRINGTON DE GONZÁLEZ, ANDRÉ BOUVILLE, PREETHA RAJARAMAN,
AND MARY SCHUBAUER-​BERIGAN
OVERVIEW
Ionizing radiation is classified as a universal carcinogen due to its abil-
ity to induce cancer in most organs following exposure at any age,
including in utero. Several organs are especially radiosensitive, partic-
ularly when exposure occurs in childhood, including the female breast,
thyroid, brain, and red bone marrow. Very few cancers, notably cervi-
cal and Hodgkin lymphoma, do not seem to be related to ionizing radi-
ation, but the reasons are unknown. For most cancers (lung may be an
exception) the relative risk decreases with age at exposure or attained
age, and time since exposure.
Currently the main sources of radiation exposure to the general pop-
ulation are from natural background radiation (e.g., residential radon)
and medical (e.g., computed tomography [CT] scans). Natural back-
ground exposure varies by location but is generally stable over time.
Medical exposure has been increasing in many countries due to the
expansion of advanced imaging technologies. Risk projection models
suggest that currently 1%–​3% of cancers could be related to medical
radiation exposure in countries like the United Kingdom and the United
States, and about 1% of cancers could be related to natural background
radiation. Occupational radiation exposures have decreased over the
last several decades. One exception is the medical workers who are
exposed to radiation from performing increasing numbers of interven-
tional fluoroscopy and nuclear medicine procedures. Historically there
have been important exposures to large populations due to nuclear
weapons detonation and testing and nuclear accidents, particularly
Chernobyl.
Although ionizing radiation is an established carcinogen, the mag-
nitude of the risk from very low-​dose acute (< 50 mGy) and protracted
exposures (< 5 mGy per hour) is still uncertain, and difficult to resolve
via epidemiological studies. In the last decade there have been new
studies based on large-​scale electronic record linkages of pediatric
CT scans, natural background radiation, environmental exposures,
and nuclear workers that have provided additional evidence support-
ing excess cancer risks from low-​dose and/​or low-​dose rate expo-
sures. Developments in molecular epidemiology, particularly tumor
sequencing to find a potential “radiation signature,” could also be a
novel approach to address this important public health question in the
next decade.
INTRODUCTION
Most ionizing radiation exposures to the general population today
are from very low doses such as CT scans, or residential radon expo-
sure. The so-​called linear no-​threshold (LNT) assumption forms the
basis for radiation protection standards for these very low doses—​the
assumption being that there is no safe level of radiation exposure
(i.e., no threshold) and that the cancer risks from very low doses
can be estimated by linear extrapolation of observed risks from stud-
ies of populations exposed to higher doses (primarily the atomic
bomb survivors). This model has been challenged, however, by both
experimental and some epidemiological data, and remains somewhat
contentious. Much of the epidemiological research in the last decade
has focused on the LNT question, primarily assessing whether there
are excess cancer risks in populations who received very low doses,
and quantifying the magnitude of the risk. Another outstanding issue
is whether the risk from protracted exposure to ionizing radiation
is lower than the risk from the same dose received acutely, due to
a greater probability of DNA repair. This is particularly relevant
for radiation protection standards for occupational groups, as their
radiation exposure is often received over many decades. As can-
cer survival continues to improve, there has been an expansion of
effort to improve and understand the late effects of cancer treatment.
Radiotherapy results in exposure to very high (> 5Gy) fractionated
doses to the healthy organs surrounding the target organ, and this is
associated with an increased risk of developing a second cancer. To
balance these potential risks against the benefits of radiotherapy, we
need to have good quantitative risk estimates of cancer risks from
high doses.
Because of the wealth of epidemiological data on the cancer risks
from moderate doses, the established carcinogenicity, and the ability to
measure biological dose, epidemiological studies of ionizing radiation
provide a rich setting for studying interactions with other carcinogens,
including gene–​ environment interactions, or genetic susceptibility.
These investigations have also been a focus of recent research efforts.
The advent of tumor sequencing has provided an exciting opportunity
to search for potential “radiation signatures” in populations with very
well characterized radiation exposures and high attributable risks, such
as the thyroid cancers diagnosed after childhood exposure to iodine-​
131 (I-​131) from the Chernobyl accident.
As there are many types of ionizing radiation exposure, modes of
exposure, methods for measuring it, and several different dose units,
we start with a review of these basic concepts before reviewing the
new epidemiological studies.
NATURE OF THE EXPOSURE
Types of Ionizing Radiation
Ionizing radiation consists of waves or particles (gamma, X-​rays, neu-
trons, alpha particles, etc.), usually produced during the radioactive
decay of unstable nuclei, that have sufficient energy to ionize atoms
in the human body, thus inducing chemical changes that may be bio-
logically important for the functioning of cells. The various forms of
radiation are emitted with different energies and penetrating power
through materials and potentially different carcinogenic potential. The
most common types of ionizing radiation are the following (each of
which can cause cancer):
• Alpha particles, consisting of helium nuclei, which can be halted by
a sheet of paper and thus can hardly penetrate the dead outer layers
of the skin;
• Beta particles, consisting of electrons, which can penetrate up to
2 cm of soft tissue; and
• Gamma radiation, consisting of photons, which traverse the entire
human body.
227
28
228 PART III:  THE CAUSES OF CANCER
Modes and Patterns of Irradiation
There are many different modes of irradiation that can impact cancer
risk and are therefore important to document and take into account
in epidemiological studies. The variety of well-​documented exposure
patterns provides an important opportunity to evaluate critical expo-
sure windows for carcinogenesis.
Internal Versus External Exposure
External exposures occur when individuals are in proximity to a
photon-​emitting radiation source. Internal exposure occurs from
intake of radionuclides, usually by inhalation or ingestion, or some-
times via absorption through intact or damaged skin or from injection
for medical reasons.
Acute, Fractionated, or Protracted Exposure
External exposure stops as soon as the source is turned off or removed,
or when the individuals move away from the radiation source. External
exposures, therefore, can be acute (i.e., delivered within seconds or
less), fractionated (consisting of a series of acute or short-​term expo-
sures delivered at relatively long time intervals), or protracted (i.e.,
occurring over a long time at a relatively constant rate). In contrast,
internal exposures, which result from the incorporation of a radionu-
clide, last as long as the radionuclide has not completely decayed or
been excreted from the body, depending on the physical half-​life and
biokinetics of the incorporated radionuclide. Internal exposures, there-
fore, cannot be acute.
Full-​Versus Partial-​Body Exposures
External exposures are usually due to photons, which can irradiate the
entire body in a relatively uniform manner, referred to as full-​body
exposure; for example the Japanese atomic bombs resulted in relatively
uniform full-​body exposure. Medical exposures to external sources,
such as diagnostic X-​rays, however, only irradiate the organs in the X-​
ray field and are referred to as partial-​body exposures. Internal expo-
sures can result in the irradiation of a specific organ of the body (for
example, the thyroid following exposure to I-​131, with other organs
receiving some exposure, e.g., stomach) or in the uniform irradiation
of the entire body (e.g., from exposure to cesium-​137).
Units of Exposure
The principal radiation quantities used to express dose are presented in
Table 13–​1. The most important quantity of radiation dosimetry that is
used in epidemiologic studies is the absorbed dose, which is defined as
the radiation energy absorbed per unit mass of organ or tissue. The unit
of absorbed dose is the gray (Gy), with 1 Gy equal to 1 joule per kg.
The absorbed dose is a physical quantity that does not take the type of
particle or the radiosensitivity of the organ or tissue into consideration.
Different types of radiation have different biological effectiveness
because they transfer their energy in different ways that can cause
or less more damage. The equivalent dose takes this into account
by weighting the absorbed dose in an organ or tissue by a radiation
weighting factor, which reflects the relative biological effectiveness
(RBE) of the radiation type. The radiation weighting factors that
are currently recommended by the International Commission on
Table 13–​1.  Principal Radiation Quantities Used to Express Dose
Quantity Unit Comment
Absorbed dose Gray (Gy) Does not account for the type of
radiation exposure
Equivalent dose Sievert (Sv) Accounts for biological effectiveness of
different types of radiation
Effective dose Sievert (Sv) Summary dose often used for partial-​
body exposures that accounts for
different radiosensitivity of organs
and biological effectiveness
Radiological Protection (ICRP) are 20 for alpha particles and 1 for
electrons and photons (ICRP, 2007). These values are based primarily
on in vitro experiments, and hence contain a number of uncertainties,
especially in their transfer to humans. The unit of equivalent dose is
the sievert (Sv).
For regulatory purposes, the primary dosimetry quantity is the effec-
tive dose, which is obtained as the sum, including all radiosensitive
organs and tissues of the body, of the equivalent doses weighted by a
tissue-​weighting factor, reflecting the radiosensitivity of the tissue or
organ. The current values of the tissue-​weighting factors that are rec-
ommended by the ICRP are 0.12 for red bone marrow, lung, stomach,
and breasts; 0.08 for gonads; 0.04 for bladder, liver, esophagus, and
thyroid; 0.01 for skin, bone surface, salivary glands, and brain; 0.12 for
the remainder of body (ICRP, 2007). Because the effective dose takes
into account the absorbed doses received by all radiosensitive organs
and tissues of the body, weighted according to their radiosensitivity
and to the radiation quality, it can be considered to be representative of
the radiation impact caused by exposure to a given source of radiation.
The effective dose is a regulatory quantity that is directly amenable to
the comparison of the radiation impacts of widely different sources of
exposure; its unit is also the sievert (Sv). Generally, it is not appropri-
ate to use estimates of effective dose in epidemiological studies.
SOURCES OF EXPOSURE
There are three broad sources of ionizing radiation exposure: environ-
mental, medical, and occupational. Currently the general population
is primarily exposed to very low doses of radiation from environmen-
tal sources from natural background radiation, and medical exposures
from diagnostic tests like CT scans (Figure 13–​1). There are also an
estimated 23 million radiation workers in the world who receive occu-
pational exposures (UNSCEAR, 2010b). Historically there have been
a number of important events that resulted in much higher doses of
radiation exposure to the general population and workers, including
the atomic bombs dropped in Japan, the Chernobyl accident, and uses
of high doses of radiation for the treatment of benign medical condi-
tions, such as ringworm (Tinea capitis). The epidemiological literature
includes populations exposed to current sources of exposure as well as
these historical sources, and therefore we review both here.
Environmental Exposures
Natural Environmental Exposures
Natural background radiation exposure makes up at least half of all
radiation exposure to the general population in most countries (Figure
13–​1). Exposure comes from radon, cosmic, terrestital gamma, and
internal sources (United Nations Scientific Committee on the Effects
of Atomic Radiation [UNSCEAR], 2010b) (Table 13–​ 2). Radon,
including thoron, is generally the largest contributor (about 50%, on
average, of the world population of natural background exposure) but
is also highly variable, depending on where people live and the con-
struction of their houses. There are several documented areas of much
higher natural background radiation in Brazil, India, Iran, and China,
where annual doses can exceed 10 mSv per year (UNSCEAR, 2010b).
Cosmic rays that reach the Earth’s surface originate either from
outer space (galactic and extra-​galactic cosmic rays) or from the sun
(solar wind) and cause exposures predominantly via external irradia-
tion. Cosmic radiation exposure to the general population varies with
latitude and altitude, and represents about 20% of the natural back-
ground exposure. Enhanced exposures are due to long-​haul air travel,
which is at high altitude; a round-​trip flight from London to Sydney
results in an estimated effective dose of 0.16 mSv.
Naturally occurring radionuclides in the earth result in effective
doses of external gamma radiation that represent about 20% of the
natural background exposure. Natural radionuclides in foods such as
dairy, cereals, and vegetables contribute the remaining 10% of natural
background exposure. Some foods can contain relatively high levels
 29

Ionizing Radiation 229

7 The atomic bombs were detonated over Hiroshima and Nagasaki
at altitudes of more than 500 meters so that the radiation doses were
Other essentially due to acute whole-​body external irradiation, immediately
6 Medical after the explosion, from photons and neutrons; there was very little
Environmental radioactive fallout because the explosions occurred at relatively high
altitudes, so that the fireballs had little interaction with the ground
5
(Cullings et al., 2006). Radiation dose levels depended primarily on
location in the city at the time of detonation and shielding. Those close
4 to the hypocenter who survived the initial blast had whole-​body doses
of > 5 Gy, resulting in acute radiation sickness and death within several
weeks. Survivors far from the hypocenter (e.g., > 2 km) had very low
3 whole-​body doses (< 5 mGy).
In contrast, the nuclear weapons tests were conducted in unpop-
ulated areas at altitudes that were generally less than 100 meters.
2 Consequently, people were not exposed to radiation occurring dur-
ing or immediately after the explosion. However, radioactive fallout,
including a large number of radionuclides, were spread over the entire
1 world (Bennett, 2002). These radionuclides led to external irradia-
tion from the photons produced during their radioactive decay, and
0 internal irradiation when they contaminated food products. Most of
USA UK Germany World
the doses were delivered within a few months after the test, with resid-
ual radiation, due to long-​lived radionuclides like 90Sr and 137Cs, with
radioactive half-​lives of about 30 years, protracted over a century or
Figure 13–​1.  Comparison of current estimated annual per capita radiation so (Bouville et  al., 2002). Even longer-​lived radionuclides, like 14C
exposure (mSv) for countries with a similar health-​care level. and 239Pu, will remain in the environment for more than 10,000 years.
Current estimates for the general population from these nuclear tests
are very low, however, at 0.005 mSv per year (Table 13–​2).
of radionuclides (although still resulting in small doses), especially The manufacture of nuclear weapons was associated with the pro-
mussels and Brazil nuts. duction of uranium or plutonium in nuclear reactors and the storage of
Also associated with natural background is a category of exposures high-​level radioactive waste. At the beginning of the nuclear era, dur-
called TENORM (technologically enhanced naturally occurring radio- ing the 1940s, little attention was paid to the environmental discharges
active materials) resulting from natural radionuclides or radiation, of radioactive material. Large amounts of 131I were released into the
exposing a small part of the population because of human activities, atmosphere at Hanford, Washington, in the United States (Shipler
such as flying, manufacturing, mineral extraction, combustion of fos- et al., 1996) and at Mayak (Eslinger et al., 2014) in the Soviet Union
sil fuels, cigarette smoking, and so on. The resulting exposures are (about 30 PBq at each facility), and substantial amounts of 90Sr, 137Cs,
usually < 0.05mSv (National Council on Radiation Protection and and other short-​lived radionuclides were discharged into the Techa
Measurements [NCRP], 2009). River near Mayak (Degteva et al., 2006).

Man-​made Environmental Exposures Nuclear Accidents.  Since 1957, nuclear power stations have been
used to produce electricity. There are currently 441 nuclear power sta-
Atomic Bombs and Nuclear Weapons Tests. The first tions operable in the entire world, including 99 in the United States
nuclear weapons test took place in July 1945 in New Mexico; it was (International Atomic Energy Agency [IAEA], 2016). Under routine
followed by dropping of atomic bombs on the Japanese cities of operation, environmental discharges of radioactive material have been
Hiroshima and Nagasaki in August 1945 and by the detonation of constantly decreasing since the 1950s and are presently very low, so
nuclear weapons tests in the atmosphere, mainly by the United States that the effective doses received by the populations of the vicinity
and the Soviet Union between 1946 and 1962 (Beck and Bennett, of these plants are very low as well (0.002 mSv per year) (National
2002). The radiation exposures caused by the atomic bombs and the Reasearch Council [NRC], 2012; UNSCEAR, 2010b). Environmental
nuclear weapons tests presented different characteristics and very dif- discharges of radioactive material and resulting doses are also low for
ferent levels of radiation exposure. the other facilities in the nuclear fuel cycle, which include the extrac-
tion of uranium, the preparation of nuclear fuel, its reprocessing (only
Table 13–​2.  Worldwide Averages and Typical Ranges of Annual in a few countries), and the storage of radioactive wastes (UNSCEAR,
Effective Doses (mSv) from Environmental Radiation 2010b).
There have been four reactor accidents that resulted in irreparable
Annual Effective Dose damage to the power plant and in substantial radiation exposures as a
(mSv) consequence of the releases of radioactive materials into the environ-
ment (Bouville et  al., 2014). The first of those accidents took place
Main Type of Worldwide Typical in 1957 at Windscale in the United Kingdom and was caused by a
Source of Radiation Exposure Average Range fire in the reactor core. The second accident took place at the Three
Mile Island (TMI) reactor in the United States in 1979 and was due to
Natural both mechanical and human errors. The third, and most severe, reac-
Cosmic External (μ, e-​, n) 0.39 0.3–​1 tor accident was at the Chernobyl nuclear power plant in the former
Terrestrial External (γ) 0.48 0.3–​1 Soviet Union in 1986, and resulted from a series of human errors dur-
Radon in air Internal (α) 1.26 0.2–​10 ing the conduct of a reactor experiment. Finally, the Fukushima acci-
Radionuclides in food Internal (α, β) 0.29 0.2–​1 dent, which occurred in northern Japan in 2011, was the consequence
Man-​made of an earthquake-​triggered tsunami that damaged the reactor cooling
Atmospheric nuclear tests External (γ) and 0.005 0–​0.05 system. The relative importance of these accidents can be assessed to
internal (β) some extent from the atmospheric discharges of 131I, which were 1 PBq
Nuclear fuel cycle External (γ) 0.002 0–​0.02 at Windscale (Clarke, 1989), 0.0006 PBq at Three Mile Island, 1,800
PBq at Chernobyl (UNSCEAR, 2011), and 120 PBq at Fukushima
Source: UNSCEAR (2010b). (Terada et al., 2012). The best-​documented doses are those related to
230

230 PART III:  THE CAUSES OF CANCER

the Chernobyl accident: in a cohort of about 12,000 children, the mean Occupational Exposures
thyroid dose from intakes of I-​131 was estimated to be 580 mGy, while
the mean whole-​body doses was 14 mGy. There are about 23 million workers who are monitored currently for
their occupational radiation exposure (UNSCEAR, 2010b). The larg-
est group is those in mining (12 million), followed by medical workers
Other Man-​made Sources of Environmental Exposure.
(7 million). In general, occupational doses have been decreasing for
Many industrial operations, security inspection systems (such as some
many decades, and are now very low (effective dose of 1–​5 mSv per
airport screening machines), medical facilities, and educational and
year), which is similar to cumulative annual exposure from natural
research institutions use radiation sources or radioactive material.
background radiation. There are a few exceptions where exposures
Members of the public may be exposed to low levels of radiation when
are increasing, particularly for physicians who perform large num-
they are in proximity to such sources, or when they are near a patient
bers of fluoroscopy-​guided interventional procedures, and radiologic
who has been administered a radiopharmaceutical. Widespread envi-
technologists who administer radionuclides and perform many nuclear
ronmental contamination and exposure of large numbers of people
medicine scans.
have occurred in a few instances when industrial and medical sources
were misplaced or stolen (UNSCEAR, 2011). These include events
that occurred in Goiania, Brazil, in 1987 (IAEA, 1998), in Juarez, ASSESSMENT OF THE EXPOSURE IN ANALYTIC
Mexico, in 1983 (Molina, 1990), and in Taipei, Taiwan, in 1982–​1983
(Chang et al., 1997).
EPIDEMIOLOGIC STUDIES

The ability to estimate a biological measure of dose provides radia-

Medical Exposures tion epidemiologists a great advantage in cancer epidemiology. Dose
reconstruction methods and the associated uncertainties vary consider-
There have been increases in ionizing radiation exposure to the gen- ably, however, according to the source of exposure. In some situations
eral population in the last few decades due to increased medical it is not feasible to estimate doses, in which case exposure is based on
radiation exposure, primarily from CT scans. In the United States the proxy measures such as number of years of employment, or number of
estimated annual per capita effective dose doubled between 1980 and CT scans. Many studies are retrospective because of the long latency
2006 from 3 to 6 mSv (NCRP, 2009). The increase was due to the period for radiation-​related cancer (5+ years for solid tumors) and this
nearly 30-​fold increase in number of CT scans over the period from brings particular challenges due to the use of historical records. The
3 to 80 million per year. Smaller increases in other higher dose diag- degree to which dose estimates are individualized is important, as is
nostic exposures, nuclear medicine procedures, and fluoroscopically the assessment of uncertainties and their impact on risk.
guided interventional procedures also contributed. CT scan use has
also increased in other countries also, although less dramatically than
in the United States (Berrington de Gonzalez et  al., 2009). Current Environmental Studies
levels of CT scan use per capita, for example, are three times lower
Radiation doses from environmental exposures are some of the most
in the United Kingdom than in the United States. Nuclear medicine
challenging and time consuming to estimate. Individual exposure
tests are 30 times less frequent in the United Kingdom than in the
assessment has been conducted for studies of the Japanese atomic
United States. Estimated per capita effective dose from medical radia-
bomb survivors (Cullings et al., 2006), and of local populations around
tion in the United Kingdom has also increased, but from 0.3 in 1988
nuclear weapons sites in Nevada (Till et al., 2014) and at Semipalatinsk
to only 0.4 mSv in 2008 (Hart et al., 2010). The total estimated per
(Gronwald et  al., 2008), and sites of high radioactive discharges at
capita dose from ionizing radiation exposure now varies considerably
Hanford (Kopecky et al., 2004), the Techa River (Degteva et al., 2006),
across countries depending on levels of diagnostic medical exposures
and around the site of the Chernobyl accident (Drozdovitch et  al.,
(Figure 13–​1).
2013). All of the radiation exposures of the study subjects occurred
Although the number of procedures has increased, efforts have been
predominantly in the 1940s and 1950s, with the exception of the
made to reduce the dose per procedure without compromising the
Chernobyl accident, which took place in 1986. In order to evaluate the
medical benefits. The range of average effective doses to the patient
impact of these events, large numbers of radiation measurements on
per procedure varies from 2 to 15 mSv for CT, from 5 to 70 mSv
both the environment and population had been conducted or collected
for fluoroscopically guided interventional procedures, and from 0.2
in most of the geographic domains of interest prior to the decision to
to 40 mSv for nuclear medicine, according to the type of examina-
conduct an epidemiologic study. The approaches for estimating doses
tion (Mettler et  al., 2009). Before 2000, CT scan doses were rarely
to study subjects varied according to the type, quality, and amount
optimized for the smaller body size and weight of children, resulting
of information that was available. No two dose reconstructions were
in unnecessarily high exposures of up to 30 mGy to the lungs/​breast
alike, but there was a general strategy to estimate doses and uncer-
from a chest CT scan and 40 mGy to the brain from a head CT (Kim
tainties that includes (Bouville et al., 2014): (1) collection of as many
et al., 2012). In the United Kingdom, organ doses have been halved for
individual-​based radiation measurements as possible for subjects in
children by optimized protocols (Lee et al., 2016).
the target population, (2) collection of questionnaire-​based individual
External-​beam radiotherapy is the use of external irradiation for
personal and lifestyle information that can influence dose, (3) collec-
the treatment of disease. The therapeutic absorbed dose to the target
tion of information on the spatial and temporal patterns and variations
volume in the patient is orders of magnitude greater than the aver-
of the radiation field, (4) calculation of realistic radiation doses with
age diagnostic dose due to conventional radiography (e.g., 40+ Gy)
efforts to minimize sources of bias, (5)  validation of the dose esti-
(Thierry-​Chef et  al., 2012). Some very high-​dose exposure to sur-
mates by independent measurements or strategies, and (6) qualitative
rounding normal tissue is also unavoidable, but technology is con-
and quantitative evaluation of the uncertainties associated with dose
tinuously evolving to try to minimize these exposures. Currently,
estimates.
radiotherapy is used mostly to treat patients with life-​ threatening
diseases such as cancer, and a limited range of benign diseases like
hyperthyroidism (McKeown et  al., 2015). During the earlier part of Medical Exposures of Patients
the twentieth century, radiotherapy was used to treat a wide variety
of benign conditions including Tinea capitis, tonsillitis, peptic ulcers, Because exposures to patients are given under controlled conditions
and hemangiomas. Once the hazards of ionizing radiation were better that are generally well documented, patients exposed to radiation
recognized, these treatments were stopped, but not before thousands of during treatment for malignant and benign diseases and for diag-
patients had been exposed. Many long-​term epidemiological studies of nostic purposes are well suited to be participants in epidemiologic
these patient populations have documented the excess cancer risks that studies (Stovall et al., 2006). For diagnostic exposures, historically
the patients suffered (Ron, 2003). the documentation was only a written description of the type of
 231
Ionizing Radiation 231
examination, with no details of the specific machines or machine
parameters. Sometimes information on protocols and machines can
be obtained from current staff or institutional archives in the diag-
nostic radiology department. In the absence of specific information,
organ dose is estimated on the basis of typical values reported in the
literature for a given examination and time (Stovall et al., 2006), or
via reconstruction of typical values using protocols or survey data
(Kim et  al., 2012). In the specific case of patients undergoing CT
scans, computational methods to readily estimate organ doses for
adults and children of various ages were incorporated into a com-
puter program called NCICT (Lee C et al., 2015). Since the wide-
spread introduction of electronic records for examinations like
CT, dose reconstruction can now be conducted using the technical
parameters directly from these records. As the exposures are usually
partial rather than whole body, information on the specific patient
anatomy is needed to help determine which organs were likely to be
in the exposure field. If patient anatomy is not available, then age-​
and sex-​specific phantoms (models of the human body) can be used,
but this will introduce some error.
For patients treated with external-​ beam radiation therapy, the
quality of the reconstructed dose depends on the degree of complete-
ness and accuracy of the treatment records, which include radiation
energy, field size, anatomic location of fields, treatment-​planning
details, and daily treatment logs and information on patient anatomy.
To estimate the absorbed doses outside the treatment beam, three
techniques are used: (1) calculation using a three-​dimensional math-
ematical computer model based on measurements made in a water
or polystyrene phantom, (2)  direct measurements in an anthropo-
morphic phantom constructed of tissue-​ equivalent material, and
(3) calculation of dose using a treatment-​planning computer program
(Stovall et  al., 2006). As with diagnostic exposures, if CT images
from the treatment-​planning process and patient height and weight
are available, this will greatly improve the accuracy of the organ
dose estimates. Without these, age-​and sex-​specific phantoms can
be used, but this will reduce dose accuracy, and uncertainty assess-
ments should be undertaken.
Occupational Studies
Since the 1960s it has been common or required for occupational
radiation workers to wear personal dosimeters, which measure exter-
nal radiation exposures. The dose measurements are monitored and
recorded for all workers. This provides an ideal scenario for epidemio-
logical studies, particularly if the records are electronic, and for many
nuclear workers personal dosimeters were available from the start
of their employment. There are still challenges in estimating organ
doses from these badge measurements, however, particularly for medi-
cal workers, because of the potential heterogeneity of exposures over
the body, differences in where the personal dosimeter is worn on the
body (e.g., whether on the collar, belt, pocket, outside a lead apron or
inside for a medical worker), and whether or not individual protective
devices (e.g., lead aprons) were used by medical workers (Bouville
et  al., 2015). Administration of detailed questionnaires to the study
subjects can be used in conjunction with badge doses to address these
factors (Bouville et al., 2014; Simon et al., 2014). Other considerations
are unmonitored dose when a dosimeter was not worn, doses below
the limit of detection, and doses received at multiple facilities and the
ability to link these records.
For exposures predating the 1960s when workers did not have
access to personal dosimeters or when the recorded doses cannot be
retrieved (e.g., for the earliest medical workers), proxy measures of
dose are generally used based on surveys and periods of employment
(Simon et  al., 2015). Occupational doses resulting from intakes of
radionuclides usually are derived from bioassay measurements. These
were available for about 40% of the Mayak workers who received
internal plutonium exposure, but are not available at many other
nuclear power facilities (Liu et al., 2016). It may be possible to esti-
mate doses for these workers using a job exposure matrix if some
measurements as well as a detailed employment history are available
(Liu et al., 2016).
BIODOSIMETRY
In addition to the physical methods of dosimetry, biological markers
can theoretically be incorporated into epidemiologic studies. The main
methods that have been used are the fluorescence in situ hybridiza-
tion (FISH) technique for analysis of stable chromosome transloca-
tions, and electron paramagnetic resonance (EPR) of tooth enamel and
bones. However, these methods are expensive, require extensive effort
in collecting, processing, and analyzing the biological specimens, and,
currently, cannot capture exposures below 0.1 Gy. Other techniques
for lower doses, such as measurement of gamma-​H2AX foci, are also
available. None of the approaches currently available is both highly
sensitive and highly specific to ionizing radiation exposure, and these
methods have not been widely employed in epidemiological studies
(Pernot et al., 2015). For further discussion of radiation biomarkers,
see the section “Cellular Assays to Measure Biological Changes in
Humans” later in this chapter.
Uncertainties
Methods for quantifying uncertainties and incorporating them into
the risk analysis are more advanced in radiation than in many other
fields, but are still at the development stage (Little et al., 2014; Simon
et al., 2015; Stram et al., 2015). A single ideal approach to evaluate and
account for all dosimetric uncertainties is not available but is an area
of active research (Kwon et al., 2016; Land et al., 2015; Li et al., 2007;
Simon et  al., 2015; Stayner et  al., 2007; Stram et  al., 2015). Until
recent years, the evaluation of the uncertainties consisted of numeri-
cal simulations in which variability and lack-​of-​knowledge uncer-
tainties were combined in Monte-​Carlo simulations. In that method,
probability density distributions are assigned to the parameter values
that are deemed to have a substantial influence on the dose estimate,
and multiple realizations of individual doses are estimated (NCRP,
2007). Consideration of whether shared errors and intra-​individual
correlations could be large is required. More sophisticated Monte-​
Carlo procedures are now being developed to separate and distinguish
between the shared and the unshared components. However, there are
always concerns that all sources of uncertainty have not been taken
into account. For example, in environmental studies, there may be
“unknown” exposure pathways or unsuspected relevant radionuclides,
among other factors.
As a rule, the quality of the individual doses required in analytical
radiation epidemiologic studies is highest when human-​based mea-
surements are reliable, available for all subjects, and representative of
the organ dose of interest. This is, for example, the case for patients
with therapeutic treatment or workers in nuclear plants. At the other
end of the spectrum, the quality of the individual doses is lowest when
human-​based measurements are not available and the doses have to
be reconstructed on the basis of sparse data and personal interviews
conducted long after the exposure occurred. This is the case for some
environmental studies. However, it is important to note that, despite
the absence of human-​based measurements, the individual doses to the
A-​bomb survivors could be reliably reconstructed, but this required
several decades of effort and very large resources.
TYPES OF CANCER CAUSED BY THE EXPOSURE
From the vast array of epidemiological studies of ionizing radiation
exposure, there is evidence that most types of cancer can be caused
by radiation, hence, its classification as a universal carcinogen
(UNSCEAR, 2006; BEIR VII). Based on standard laboratory tests of
carcinogenicity, ionizing radiation is frequently referred to as a weak
carcinogen compared to many chemicals (NCRP, 1997). However, this
comparison and generalization are misleading. First, many chemicals
have tissue-​specific effects and only cause cancer in certain organs
(NCRP, 1989). Also there is direct evidence from human studies of
high risks in certain organs following radiation exposure in childhood.
For example, in the Japanese Life Span Study (LSS), the estimated
23
232 PART III:  THE CAUSES OF CANCER
excess relative risk (ERR)/​Gy for exposure < age 1 year for leukemia
is 50 (at attained age 20), 9 for thyroid, and 4.5 for breast cancer (Hsu
et al., 2013; Preston et al., 2002a; Veiga et al., 2016).
Several national and international radiation protection agencies
review the epidemiological data periodically and summarize the evi-
dence regarding cancer risks for each cancer site. Here we provide
a meta-​summary of the most recent findings from BEIR VII (2006),
UNSCEAR (2006), and the Advisory Group on Ionising Radiation
(2011) to categorize each cancer site as related, probably related, or
uncertain relation to ionizing radiation. We have also incorporated evi-
dence from recent studies that were published after these reports. The
majority of cancer sites can be classified as radiation-​related, generally
based on evidence of a significant dose–​response relationship from
several rigorous epidemiological studies without major biases.
The Life Span Study (LSS) of the Japanese atomic bomb survivors
remains the gold-​standard radiation epidemiology study and the pri-
mary source of data for the reports described in the preceding paragraph
and the basis for the classification of cancer sites here (Table13-​3).
The cohort includes about 105,000 individuals and 22,500 incident
cancers during the seven decades of follow-​up (Grant et al., 2017. Key
features of the study include the whole body exposure, wide dose-​
range to healthy individuals of all ages, accurate dose reconstruction,
and follow-​up via cancer registries and national death records. For a
detailed description of the study methods and dosimetry, see Preston
et  al. (2007) and Cullings et  al. (2016). For some cancer sites such
as sarcomas (Henderson et al., 2012), pancreatic cancer (Dores et al.,
2014) and rectal cancer (Sakata et al., 2012), higher-​dose therapeutic
exposures (> 5Gy) are the primary basis for our classification. Absence
of significantly increased risks from lower-​dose studies for these can-
cers likely reflects lack of power rather than evidence of a threshold for
these sites. Cancers where there is some evidence of a dose–​response
relationship, but uncertainty about potential confounders or biases, are
described as possibly related to radiation (e.g., chronic lymphocytic
leukemia [CLL], multiple myeloma, and endometrial cancer). Those in
the “unclear” category are sites where there are no high-​quality studies
with reasonable power that support a dose–​response relationship with
radiation exposure or sites for which there are inconsistent findings
across studies: non-​Hodgkin lymphoma (NHL); Hodgkin lymphoma
(HL); kidney, cervical, and gallbladder cancers; and melanoma. These
classifications are difficult due to conflicting results and the rarity of
some of these cancers, and the distinction between possibly related
and unclear should be interpreted cautiously.
To illustrate the range in the magnitude of the risks across cancer
sites, we present estimates of the ERR/​Gy for cancer incidence from
the LSS of the Japanese atomic bomb survivors for an individual
exposed at age 30 with an attained age of 70 (Table 13–​3) (Preston
et al., 2007). Why there are large differences in radiosensitivity of dif-
ferent organs is an interesting question that could provide insights into
radiation carcinogenesis. The weighting factors used to estimate the
effective dose (described in the section “Units of Exposure” earlier in
this chapter) aim to capture these differences in sensitivity for radia-
tion protection standards (ICRP, 2007).
MAJOR NEW STUDIES AND UPDATES
We reviewed studies of environmental, medical, and occupational
exposures published since 2006. For studies that have not reported
significant updates, see the previous edition of this text (Boice, 2006).
Summary characteristics of the studies are shown in Table 13–​4.
Environmental Exposures
Japanese Atomic Bomb Survivors
As described in the preceding section, the LSS study has demonstrated
that most types of cancer can be caused by ionizing radiation exposure,
and has provided quantification of the risks per unit dose and variation
with gender, attained age, age at and time since exposure. The cohort
continues to provide new information about the long-​term effects of
radiation exposure, especially from childhood exposure, as about
80% of those exposed before age 10 are still alive (Grant et al., 2017).
The most recent analysis of all solid cancer incidence with follow-​up
extended to 2009, which includes 22,538 cancers, incorporates adjust-
ment for smoking for the first time and has updated dose estimates. The
dose–​response for females was linear (ERR/​Gy = 0.64; 95% CI: 0.52,
0.77), and similar in magnitude to the previous analysis (Preston et al.,
2007). For males, there was evidence of significant upward curvature
described by a linear-​quadratic model with an ERR at 1 Gy of 0.2 (0.12,
0.30), which is significantly lower than for females. The EAR estimate
for females was 54.7 (95%CI:45, 65), while for males the estimate was
42.9 (95%CI:27, 58) cases per 10,000 PY at 1 Gy. When restricted to
doses < 0.1Gy, there was still a statistically significant dose–​response
relationship using a sex-​averaged linear model (p = 0.038). The addi-
tional follow-​up confirmed that the solid cancer risks remain signifi-
cantly increased for more than 60 years after radiation exposure. The
risk decreased with increasing age at exposure or attained age. There
was evidence that a previous finding of an increase in risk for exposure
after age 60 (Preston et  al., 2007)  was an artifact due to cases only
reported on autopsy (Grant et al., 2017). No simple explanation for the
introduction of curvature in the dose–​response relationship for cancer
incidence in the males could be identified. The revised dosimetry and
increased follow-​up time tended to increase the evidence for curvature,
while smoking adjustments and sex-​specific cancers were ruled out.
There will be a series of updated site-​specific cancer incidence papers
over the next few years that will assess evidence for curvature for each
site in more detail, and that will incorporate additional lifestyle factors
as potential effect modifiers.
The updated analysis of hematopoetic malignancies with cancer
incidence data to 2001 reported that elevated leukemia risks, partic-
ularly acute myeloid leukemia, persist for more than 50  years after
exposure (Hsu et  al., 2013). The dose–​ response relationship was
linear-​quadratic for acute myeloid leukemia (AML), but linear for
acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia
(CML). There is emerging evidence of an increased risk of CLL and
NHL in males, but still no evidence that multiple myeloma or Hodgkin
lymphoma are related to radiation exposure. For thyroid cancer, addi-
tional follow-​up suggests that the excess risk persists for more than
50 years after exposure, but is still largely restricted to exposure before
age 20 (Furukawa et al., 2013). An updated analysis of the joint effect
of smoking and radiation on lung cancer risk suggested a complex
relationship with smoking intensity where the joint effect was mul-
tiplicative for lower smoking intensities (< 10 cigarettes/​day) and
additive or sub-​additive for higher intensities (Furukawa et al., 2010).
For uroethelial cancer, the joint effect of smoking and radiation was
best described by a multiplicative model, although the additive model
could not be rejected (Grant et al., 2012).
Natural Background Radiation
Most studies of high natural background radiation have used an eco-
logical design, which is susceptible to many biases (Hendry et  al.,
2009). The major exception is the case-​control studies of residential
radon exposure, which have provided convincing evidence of a link to
lung cancer due to relatively high doses, careful dose reconstruction,
and pooling of multiple studies (Darby et  al., 2005; Krewski et  al.,
2006). The risk estimates from these pooled analyses of residential
exposure are compatible with the high-​dose studies of radon-​exposed
underground miners (Lubin et al., 1997). The joint effect of smoking
and radon was multiplicative, which means that the absolute hazard
from radon exposure is much higher for smokers. They estimated that
the lifetime lung cancer risk for smokers with high residential radon
exposure (e.g., 800 Bq/​m2 usual exposure) could be increased from
10% to 22%, whereas in non-​smokers the lifetime risk is increased
from 0.4% to 0.9% (Darby et al., 2005).
There also have been several case-​ control studies of natural
background radiation and childhood cancer. A  recent record-​based
case-​control study in the United Kingdom (n  =  27,447 cases) using
radiation exposure from mother’s residence at the child’s birth from
national databases found a significant dose–​ response relationship
(ERR/​mGy = 0.12, 95%CI:0.03–​0.22) for leukemia in relation to red
 23

Ionizing Radiation 233

Table 13–​3. Cancers Related to Ionizing Radiation and Estimated Excess Relative Risk (ERR) at 1 Gy from the Life Span Study (LSS) of Atomic Bomb
Survivors for Age at Exposure 30 and Attained Age 70

Cancer Radiation Related ERR at 1 Gy* LSS (90% CI) N Cases in LSS Comment

Bladder Yes 1.23 (0.59, 2.10) 469

Breast Yes 0.87 (0.55, 1.30) 1073
Lung Yes 0.81 (0.56, 1.10) 1759 ERR increases with age at exposure.
Leukemia (non-​CLL) Yes 0.79 (0.03, 1.93) 416 Linear term of linear-​quadratic model provided
here.
Brain/​CNS Yes 0.62 (0.21, 1.20) 281
Ovary Yes 0.61 (0.00, 1.5) 245
Thyroid Yes 0.57 (0.24, 1.1) 471 ERR decreases with age at exposure.
Colon Yes 0.54 (0.30, 0.81) 1516
Oesophagus Yes 0.52 (0.15, 1.00) 352
Oral Yes 0.39 (0.11, 0.76) 277 Increase driven by salivary gland, confirmed in
high-​dose radiotherapy studies (Boukheris
et al., 2013).
Stomach Yes 0.34 (0.22, 0.47) 4730
Liver Yes 0.30 (0.11, 0.55) 1494
Non-​melanoma skin Yes 0.17 (0.003, 0.55) 330 ERR decreases with age at exposure.
Bone Yes na 20 Dose–​response relationship reported after high-​
dose radiotherapy (e.g., Henderson et al.,
2012; Rubino et al., 2005).
Soft tissue Yes na 33 Dose–​response relationship reported after high-​
dose radiotherapy (e.g., Henderson et al.,
2012; Rubino et al., 2005).
Pancreas Yes 0.26 (< 0.07, 0.68) 512 Dose–​response relationship reported after
high-​dose radiotherapy (Dores et al., 2014;
Hauptmann et al., 2016).
Rectum Yes 0.19 (−0.04, 0.47) 838 Dose–​response relationship reported after
high-​dose radiotherapy (e.g., Sakata et al.,
2012) and in UK nuclear workers (Muirhead
et al., 2009)
Endometrial Possibly 0.29 (−0.14, 0.95) 184 Possibly increased for exposure < age 20 in
LSS and after high-​dose radiotherapy (e.g.,
Sakata et al., 2012).
Chronic lymphocytic Possibly na 12 Dose–​response relationship reported in
leukemia Chernobyl cleanup workers (Zablotska et al.,
2013) but not in nuclear workers (Leraud
et al., 2015).
Multiple myeloma Possibly 0.38 (−0.23 to 1.36) 136 Dose–​response relationship for cancer incidence
in UK nuclear workers (Muirhead et al.,
2009) but not for mortality in INWORKS
(Leuraud et al., 2015).
Non-​Hodgkin lymphoma Unclear See comment 402 ERR at 1 GY = 0.46 (−0.08, 1.29) for males and
0.02 (< −0.44, 0.64) for females.
Prostate Unclear 0.11 (−0.10, 0.54) 387 No evidence of increased risks in occupational
cohorts (Muirhead et al., 2009).
Renal cell Unclear 0.13 (−0.25-​0.75) 247
Cervix Unclear 0.06 (−0.14, 0.31) 859 No evidence of increased risks after high-​dose
radiotherapy (e.g., Sakata et al., 2012).
Gallbladder Unclear −0.05 (< −0.3, 0.3) 549
Melanoma Unclear na 17

*For age at exposure 30, attained age 70 (solid cancers from Preston et al., 2007, and hematopoietic from Hsu et al., 2013).
na = not available.

bone marrow dose from gamma radiation (mean RBM dose = 4mSv;
range  =  0–​31mSv) (Kendall et  al., 2013). This was also consistent
with the dose–​response relationship from higher dose rate studies,
such as the LSS (Hsu et  al., 2013). There was a weak but not sta-
tistically significant relationship between radon exposure and leuke-
mia, and no association between gamma or radon dose with any other
childhood cancers. Previous case-​control studies that utilized a similar
design were null, or not statistically significant for gamma radiation,
but based on a much smaller sample size (range  =  50 to 860 cases
vs. 27,447) (Laurier et al., 2001; Raaschou-​Nielsen, 2008). There is
evidence from previous case-​control studies with residential measure-
ments of radon concentration of an increased risk of childhood ALL
(Raaschou-​Nielsen, 2008). The UK study is currently being further
expanded and dose estimates refined.
The Chernobyl Accident
The Chernobyl accident in 1986 is the worst nuclear accident to date,
and the studies of the exposed children, in particular, are the most
important source of information on the risks from internal I-​131 expo-
sure in the general population. There are ongoing follow-​up studies in
Ukraine, Belarus, Russia, and other Baltic countries of children exposed
to internal radiation, primarily from consumption of contaminated milk
and foods, and of the clean-​up workers. A cohort of Ukrainian children
(n  =  12,514) with I-​131 exposure estimated from measurement and
234

234 PART III:  THE CAUSES OF CANCER

Table 13–​4. Summary of the Characteristics of Recent Epidemiological Studies

Typical
Source Study Exposure Type Exposure Pattern Dose Range Outcomes

Environmental Life Span Study Gamma, neutrons Acute 0–​2 Gy All cancer incidence
Residential radon pooled analysis Radon Chronic 0–​1400 Bq/​m3 Lung cancer incidence
UK Background Gamma Chronic 0–​0.015 Gy Childhood cancer incidence
Chernobyl UKRAM cohort I-​131 Chronic 0–​4 Gy Thyroid cancer incidence
Chernobyl BELAM cohort I-​131 Chronic 0–​10 Gy Thyroid cancer incidence
Swiss Nuclear Power Residents External Chronic na Childhood cancer incidence
France Nuclear Power Residents External Chronic na Childhood cancer incidence
German Nuclear Power Residents External Chronic na Childhood cancer incidence
Techa River Gamma, Cesium Chronic 0–​0.5 Gy Cancer incidence

Medical UK Pediatric CT X-​rays Acute, fractionated 0–​0.1 Gy Cancer incidence

Australian Pediatric CT X-​rays Acute, fractionated na Cancer incidence
US Scoliosis X-​rays Acute, fractionated 0–​1 Gy Breast cancer incidence
BRCA cohort X-​rays Acute, fractionated na Breast cancer incidence
Kuwait Thyroid case-​control X-​rays Acute, fractionated na Thyroid cancer incidence
US Brain Cancer case-​control X-​rays Acute, fractionated na Brain cancer incidence
USRT personal diagnostic exposures X-​rays Acute, fractionated na Thyroid cancer incidence
UKCCS X-​rays Acute, fractionated na Childhood cancer incidence
CCSS X-​rays Acute, fractionated 0–​80 Gy Second cancer incidence
UKCCS X-​rays Acute, fractionated 0–​80 Gy Second cancer incidence
French childhood cancer survivors X-​rays Acute, fractionated 0–​80 Gy Second cancer incidence
Hodgkin’s lymphoma survivors X-​rays Acute, fractionated 0–​80 Gy Second cancer incidence
Second GI cancers study X-​rays Acute, fractionated 0–​80 Gy Second cancer incidence
Retinoblastoma cohort X-​rays Acute, fractionated 0–​80 Gy Second cancer incidence

Occupational Mayak workers Gamma, plutonium Chronic 0–​4 Gy Cancer incidence and mortality
15 Countries Study Gamma Chronic 0–​0.05 Gy Cancer mortality
INWORKS Gamma Chronic 0–​0.05 Gy Cancer mortality
UKNRRW Gamma Chronic 0–​0.05 Gy Cancer incidence
French nuclear workers Gamma Chronic 0–​0.05 Gy Cancer mortality
US nuclear workers Gamma Chronic 0–​0.05 Gy Cancer mortality
Flight crew pooled analysis Cosmic Chronic na Cancer mortality
Scandinavian flight crew Cosmic Chronic na Breast cancer incidence
US flight crew Cosmic Chronic na Breast cancer incidence
Chinese medical workers X-​rays Chronic 0–​0.4 Gy Cancer incidence
USRT X-​rays Chronic 0–​0.1 Gy Cancer incidence

na = not available.

interviews has undergone four rounds of thyroid screening. In the most
recent analysis, the linear dose–​response relationship for thyroid can-
cer (n = 65, ERR/​Gy = 1.91; 95% CI: 0.43,6.34), was consistent with
the risk from external acute exposure in the Japanese atomic bomb sur-
vivors (Brenner et al., 2011). Similar results were reported in a cohort
of children in Belarus (n = 84 thyroid cancers) (Zablotska et al., 2011).
Assessment of dose uncertainty did not significantly alter these risk
estimates (Little et al., 2014, 2015). More details on the relationship
between I-​131 and thyroid cancer are provided in Chapter 44.
Interview-​ based case-​ control studies of adulthood exposures
received by the liquidators reported an increased risk of thyroid can-
cer (n  =  107, median thyroid dose  =  69 mGy) (Kesminiene et  al.,
2012) and leukemia (n = 137) including both CLL and non-​CLL (con-
trols mean RBM dose = 82 mGy) (Zablotska et al., 2013). Although
the non-​ CLL leukemia results were consistent with the Japanese
atomic bomb survivors, the excess risks for CLL and thyroid cancer
after adulthood exposure were much higher than those observed in
the LSS (Hsu et al., 2013; Preston et al., 2007). Prevalent case-​control
studies conducted more than 20 years after the accident could be sub-
ject to recall bias. In the leukemia/​CLL case-​control study, 50% of the
cases compared to 5% of the controls had died, and dosimetry was
based on proxy responders. The ERR/​Gy was lower in the subset with
direct interviews (0.88) than proxy responders (3.98), but confidence
intervals were wide due to the small number of controls with proxy
interviews (Zablotska et al., 2011).
Cancer Near Nuclear Power Stations
Residents living near nuclear power stations remain concerned about
potential cancer risks, especially childhood leukemia, since the early
reports of potential cancer clusters (Black, 1984). Study design issues
include small sample size and ecological design. A recent large cohort
study based on the Swiss Childhood Cancer Registry (n  =  2925)
using distance from residence at birth from a nuclear power plant and
national census data found no evidence of a relationship between dis-
tance and childhood leukemia (Spycher et al., 2011). The study could
not, however, rule out small risks due to limited statistical power, and
distance is a crude and potentially inaccurate proxy for radiation expo-
sure. Two studies with a similar design in France and Germany found
some evidence of a relationship between proximity to a power sta-
tion and leukemia (Kaatsch et al., 2008; Sermage-​Faure et al., 2012).
A  review of all the studies and new UK data concluded that there
remained suggestive evidence of small risks, but confounding could
not be ruled out, especially given the finding of a similar association
with distance from sites for proposed nuclear power stations that were
 235

Ionizing Radiation 235

never built (Stather, 2011). A proposed US study was canceled after
feasibility work suggested that the time and costs involved were exces-
sive (Nuclear Regulatory Commission, 2015). An earlier US study of
cancer mortality in 107 counties near nuclear facilities and matched
control counties was null, but with the caution that the risks may have
been too small to detect with the ecological study design (Jablon
et al., 1991).
Techa River Residents
The population living near the Techa River received protracted low-​
dose radiation exposure from internal and external sources following
radioactive releases into the river from the Mayak nuclear weap-
ons plants. In the cohort of residents followed for cancer incidence
(n  =  17,433) with a mean organ dose around 50 mGy, there was a
statistically significant linear dose–​response relationship for all solid
cancers and leukemia (excluding CLL) (Krestinina et al., 2007, 2013).
There is limited power for site-​specific solid cancer risks (n = 2059),
but, of 15 sites evaluated, significant dose–​ response relationships
were recently reported for cancer of the esophagus and uterus (Davis
et al., 2015).
Medical Exposures
Diagnostic Medical Radiation
The increase in CT scan use and publications reporting unnecessarily
high dose levels in children in 2001 (Paterson et al., 2001) prompted
the initiation of a number of retrospective cohort studies of pediatric
CT scans and cancer. Collaboration between the investigators ensured
that protocols were broadly similar to facilitate future pooling of the
data. The UK cohort consists of approximately 180,000 children and
young adults (age < 22 years) who underwent CT scans between 1980
and 2002 in about 100 hospitals (Pearce et al., 2012). The exposure
data were abstracted from electronic databases in radiology depart-
ments and were linked to national cancer registration and vital status
databases. Patients with cancer diagnosed before the date of the first
CT scan were excluded. Organ-​specific dose estimates were semi-​
individualized, as they were based on body region scanned, date of
scan, and age at scan. With a 2-​year lag period, there was evidence of a
significant dose–​response relationship for leukemia/​MDS (n = 74) and
red bone marrow dose (mean = 12 mGy) (Figure 13–​2). The ERR/​mGy
was statistically compatible with the risk estimate from the Japanese
8
7 (n = 3010) reported a borderline significant dose–​response relationship
6 2008). The mean breast dose was 120 mGy and the dose–​response
5 ily history of breast cancer, although this was based on small numbers.
RR (& 95% CI)
atomic bomb survivors when restricted to a similar exposure age and
follow-​up period. The dose–​response relationship for brain tumors
(n = 135) and estimated brain dose (mean = 43 mGy) was also statisti-
cally significant, but about four times higher than the comparable risk
estimate in the LSS. Sensitivity analyses that assessed additional clini-
cal information suggested that there was some evidence of bias due to
unreported previous brain tumors, and when these were excluded the
ERR/​mGy was still statistically significant but slightly closer in mag-
nitude to the LSS (Berrington de Gonzalez et al., 2016). The cohort is
currently being expanded to include patients who underwent CT scans
up to 2010. Additional data have been collected to refine the dosimetry
and conduct analyses of the impact of dose uncertainty (Lee et  al.,
2016). The cohort also forms one of the centers of the multi-​center
EPI-​CT study (Bosch de Basea et al., 2015). With data from nine coun-
tries across Europe, the pooled study aims to include approximately
one million children, and results are due in the next few years.
An Australian cohort used Medicare (universal healthcare scheme)
records to identify 680,000 children who had CT scans between 1985
and 2005, aged < 20 years, and approximately 10 million children who
were not exposed (Mathews et  al., 2013). Through record linkage,
3150 cancers were recorded in the exposed children. They reported an
increase in incidence rate ratio for all cancers of 0.16 (95%CI:0.13–​
0.19) for each additional CT scan. Site-​specific analyses suggested
increased risks of solid cancers in digestive organs, melanoma, soft tis-
sue, female genital, urinary tract, brain, and thyroid cancers, and also
leukaemia, myelodysplastic syndromes, and some other lymphoid can-
cers. The results are difficult to compare with the UK cohort because
of the difference in analytic approach (organ dose versus number of
CT scans) and different exclusion periods (2–​5 years in the UK versus
1 year in the Australian study). The lack of specificity by cancer site
and increased risks for cancers not usually considered to be radiation-​
related (e.g., melanoma and lymphomas) raised concerns about poten-
tial bias from preexisting conditions. Dose reconstruction is underway
using methods similar to the UK CT study, which should facilitate
comparisons. A Canadian cohort is also in progress with an identical
design to the UK cohort using electronic medical records from Cancer
Care Ontario linked to cancer registrations (Einstein, 2012). This is the
only study currently that will also include adulthood exposures.
Conventional diagnostic X-​rays continue to be a common source
of medical radiation exposure, although doses are typically one-​tenth
of the dose of CT scans to the equivalent body region. Direct studies
of potential cancer risks face a number of challenges, including low
power and exposure misclassification. Cohorts of special populations
who received unusually high exposure levels (e.g., women with sco-
liosis and tuberculosis) based on medical records have, however, pro-
vided important information about the cancer risks from repeated low
doses of radiation. An updated follow-​up of the US scoliosis cohort
for breast cancer (ERR/​Gy = 2.86, n = 78, p = 0.058) (Ronckers et al.,
relationship was significantly greater for women who reported a fam-

Several recent case-​ control studies reported increased risks for

brain and thyroid tumors after dental X-​rays, and breast cancer after
4 chest X-​rays in BRCA mutation carriers (Andrieu et al., 2006; Claus
et al., 2012; Memon et al., 2010). However, recall bias is a concern in
3 case-​control studies that rely on self-​reported exposure information.
In a cohort of US radiologic technologists there was evidence of an
2 increased risk of thyroid cancer after childhood dental X-​rays based
on prospective follow-​up after self-​reporting of X-​ray exposure his-
tory at baseline (Neta et al., 2013). Compared to the general popula-
1
tion, these medical workers should be able to report their history of
diagnostic exposures more reliably. Analyses of other cancer sites and
0 personal diagnostic exposures are ongoing. The UKCCS case-​control
0 10 20 30 40 50 60
study (n = 2690 childhood cancer cases diagnosed 1976–​1996), which
RBM dose (mGy) used record linkage to evaluate diagnostic X-​rays in utero and in early
infancy (< 100 days), reported a non-​statistically significant increased
Figure 13–​2.  Relative risk (and 95% CI) for leukemia/MDS according to risk from in utero X-​rays for all cancers (OR  =  1.14; 95%CI:0.90,
the estimated absorbed red bone marrow (RBM) dose (Gy) from pediatric 1.45) and leukemia (OR = 1.36; 95%CI:0.91, 2.02) (Rajaraman et al.,
CT scans in the UK cohort. Source: Pearce et al. (2012). 2011). The results are compatible with lower doses compared to the
236
236 PART III:  THE CAUSES OF CANCER
period of the earlier studies in the United Kingdom and northeastern
United States (Doll and Wakeford, 1997).
Radiotherapy
With the increasing population of cancer survivors and longer survival,
the risk of a treatment-​related second cancer is an increasing clinical
and public health concern. Approximately half of all cancer patients
in countries like the United States receive radiotherapy as part of their
initial treatment. Although there are increasing efforts to minimize the
dose to the normal tissue surrounding the tumor, some very high doses
(< 40 Gy) to some proximal organs are unavoidable. In the last decade
there has been considerable progress in our understanding of the can-
cer risks from partial-​body, high-​dose fractionated exposure, due to
the publication of a plethora of new dose–​response studies for sec-
ond cancers after radiotherapy (Berrington de Gonzalez et al., 2013;
NCRP, 2011). In general, these case-​control studies of second solid
cancers (breast, lung, stomach, pancreas, thyroid, brain, sarcoma, skin,
esophagus, bladder, colon and rectum) based on medical records and
individual dose reconstruction, suggest a linear dose–​response rela-
tionship even for very high, fractioned, organ doses (40+ Gy), which
was in contrast to the expectation of a flattening or even downturn
in risk at high doses due to cell killing. However, the ERR/​Gy from
these high-​dose fractionated exposures is lower than the risk from the
acute exposure in the Japanese atomic bomb survivors (Figure 13–​3).
Thyroid cancer is the only clear exception where there is a clear down-
turn in risk after about 20 Gy in childhood cancer survivors (Bhatti
et al., 2010b; Veiga et al., 2012) (Figure 13–​3).
Although the ERR/​Gy is lower than reported in the LSS, the very
high doses can result in some high absolute risks for common cancers.
For, example an HL patient treated with 40+ Gy to the chest at age 25 is
estimated to have a 30% risk of developing radiation-​related breast can-
cer by age 55, which is comparable to a BRCA2 mutation carrier (Travis
et al., 2005). The ERR/​Gy is generally higher for childhood exposure,
as observed in the LSS, which also contributes to high absolute risks
(Berrington de Gonzalez et al., 2013; Grant et al., 2017. As described
earlier, several of these recent case-​control studies of high-​dose radio-
therapy provided the first clear evidence that pancreatic cancer (Dores
et  al., 2014; Hauptmann et  al., 2016), rectal cancer (Sakata et  al.,
2012), and sarcomas (Henderson et al., 2012; Rubino et al., 2005) are
radiation-​related. For more details on second cancers, see Chapter 60.
Occupational Exposures
Nuclear Workers
Hundreds of thousands of workers worldwide have been exposed to
radiation during employment in nuclear weapons and energy facilities.
Breast cancer after Childhood cancer (n = 107)
(Inskip et al., 2009)
20.0
15.0
RR (& 95% CI)
10.0
5.0
0.0
0 10 20 30 40 50
Mid-point of dose category (Gy)
Figure 13–​3.  Relative risk (and 95% CI) for subsequent cancer according to the estimated absorbed radiation dose (Gy) from fractionated radiotherapy.
Dotted black line indicates fitted dose-response for that study. Dashed grey line indicates the RR for similar age at exposure and attained age based on the
BEIR VII risk models for low-dose exposure (BEIR VII, 2006). The fitted linear dose-response model for Bhatti et al (2010)b is based on the linear term
from the linear-quadratic model.
Studies of workers at these facilities have provided information on
risks of cancer following low-​dose, protracted exposure to external
ionizing radiation. An important feature of these populations is the
routine dose monitoring, which can be used to reconstruct individ-
ual long-​term dose histories. These studies generally aim to assess
whether the risk of cancer per unit dose at low doses and low-​dose
rates is similar to that estimated from acute doses in the Japanese LSS.
The major studies published in the past 10 years, which are discussed
in the following paragraph, include those of workers at the Mayak
facility and of cleanup workers at the Chernobyl nuclear power plant,
the 15-​country study by the International Agency for Research on
Cancer (IARC), and its successor the International Nuclear Workers
Study (INWORKS). Also discussed are major national cohorts of
nuclear workers exposed to external ionizing radiation, such as the UK
National Registry of Radiation Workers, the Canadian National Dose
Registry, and pooled studies of US nuclear workers.
Studies of workers at the plutonium production facility in the
Russian Federation (former Soviet Union) have been highly informa-
tive on the health effects of protracted exposure to gamma radiation
exposure, and provide a rare opportunity to study the risks from plu-
tonium exposure. Workers in certain plants at the Mayak Production
Association received high plutonium doses (mean lung doses: 0.12 Gy,
range 0–​1 Gy), due to several spills and accidents that occurred during
periods of heavy production between 1948 and 1958. The key recent
studies addressing the effects of plutonium include an updated analysis
of lung cancer mortality (Gilbert et al., 2013) and incidence (Labutina
et al., 2013), as well as the incidence of liver, bone, and other cancers
(Hunter et  al., 2013; Labutina et  al., 2013). Strengths of the Mayak
studies include the large cohort size, high exposures, relatively large
numbers of exposed female workers, availability of cancer incidence
data, and extensive efforts to characterize dose. Challenges of these
studies include a lack of complete biomonitoring for plutonium expo-
sure, resulting in large dose uncertainties, and high rates of smoking
and heavy alcohol consumption, which have led to concerns about
potential confounding and have raised questions about transfer of risks
to other exposed populations.
Major attention has focused in the Mayak cohort on cancer in lung,
liver, and bone, as these are the primary sites associated with plutonium
deposition following inhalation exposure. With 486 deaths from lung
cancer (most among men), the latest study found substantial eleva-
tions in risk with increased plutonium dose: ERR per Gy was 7.4 (95%
CI: 5.0, 11) among men with an attained age of 60 and declined with
increasing age (Gilbert et al., 2013). Among women, ERR/​Gy at age
60 was 24 (95% CI: 11, 56). Restricting analyses to workers exposed
at lower plutonium doses found similar risks per unit dose as in the full
cohort, and ruled out anything but very small departures from linearity.
Importantly, the study was able to adjust for tobacco smoking and to
Thyroid cancer after Childhood cancer (n = 115)
(Bhatti et al., 2010)
40.0
35.0
30.0
RR (& 95% CI)
25.0
20.0
15.0
10.0
5.0
0.0
60 0 10 20 30 40 50
Mid-point of dose category (Gy)
 237
Ionizing Radiation 237
evaluate the form of interaction between smoking and plutonium dose.
It found a sub-​multiplicative but super-​additive interaction (discussed
further in the section on effect modification). Analyses of lung cancer
incidence supported the main findings of a steep dose-​response rela-
tionship (Hunter et  al., 2013; Labutina et  al., 2013). An analysis by
lung tumor subtype found a much higher ERR/​Gy for adenocarcinoma
than for squamous cell subtypes, suggesting an important etiologic dif-
ference for these two subtypes. Bone and connective tissue cancer inci-
dence was also found to be highly elevated (RR = 13.7; 95% CI: 3.0,
58.5) among a group of unmonitored female workers employed before
1950 at a plutonium-​processing facility with heavy exposure potential
(Cardis et al., 2007). Studies of other cancer types have found a highly
significant dose–​response relationship for liver cancer and plutonium,
but not most other specific cancers (Hunter et al., 2013; Labutina et al.,
2013). Efforts are ongoing to assess the impact of the large uncertain-
ties in the plutonium dose estimates (Stram et al., 2015).
The IARC has led a number of pooled international studies of
nuclear workers. In the first decade of the 2000s, a series of stud-
ies was published for solid cancer and leukemia mortality risks in a
pooled study of nuclear workers in 15 countries (Cardis et al., 2005,
2007; Vrijheid et al., 2007, 2008). The study, which included 407,000
workers exposed to an average cumulative dose of 19 mSv, found an
ERR/​Sv of 0.97 (95% CI: 0.14, 1.97) for all cancers excluding leuke-
mia and 1.93 per Sv (95% CI: < 0, 8.47) for leukemia excluding CLL
(Cardis et al., 2005). Although no significant heterogeneity in risk was
seen in these results by country or large facility (Cardis et al., 2007), a
number of subsequent publications questioned the results of the study,
pointing out that findings contributed by Atomic Energy of Canada
Ltd seemed highly influential on the statistical significance of the solid
cancer results, and questions arose about the quality of the dosimetry
data for this cohort (Zablotska et al., 2014; more information is given
about this later in this chapter). In addition, it was noted that the exclu-
sion of workers with substantial neutron exposure or radionuclide con-
tamination reduced the overall power of the study, as workers with
neutron dose or internal dose contamination also were more likely to
have high photon doses (Boice et al., 2006). Despite these criticisms,
the 15-​country study remains an important contributor to information
about effects of dose protraction on cancer risk from photon radia-
tion exposure, particularly with regard to lymphatic and hematopoietic
cancers, in which the influence of the Canadian cohort was minimal.
Strengths of the study include the use of a common protocol and a
focus on evaluation of workers exposed only to external ionizing radi-
ation, which minimized the influence of poorly characterized internal
exposures (IARC, 2012).
Since the publication of the 15-​country study, it was recognized
that continuing mortality follow-​up of its contributing cohorts would
provide an important addition to knowledge on low-​dose cancer risk
from photon exposure, as only a small percentage of each cohort
was deceased at the time follow-​up ended for the 15-​country study
(NRC, 2006).
INWORKS was formed by a team from the IARC and international
collaborators involved in the 15-​country study, to study radiation-​
related risks of cancer mortality in the nuclear worker cohorts that
contributed more than 80% of deaths in the 15-​country study: the UK
National Registry of Radiation Workers (NRRW; Muirhead et  al.,
2009), the French combined nuclear workers study (Metz-​Flamant
et  al., 2013), and the US pooled nuclear workers study (Schubauer-​
Berigan et al., 2015b). All three studies have updated mortality follow-​
up since the publication of the 15-​country study (Hamra et al., 2015),
and in some cases (Schubauer-​Berigan et  al., 2015b) included addi-
tional cohorts primarily exposed to photon radiation. The Canadian
workers were not included, and this avoids the problems with this
cohort described earlier.
INWORKS includes more than 300,000 workers, with 531 leuke-
mia (other than chronic lymphocytic) deaths (Leuraud et  al., 2015)
and nearly 18,000 deaths from solid cancers (Richardson et al., 2015).
The pooled analysis found a significantly elevated risk of leukemia
(ERR/​Gray [Gy]: 2.96; 90% CI: 1.17, 5.21) and solid cancers (ERR/​
Gy: 0.48; 90% CI: 0.18, 0.79) (Leuraud et  al., 2015; Richardson
et al., 2015) (Figure 13–​4). These point estimates changed little when
the data were restricted to lower dose ranges (< 100 mGy), or when
excluding or adjusting for exposure to neutrons or internal emitters.
Indirect evidence suggested little potential for confounding by smok-
ing in the analysis of all solid cancers, as the risk estimates were
similar when restricted to non-​smoking-​related cancers. The leuke-
mia subtype showing the highest risk was CML, for which the ERR/​
Gy was 10.45 (90% CI: 4.48, 19.65), and this pattern was consistent
across the countries (Leuraud et al., 2015). The ERR/​Gy for AML was
1.29 (90% CI: –​0.82, 4.28). Although the mean cohort dose was only
25 mGy, the risks per unit dose and subtype patterns were similar to
the recent analysis in the LSS (Hsu et al., 2013). The size, high-​quality
dosimetry, and lengthy follow-​up of the INWORKS cohort suggest
that it will remain an important study through which to understand
the risk of protracted exposure to low-​dose photons, primarily in adult
males. The pooled cohorts will also be informative on site-​specific
cancer risks and effect modification by temporal factors, especially as
follow-​up is extended for the 78% alive at the end of the recent study.
Studies of the component cohorts of INWORKS have also yielded
useful information about risk of grouped and individual cancers. The
UK NRRW cohort included 174,541 workers monitored for exter-
nal ionizing radiation (Muirhead et  al., 2009), followed for cancer
incidence and mortality through 2001, with 16% deceased. Major
strengths of the cohort include its large size, well-​ characterized
gamma doses, wide representativeness of the facilities included, and
availability of cancer registry linkage. A  limitation of this cohort is
the lack of specificity about which workers may have had substantial
internal (e.g., plutonium) dose. The ERRs per Sv observed for leuke-
mia (excluding CLL) mortality and incidence (respectively) were 1.71
(90% CI: 0.06, 4.29) and 1.78 (90% CI: 0.17, 4.36). For all cancers
excluding leukemia, the ERR/​Sv was 0.28 (90% CI: 0.02, 0.56) and
0.27 (90% CI:  0.04, 0.51), respectively. Lymphoma showed a bor-
derline positive trend with radiation dose (p  =  0.081; 81). Findings
for multiple myeloma differed between the mortality and incidence
follow-​up:  the ERR/​Gy was 1.20 (90% CI:  –​0.88, 5.96) for mortal-
ity (n = 113) and 3.60 (90% CI: 0.77, 8.94) for incidence (n = 149),
respectively (Muirhead et al., 2009).
The US pooled nuclear worker cohort (Schubauer-​Berigan et  al.,
2015b) includes 119,195 workers monitored for external ionizing radi-
ation, from four Department of Energy (DOE) nuclear weapons sites
(Hanford, Idaho National Laboratory, Oak Ridge National Laboratory,
and Savannah River Site) and the Portsmouth Naval Shipyard. With
mortality follow-​up through 2005, 35% of the cohort was deceased,
and 10,877 cancers (excluding leukemia) and 369 leukemias (exclud-
ing CLL) were observed. Few of these workers received a confirmed
deposition of internal radiation, and neutron dose was less than 2% of
the total dose for the cohort. The study found ERR/​Sv values of 1.7
(95% CI: –​0.22, 4.7) for leukemia and 0.14 (95% CI: –​0.17, 0.48) for
all cancers excluding leukemia. For the latter group, findings differed
by cancers classified into those related to smoking (ERR/​Sv: –​0.079;
95% CI: –​0.43, 0.32) and those unrelated to smoking (ERR/​Sv: 0.70;
95% CI:  0.058, 1.5). This heterogeneity suggests that negative con-
founding may exist with cigarette smoking (where adjustment would
shift the risk estimate away from the null), which was also supported
by facility-​specific analyses of lung cancer and chronic obstructive
pulmonary disease. The ERR/​Sv for mesothelioma of 2.5 (95% CI: –​
1.3, 10) suggests that positive confounding by asbestos exposure may
exist. Other notable findings include significant dose–​response pat-
terns for lymphoma (ERR/​Sv: 1.8; 95% CI: 0.027, 4.4) and multiple
myeloma (ERR/​Sv: 3.9; 95% CI: 0.60, 9.6).
The French cohorts in INWORKS include 59,021 workers followed
for mortality between 1968 and 2004 at three large nuclear energy
or weapons cohorts:  Commissariat à l’Energie Atomique (CEA),
Electricité de France (EDF), and AREVA Nuclear Cycle (AREVA)
(Leuraud et al., 2015). Mean cumulative effective dose was 22.5 mSv.
With just 11% of the cohort deceased, the ERR/​Sv was 0.34 (90%
CI: –​0.56, 1.4) for all solid cancers, 4.0 (90% CI: < 0, 17) for leuke-
mia excluding CLL, and was non-​calculable for multiple myeloma and
lymphoma.
The Canadian National Dose Registry (CNDR) is a centralized
occupational radiation dose registry, containing records for more than
238

238 PART III:  THE CAUSES OF CANCER

(a) Leukemia (b) Solid cancer
1.7
6
1.6
5
1.5

RR (& 90% CI)

RR (& 90% CI) 4 1.4

1.3
3
1.2
2
1.1

1 1.0

0.9
0 0 100 200 300 400 500 600 700
0 50 100 150 200 250 300 350 400 450
Cumulative dose (mGy)
Cumulative RBM dose (mGy)

Figure 13–​4.  Relative risk (and 90% CI) for leukemia (excluding CLL) and solid cancer according to the cumulative radiation dose (Gy) from occupational
radiation exposures in the INWORKS cohort. Source: Leuraud et al. (2015); Richardson et al. (2015).

600,000 workers, including underground miners exposed to radon,
nuclear power plant workers, and medical personnel (Ashmore et al.,
1998). The cohort or subcohorts within it have been periodically linked
to mortality and cancer registry databases (Sont et  al., 2001). Mean
cumulative doses were highest in nuclear power workers (20 mSv) and
lowest in dental and medical workers (0.3 and 4 mSv, respectively).
The study found a significantly elevated ERR/​Sv among male (but
not female) registrants, including all leukemias combined, all cancers
excluding leukemia, and for many individual cancer sites (Sont et al.,
2001). Since then, studies assessing the impact of dose censoring (i.e.,
doses below certain thresholds were unrecorded during the early regis-
tration years) and cancer risk in a subgroup of medically exposed reg-
istrants have been published (Shin et al., 2005; Zielinski et al., 2009).
No extension of follow-​up has occurred past the late 1980s (cancer
incidence) or mid-​1990s (cancer mortality) for the CNDR. Since the
publication of the 15-​country study, critical attention has focused on
the completeness of the dosimetry and registry information for one
of the component cohorts (Atomic Energy of Canada Ltd; Ashmore
et  al., 2010). It was noted that risk estimates for this cohort greatly
increased in studies based on CNDR data (e.g., Cardis et  al., 2005,
2007; Sont et al., 2001; Zablotska et al., 2004) as compared to earlier
studies based directly on the facility data (e.g., Cardis et  al., 1995).
Efforts are currently focused on ascertaining that dosimetry and regis-
trants in the CNDR are complete and accurate (Ashmore et al., 2010;
Zablotska et al., 2014).
A new, large-​scale study, the Million Worker Study (MWS) has
been developed with the aim of evaluating cancer risk from pro-
tracted radiation exposures of < 100 mGy by combing various groups
of US workers, including “atomic veterans” (i.e., military personnel
who witnessed atomic test blasts), nuclear weapons workers, nuclear
power plant workers, industrial radiographers, and medical workers
exposed to radiation (Bouville et al., 2015). While the proposed sam-
ple size is impressive, at this stage the epidemiological methods for
obtaining complete and accurate follow-​up for each cohort (including
confirming who is alive, and cause of death) have not been described
and may be prohibitively expensive. Inaccurate follow-​up can be an
important, but often overlooked, source of bias in epidemiological
studies; non-​differential outcome misclassification will bias risk esti-
mates towards the null. There are also considerable challenges in the
dose reconstruction, including substantial dose from radionuclides
among some contributing DOE cohorts, which will require exten-
sive dose reconstruction efforts and possibly involve large uncertain-
ties (e.g., Mound and Rocketdyne; Bouville et  al., 2015). For the
proposed group of 240,000 medical workers, the dosimetric chal-
lenges will include non-​uniform exposures, lack of compliance with
badge monitoring, employment in multiple facilities, and variation
in radiation protection such as lead apron usage (Linet et al., 2010;
Simon et al., 2014).
Flight Crew
Studies of cancer in flight crew have provided equivocal evidence of
cancer risk following repeated exposure to cosmic radiation. Typical
doses in these studies are low and have little within-​cohort varia-
bility:  for example, a mean absorbed, whole-​body dose of 12 mGy
(standard deviation 11 mGy) was observed in a recent breast cancer
incidence study among flight attendants (Schubauer-​Berigan et  al.,
2015a). Empirical evidence also suggests that the neutron dose qual-
ity factor associated with commercial flight conditions is lower than
previously thought (e.g., 2–​2.5; Burda et  al., 2013), amplifying the
low-​dose limitations of these studies. Recent studies of flight crew,
including a pooled international study, found no elevation in breast
cancer mortality (compared to the general population) and no asso-
ciation with cosmic radiation (Hammer et al., 2014; Pinkerton et al.,
2012). A large, pooled Scandinavian cancer incidence and case-​control
study found a 50% higher risk of breast cancer than in the general pop-
ulation, but no association with cosmic radiation or other occupational
exposures (Pukkala et al., 2012). Another large study of breast cancer
incidence among US flight attendants found that, while the rate of inci-
dent breast cancer was 37% higher than among the general US popula-
tion, the increase was probably due to the much older age at first birth
and lower parity in the cohort compared to US women (Schubauer-​
Berigan et al., 2015a). No association was observed between cosmic
radiation dose and breast cancer incidence, except among high-​parity
women and those with younger age at first birth (Pinkerton et al., 2016;
Schubauer-​Berigan et al., 2015a). This pattern, which is the opposite
of the expected interaction of radiation with reproductive risk factors
(e.g., Ronckers et al., 2005), may be associated with circadian disrup-
tion, which was highly correlated with radiation dose in the cohort.
In addition to breast cancer, the occurrence of melanoma has been
of interest among flight crew. A recent meta-​analysis of 19 studies of
cockpit and cabin crew found that, compared to the general popula-
tion, melanoma incidence rates are approximately doubled for flight
crew, with a similar excess observed in both cockpit and cabin crew
(Sanlorenzo et  al., 2015). The authors attribute this excess to occu-
pational sources, including potentially ultraviolet-​ A radiation and
cosmic radiation, although no direct adjustment for factors such as
recreational sun exposure was made.
Medical Workers
Studies of increased leukemia risks in the earliest radiologists pro-
vided the first evidence of a link between radiation and cancer (March,
1950). Most of the studies of medical radiation workers have limited
 239
Ionizing Radiation 239
exposure information, particularly for the early workers, when radi-
ation protection and dosimeters were rare. A  new follow-​up of a
cohort of 27,000 Chinese medical radiation workers with individual
dose estimates (mean = 0.086 Gy) found a significant dose–​response
relationship for solid cancer incidence that was higher than, but sta-
tistically compatible with, risk estimates from other low-​dose stud-
ies (Sun et al., 2016). Individual dose reconstruction has also recently
been completed for the US Radiologic Technologists (USRT) cohort
of about 110,000 (mostly female) workers (Simon et al., 2014). There
was no evidence of a dose–​response relationship for basal cell skin can-
cer in these workers, even though some received estimated skin doses
of > 1 Gy (Lee T et al., 2015), or for brain cancers, even among those
who performed fluoroscopically guided procedures (Kitahara et  al.,
2017). A significant dose–​response relationship was found, however,
for breast cancer for those workers who started work before 1950 and
received the highest doses (estimated mean organ dose = 280 mGy)
(Preston et al., 2016). Dose–​response analyses for other cancer sites
are ongoing, but power is generally limited for sites other than breast
cancer due to low mean doses and relatively small numbers of cases.
Some case reports of brain tumors in physicians who perform fluo-
roscopically guided procedures have raised concerns about current
exposure levels in these physicians (Roguin et al., 2013). In a subset
of the USRT cohort, technologists who reported performing fluoro-
scopically guided interventional procedures were at an approximately
two-​fold increased relative risk for brain cancer mortality (HR = 2.55;
95% CI: 1.48, 4.40), as well as modestly elevated risk for incidence
of breast cancer (HR = 1.16; 95% CI: 1.02, 1.32) and melanoma (HR
= 1.30; 95% CI: 1.05, 1.61) compared to those who never performed
these procedures. No elevated risk was observed for cancers of the thy-
roid, non-​melanoma skin, prostate, lung, colon-​rectum, or non-​CLL
leukemia in workers who performed these procedures. While exposure
to radiation in the workplace is one possible explanation for these find-
ings, the role of chance or unmeasured confounding by non-​radiation
risk factors cannot be ruled out until these results are replicated in
more studies, and as noted above in subsequent analyses there was no
relationship with dose (Rajaraman et al., 2016; Kitahara et al., 2017).
The first study to examine this question systematically in physicians,
did not find evidence of an increased risk of brain tumors (Linet et al.,
2017). Nuclear medicine procedures have also increased dramatically
in the United States, and some radiologic technologists who routinely
perform these may be exposed above the recommended dose limits.
In an analysis of technologists in the USRT cohort who ever (versus
never) perform various nuclear medicine procedures, there was an
increased risk for squamous cell carcinoma of the skin (HR = 1.29;
95% CI: 1.01, 1.66) with ever performing diagnostic radionuclide pro-
cedures and of breast cancer (HR = 2.68; 95% CI: 1.10, 6.51) with ever
performing other radionuclide therapy procedures (excluding brachy-
therapy and radioactive iodine) (Kitahara et al., 2015). Increasing risks
were also observed with greater frequency of performing these pro-
cedures, particularly before 1980. Reconstruction of individual doses
to a group of nuclear medicine technologists is underway, and further
follow-​up is needed of the potential long-​term risks in these occupa-
tional groups.
EXPOSURE AND HOST PARAMETERS
THAT INFLUENCE RISK
The focus of many of the current radiation epidemiology studies is
the understanding of the effect of dose protraction or fractionation.
This has important practical implications for predicting cancer risk
from occupational, environmental, and diagnostic medical exposures,
which are typically received as low and fractionated (or protracted)
doses and also contribute most to the collective dose received in the
general population. Theoretically, the risk per unit dose could be
lower if the dose is protracted or fractionated because of DNA repair
mechanisms. The results from low-​dose epidemiological studies have
been mixed. However, it is difficult to find exposed populations that
are identical in all ways other than the manner in which they received
their radiation exposure. The most authoritative risk assessments for
low and protracted doses of radiation have been carried out by the US
National Academies as a series of reports on the “Biological Effects
of Ionizing Radiation” (BEIR) and by the United Nations Committee
on the Effects of Atomic Radiation (UNSCEAR, 2010b). The most
recent BEIR report (BEIR VII Phase 2, 2006)  reviewed the animal
and epidemiological data and derived a dose-​and-​dose-​rate adjustment
factor (DDREF) of 1.5 (95% credible interval), which implies that
the risk per unit dose is reduced by one-​third if the dose is protracted
or below 100 mGy. However, the recent studies of occupationally
exposed individuals, such as INWORKS, natural background radia-
tion, Techa River residents, and the UK CT (computed tomography)
study reported dose–​response relationships from these protracted/​frac-
tionated low-​dose exposures that were compatible with the Japanese
atomic bomb survivors, implying compatibility with a DDREF of 1. In
the next few years there will be additional results from nuclear worker
and CT scan cohorts that will provide further information on this ques-
tion, which is central to radiation protection limits.
The impact of fractionation and dose level is also critical in the
study of second cancer risks after radiotherapy to aid clinical decision-​
making, and also provides insights into biological mechanisms.
Mostly the dose–​response studies have found that the risk per unit
dose is 5–​10 times lower following these high-​dose (5+ Gy) highly
fractionated (e.g., 40 fractions) exposures compared to the acute expo-
sure of < 2 Gy in the Japanese atomic bomb survivors (Berrington de
Gonzalez et al., 2013). The theory is that both cell killing and DNA
repair contribute to the lower cancer risk per unit dose. Surprisingly,
these studies have also shown that there is little evidence that the dose–​
response curve is nonlinear in the direction of a downturn in risk, even
at organ doses of ≥ 60 Gy. It was previously assumed that high levels
of cell killing would result in a downturn or plateau in risk at very
high doses (e.g., > 5Gy organ dose; Gray, 1965). Thyroid cancer is
the only site currently where there is strong evidence of a downturn
above doses of 20 Gy to the thyroid from radiotherapy for childhood
cancer (Veiga et al., 2012). The lack of downturn in other cancer sites
has been hypothesized to be related to cellular repopulation between
fractions (Sachs and Brenner, 2005).
The type of ionizing radiation exposure also influences the risk of
cancer. As described earlier (see section “Units of Exposure”), neu-
trons may be 20 times more carcinogenic per unit dose than X-​rays.
Most of the estimates of the relative biological effectiveness of dif-
ferent types of radiation exposure come from animal or other labora-
tory studies, as few human studies are available where the populations
are comparable other than with respect to the type of radiation. More
human studies are needed, however, especially of the RBE of neutrons
and protons due to the increasing use of proton therapy to treat cancer
patients. Certain types of proton therapy systems expose the patient to
a whole-​body scatter dose of neutrons, and the long-​term risks from
this are uncertain.
The impact of age at radiation exposure has been studied exten-
sively (BEIR VII Phase 2, 2006). These studies have established that
childhood exposure to ionizing radiation results in a higher cancer risk
than adulthood exposure; the one possible exception is for lung can-
cer (Preston et al., 2007). Some organs are especially radiosensitive in
childhood, including the red bone marrow, thyroid, breast, and brain
(Braganza et al., 2012; Hsu et al., 2013; Preston et al., 2002a, 2002b;
Veiga et al., 2016). In contrast, the thyroid and brain seem to have very
low radiation sensitivity if exposure is in adulthood (Braganza et al.,
2012; Preston et al., 2007; see also Chapter 44 in this volume).
Long-​term follow-​up of more than 50 years of the Japanese atomic
bomb survivors and other studies, including the Canadian fluoros-
copy cohort (Howe and McLaughlin, 1996), have demonstrated that
the cancer risk from ionizing radiation exposure remains elevated for
decades, probably for the rest of a person’s lifetime; that is, unlike
smoking, the risk never returns to baseline (BEIR VII Phase 2, 2006).
This is consistent with the notion of ionizing radiation being an initia-
tor, as well as potentially a cancer promoter. The risk does decline,
however, with time since exposure.
In many studies, women have higher cancer risks than men follow-
ing radiation exposure. For example, the ERR/​Gy in the LSS for all
solid cancers (exposure at age 30, attained age 70) is 0.58 for women
240
240 PART III:  THE CAUSES OF CANCER
and 0.35 for men, and differences remain even after removal of sex-​
specific cancers (Preston et al., 2007). However, it is uncertain whether
this reflects true biological differences in radiosensitivity, interac-
tions with other cancer risk factors, or differences in background
cancer rates.
There have been a large number of studies of the joint effect of
smoking and radiation exposure. The findings are not consistent,
varying from a complicated joint effect model in the Japanese atomic
bomb survivors to multiplicative in several studies of radiotherapy
and second cancers. Studies of high-​LET radiation, including those
of uranium miners exposed to radon progeny and the Mayak pluto-
nium cohort, have found joint effects that appear to be super-​additive
but sub-​multiplicative (Gilbert et al., 2013). Reproductive factors and
breast cancer risk have also been evaluated in several radiation-​exposed
populations, but there is little consistency with findings regarding the
joint effects (Ronckers et al., 2005). Studies of genetic susceptibility
also have not produced clear-​cut findings, even where there is an obvi-
ous potential mechanism such as DNA repair and BRCA mutation (see
discussion of radiosensitivity later in this chapter). Given how well the
risks from ionizing radiation are known, these difficulties with joint
effects analyses are a reminder about how difficult these questions are
to address via epidemiological studies.
MECHANISMS OF CARCINOGENESIS
Each of the most common types of ionizing radiation exposure in
humans (fractionated high-​dose exposures such as those experienced
by patients undergoing cancer radiotherapy; acute low-​ moderate
doses, such as those experienced by many Japanese atomic bomb
survivors; chronic low-​dose exposures received by radiation work-
ers; and fractionated low-​dose exposures from diagnostic medical
examinations) has been associated with increased risk of cancer. The
development of cancer is characterized by distinct biological abilities
acquired during the multistep development of human tumors. These
include sustained proliferative signaling, evasion of growth suppres-
sors, resistance of cell death, induction of angiogenesis, activation
of invasion and metastasis, reprogramming of energy metabolism,
and evasion of immune destruction (Hanahan and Weinberg, 2011).
These hallmarks of cancer are driven by genomic instability (which
generates genetic diversity leading to the acquisition of hallmark fea-
tures) and inflammation (which fosters multiple hallmark functions).
Cellular damage from exposure to ionizing radiation occurs when
radiation is absorbed by biological tissue and interacts either directly
or indirectly with atoms of critical targets. As radiation moves through
the tissue, energy is deposited, causing ionization (ejection of an elec-
tron from an atom) along the track, with some clustering at the ends.
Direct action results when the radiation energy itself causes ionization
of the critical target. This is the dominant process for radiation with
high linear energy transfer (LET), such as neutrons or alpha-​particles
(Hall and Giaccia, 2006). Indirect action occurs when radiation inter-
acts with other atoms or molecules in the cell, such as water, to pro-
duce highly reactive free radicals that can break chemical bonds and
damage the critical target, initiating the chain of biological events that
eventually leads to cancer.
The carcinogenic effects of ionizing radiation generally result from
various types of damage to DNA, including damage to nucleotide
bases, single-​strand breaks (SSBs), double-​strand breaks (DSBs),
and DNA crosslinks, often forming clustered/​multiple damage sites
which represent two or more lesions formed within one or two heli-
cal turns of DNA (BEIR VII Phase 2, 2006). Base damage is repaired
by mechanisms that involve excision and replacement of individual
damaged bases (base-​excision repair) or larger oligonucleotide frag-
ments (nucleotide excision repair). The repair of SSBs uses a similar
process to base-​excision repair. The repair of DSBs, on the other
hand, usually involves several processes. In some instances, DSBs
are rejoined end to end in a process called non-​homologous end
joining. An alternative pathway for DSB repair is the homologous
recombination process, in which the broken strand is repaired by
crossing over with an adjacent identical DNA sequence. In addition
to direct DNA damage, radiation also causes the formation of reac-
tive oxygen species (ROS), which are free radicals involving oxy-
gen, and reactive nitric oxide species (RNOS), which induce stress
responses, inflammation, and release of cytokines, growth factors,
and chemokines (Barnett et al., 2009).
In normal circumstances, when cells detect DNA damage caused
by free radicals, they respond by undergoing cell cycle arrest
in order to repair the damage, and the majority of the damage is
repaired. When this damage cannot be repaired, the cell under-
goes death via necrosis or apoptosis within a few cell divisions.
Incorrectly repaired or unrepaired DNA damage, on the other hand,
can lead to mutation and genomic instability, and cancer can occur
after many years.
Until recently, research in radiobiology focused mainly on
pathways related to the repair of DNA damage. Although the
role of repair pathways remains a key area of investigation, there
is increasing interest in understanding the mechanisms involved
in radiation-​induced inflammatory and stress responses to ROS.
These mechanisms are particularly important for understanding the
effects of radiation on cells that are not directly irradiated (West and
Barnett, 2011).
Types of Evidence
It is becoming increasingly apparent that the assessment of disease risk
following radiation exposure is a complex process that needs to extend
beyond traditional assessment by epidemiologic methods to incor-
porate biological evaluation of differences in susceptibility between
individuals. Biological changes leading to cancer can be studied at dif-
ferent levels, and using various endpoints. At the cellular level, radio-
sensitivity measures the degree of response of a cell to radiation, with
a stronger response indicating higher sensitivity. Typical cellular end-
points include phenomena such as cell killing or measurable chromo-
somal damage. Radiation response can also be observed at the tissue
level: tissues can be more or less sensitive to radiation. Finally, differ-
ences in susceptibility can be observed at the level of individuals, with
some humans being less tolerant of the effects of a fixed amount of
radiation exposure than others (Advisory Group on Ionising Radiation
[AGIR], 2013).
The path from radiation exposure to the development of cancer can
be represented as a theoretical continuum of effects that includes exter-
nal dose, internal dose, early biological effects, and finally, disease
outcome. Potential exposure to other genotoxic agents can also play a
role. Measures of different biological changes can be used to quantify
various points within the continuum between external radiation dose
and final outcome of interest. A biological marker (or biomarker) may
be suitable as a measure of dose, or as a measure of early or late effect,
or in some scenarios may serve as a measure of both internal dose and
effect, whereby some measure (e.g., induction of chromosome aberra-
tions) could tell us not only about the likely dose of ionizing radiation
experienced by an individual, but could also be used to predict risk of
disease outcome(s) of interest (Pernot et al., 2012; see also Chapter 6
in this volume).
Several factors need to be considered in the selection of appropri-
ate biomarkers for characterization of radiation risk. First, natural
and meaningful variation of the proposed marker should exist in the
human population. A test for a reliable biomarker should be sensi-
tive and specific, and highly reproducible among different labora-
tories. For use in human populations, the ideal biomarker should
be easily obtained with minimal discomfort or risk to the patient.
Given that levels of a biomarker often change over time and can
differ between cells or tissues, details such as the appropriate timing
of obtaining the sample from which the biomarker is to be mea-
sured and the biological source are crucial. Finally, a rapid readout
of results is preferable. Although a single test may not possess all of
these characteristics (e.g., a highly reliable test may not have a rapid
readout), and some characteristics may be more important than oth-
ers depending on the intended use of the biomarker, it is useful to
keep all in mind during biomarker selection.
 241
Ionizing Radiation 241
Cellular Assays to Measure Biological Changes
in Humans
The first human cell studies of radiosensitivity were clonogenic assays
performed on fibroblasts cultured from the skin of individuals with
severe radiation toxicity. In these assays, different levels of radiation
are applied to samples of cells that are then plated in a tissue culture
vessel and allowed to grow, and the resulting colonies are fixed, stained,
and counted. At the conclusion of the experiment, the percentage of
cells surviving at each dose is measured, and a cell survival curve is
plotted to graphically represent the dose of ionizing radiation versus
survival (Franken et al., 2006). These initial studies indicated extreme
radiosensitivity in individuals with severe radiation toxicity (Arlett
and Priestley, 1983; Smith et al., 1980; Woods et al., 1988). Further
studies demonstrated that fibroblast sensitivity significantly differed
between cells cultured from individuals with and without known
genetic syndromes associated with radiosensitivity, such as patients
with ataxia telangectasia (AT) or retinoblastoma (RB) (Deschavanne
et  al., 1986). The variation in sensitivity between normal cells and
cells with mutations characterized by defects in repair mechanisms
seems to be greater when doses are delivered as chronic low dose-​rate
exposures versus doses delivered at high dose rates (Kato et al., 2009).
Although these observations suggested the possibility of using cellular
radiosensitivity to predict a patient’s probable reaction to radiother-
apy, studies have not indicated any clear and consistent associations
between cellular radiosensitivity and reaction to radiation exposure in
patients undergoing radiotherapy for cancers of the breast (Djuzenova
et al., 2006; Peacock et al., 2000), cervix (West et al., 2001), or head
and neck (Geara et  al., 1993; Rudat et  al., 1999). Furthermore, the
relationship between acute toxicity after radiotherapy and late effects
(e.g., cancer) remains unclear.
Most cellular assays of cancer susceptibility in human populations
to date have focused on DNA repair capacity. These assays generally
compare DNA damage induced in circulating lymphocytes from can-
cer patients to circulating lymphocytes from cancer-​free controls, with
the subsequent quantification of repair in both groups. Ionizing radia-
tion (or some other agent, such as the radiomimetic chemical bleomy-
cin) is applied to the cell culture, a specified period of time is allowed
to pass for repair to occur, and the remaining damage is measured in a
variety of ways (e.g., unrepaired SSBs, DSBs, or the incorporation of
a radioisotope). Cellular assays of DNA repair can be broadly grouped
into the following categories (Berwick and Vineis, 2000):
1. Tests based on DNA damage to cells induced by chemical or physi-
cal agents (e.g., bleomycin or ionizing radiation), such as the muta-
gen sensitivity assay, the G2-​ radiation assay, the micronucleus
assay, and the comet assay.
2. Indirect tests of DNA repair, such as assays of unscheduled DNA
synthesis, activity of repair enzymes, or measures of gamma-​
H2AX or 53BP1 foci. Levels of enzyme activity or DNA synthesis
are measured in radiolabeled cells, usually by scintillation counting
or radiography. Gamma-​H2AX or 53BP1 foci are assessed using
fluorescence microscopy.
3. Tests based on more direct measures of repair kinetics (e.g., plasmid
host cell reactivation assay). Separate sets of fresh or cryopreserved
lymphocytes are transfected with both damaged and undamaged
plasmids incorporating the chloramphenicol acetyltransferase (cat)
or Luciferase gene as a marker. Repair can then be measured as a
rate, such as the amount of radiation or fluorescence at a given point
in time.
Early assays of DNA repair measured chromatid breaks and gaps fol-
lowing the administration of bleomycin (Hsu et al., 1989) or gamma-​
radiation in the G2 phase of the cell cycle (Sigurdson and Stram,
2012) to assess repair efficiency following exposure to various muta-
gens in a range of cell types (Berwick and Vineis, 2000; Li et al., 2009;
Wu et al., 2007). Studies using the G2 assay have demonstrated greater
sensitivity to radiation in first-​degree relatives of cancer patients com-
pared to non-​cancer controls (Kato et  al., 2009). Tests of genotoxic
response to bleomycin in lymphocytes blood cultures indicate a wide
variance in normal individuals (0.20 to more than 2.00 average chro-
matid breaks per cell). While one study showed distinctly different
responses for patients with cancers of the colon, upper aerodigestive
tract, and lung from those of the control population, the sensitivity pro-
file of patients with breast cancer was similar to that of the control pop-
ulation, suggesting that mutagen sensitivity response differs between
tissues (Hsu et al., 1989).
More recent assays for the detection of DNA double-​strand breaks
quantify the levels of nuclear foci of DNA damaged proteins, includ-
ing the gamma-​H2AX and 53BP1 assays, which complement more
traditional DNA damage/​repair assays, such as pulsed field gel elec-
trophoretic assessment of DNA double strand breaks and comet assays
(AGIR, 2013). The gamma-​H2AX assay uses immunocytochemistry
to visualize foci of phosphorylated histone 2AX (H2AX), which accu-
mulates at the site of double-​strand break damage during activation of
the DNA damage response signaling pathway (Nikolova et al., 2014).
Studies using these newer assays indicate an approximately 1.5-​fold
reduction in the repair efficiency of strand breaks among AT heterozy-
gotes and RB family members versus phenotypically normal individu-
als (Sigurdson and Stram, 2012).
Apart from DNA repair assays, other techniques in development
include the ability of fibroblasts to undergo radiation-​induced differ-
entiation, telomere length assays, and combinations of various cellular
assays (AGIR, 2013), as well as measuring the expression of markers
of inflammation (e.g., plasma transforming growth factor [TGF]-​β1) in
serum or plasma. Given the rapidly evolving nature of this field, work
in this research area is likely to undergo considerable evolution in the
next few years.
Evidence for Differing Sensitivity to Radiation
Exposure from Epidemiological Studies
As illustrated in Table 13–​3, data from the LSS have clearly indicated
that different organs and tissues have different sensitivities to the
effects of radiation exposure. In atomic bomb survivors, for example,
excess relative risks due to radiation are particularly notable for can-
cers of the esophagus, colon, lung, breast, ovary, and bladder (Preston
et al., 2007).
The idea that some people are more sensitive to the effects of radia-
tion has been accepted for several decades. Individuals with certain rare
hereditary disorders (e.g., ataxia telangiectasia and Nijmegen break-
age syndrome) are known to be particularly sensitive to the effects of
radiation (Taalman et al., 1983; Taylor et al., 1975). However, these
cancer susceptibility syndromes affect only a small proportion of the
general population. More relevant for the majority of the population is
the theory that some part of the genetic contribution defining radiation
susceptibility is likely to follow a polygenic model, whereby inheri-
tance of several low-​penetrance risk alleles can lead to elevated risk of
cancer. This theory (the “common-​variant-​common-​disease” model)
is supported by the fact that multiple genetic pathways have been
implicated in radiosensitivity, including DNA damage repair, radiation
fibrogenesis, oxidative stress, and endothelial cell damage (Barnett
et al., 2009).
Most studies of the effects of ionizing radiation in humans have
focused on the DNA repair pathway. A  review of population-​based
studies conducted prior to 2000 found that the combined evidence for
tests based on DNA damage and direct/​indirect tests of DNA repair
indicated mainly positive associations between DNA repair capac-
ity and occurrence of cancer (Berwick and Vineis, 2000; Vineis and
Perera, 2000). However, these studies faced a number of limitations,
including small sample size, the use of the case-​control study design
(which cannot address the question of temporality between exposure
and disease), the use of “convenience controls,” the possibility of con-
founding by factors other than ionizing radiation that could affect DNA
repair, and use of cells different from the target organ. Subsequently,
a number of population-​based epidemiological studies have examined
susceptibility to radiation-​related risk of cancer with respect to genes
in the DNA repair and other relevant biological pathways. Results
from the “candidate-​SNP” approach, which assumes prior knowledge
of one or more functional single nucleotide polymorphisms (SNPs),
have not been convincingly replicated to date (Bhatti et  al., 2008,
24
242 PART III:  THE CAUSES OF CANCER
2010a; Bondy et al., 2001; Hu et al., 2002; Liu et al., 2010; Rajaraman
et al., 2008; Sigurdson et al., 2007, 2009).
An alternate approach to examine genetic susceptibility is to quan-
tify cancer risk in groups of high-​risk individuals. Most (Andrieu
et al., 2006; Gronwald et al., 2008; Lecarpentier et al., 2011), but not
all (John et al., 2013) interview-​based studies of diagnostic chest X-​
rays in BRCA1 and BRCA2 mutation carriers have reported a slightly
elevated risk of breast cancer in at least one subgroup of X-​ray expo-
sure (e.g., exposure at younger age). On the other hand, the association
has generally been null for mammograms (Giannakeas et  al., 2014;
Goldfrank et al., 2006; Narod et al., 2006). Breast doses from chest X-​
rays are generally very low, and recall bias cannot be ruled out.
Studies have also reported some indication of increased risk follow-
ing radiotherapy in individuals carrying rare mutants in genes in DNA
damage repair pathways. A  case-​only study of contralateral breast
cancer (CBC) reported increased prevalence of pathogenic germline
mutations in DNA repair genes BRCA1, BRCA2, CHEK2, and ATM
in women with CBC following radiotherapy for their primary breast
cancer compared with women with CBC who were not irradiated for
their first breast cancer (Broeks et  al., 2007). A  larger case-​control
study of women with CBC (cases) compared to matched controls with
unilateral breast cancer reported evidence of greater CBC risk follow-
ing radiation among women who carried rare ATM missense variants
(Bernstein et al., 2010) and individuals who carried a rare haplotype
in RAD50 (Brooks et  al., 2012)  than in unexposed carriers, but no
increase in risk with radiation dose in carriers of other rare variants,
including BRCA1/​2 mutations (Bernstein et al., 2013).
The interpretation of these genetic findings (candidate SNP, radia-
tion exposure in high-​risk genetic populations, or rare mutations in
patients exposed to radiotherapy) has been complicated by the fact that
many of these studies are subject to one or more of the following: lack
of replication in an independent population; exposure based on self-​
report; lack of a consistent dose–​response association; subgroup find-
ings that could be due to chance; and overlap of study populations.
While earlier genetic studies focused on a handful of candidate
genes, the development of technologies that can rapidly analyze thou-
sands of genetic markers at relatively low cost, along with the mapping
of linkage disequilibrium between common SNPs across the genome
(International HapMap et  al., 2010)  and the definition of functional
elements critical for regulation and genomic stability (Encode Project
Consortium, 2012), have allowed us to comprehensively examine the
approximately 25,000 coding genes and associated functional ele-
ments. The genome-​wide association study (GWAS) approach has
successfully identified hundreds of risk loci in germline DNA for vari-
ous cancers (Chung and Chanock, 2011). However, the assessment of
gene–​environment interaction for most environmental carcinogens,
including radiation, has remained elusive. A GWAS of 100 Hodgkin
lymphoma survivors treated with radiotherapy identified two loci in
the PRDM1 gene potentially associated with increased risk of sec-
ondary malignancy (Best et  al., 2011), but these loci have yet to be
consistently confirmed. Genome-​wide association studies have also
been completed in adult women with contralateral breast cancer in
the WECARE study (Bernstein et  al., 2004)  and in individuals with
subsequent malignancies in the Childhood Cancer Survivor Study
(Robison et  al., 2009), both studies having detailed radiation doses
from radiotherapy. Results from these additional GWAS are expected
to be published shortly. For additional details on genetic susceptibilil-
ity to second cancers following radiotherapy, see Chapter 60.
Radiation Signatures
The pursuit of a “molecular signature” that would be able to discrim-
inate radiation-​induced tumors from “sporadic” tumors has obvious
and important implications for radiation protection. The search for ion-
izing radiation signatures started several decades ago, particularly in
the context of sarcomas after radiotherapy and thyroid cancers follow-
ing head/​neck radiotherapy and after environmental radiation expo-
sure. For sarcomas, most of the studies of molecular signatures use
some modification of the 1948 Cahan criteria for classifying tumors
as radiation-​induced: the tumor must be in the irradiated field, must
be histologically different from the primary cancer, and must have a
latency period of at least 5 years (Cahan et al., 1948). While satisfying
these criteria is likely to result in an increased probability that the tumor
is radiation-​related, it does not guarantee that it was radiation-​induced.
Early work in search of a radiation signature for sarcoma mainly used
conventional cytogenetic analysis to identify large-​scale chromosomal
abnormalities. These studies were limited by small sample sizes and
lack of a comparison group of non-​radiation-​induced tumors. Later
studies using polymerase chain reaction followed by direct sequencing
were able to examine mutations in specific genes such as TP53, but did
not address the probability of multi-​gene involvement, and potential
gene–​gene interactions (Berrington de Gonzalez et al., 2012). A more
recent study using microarray analysis to identify a signature of 135
genes from a learning/​ training set of 12  “radiation-​ induced” and
12 “sporadic sarcomas” was able to discriminate “radiation-​induced”
from “sporadic sarcomas” in an independent set of 36 sarcomas with
96% sensitivity and 62% specificity, but this study remains to be inde-
pendently replicated (Hadj-​Hamou et al., 2011).
For thyroid tumors, several lines of evidence indicate that radiation-​
related tumors may present differently than sporadic tumors. A high
frequency of RET/​PTC (RET proto-​oncogene/​papillary thyroid carci-
noma) gene rearrangements has been observed in papillary thyroid car-
cinomas (PTCs) of children exposed to radioactive fallout in Belarus
after the Chernobyl accident (Fugazzola et al., 1995; Ito et al., 1994;
Leeman-​Neill et  al., 2013)  and in thyroid tumors following external
radiotherapy (Bounacer et al., 1997). The relationship between these
gene rearrangements and radiation dose, however, remains unclear: no
significant association was observed between RET/​PTC activation
and individual I-​131 doses in post-​Chernobyl cancers occurring in the
Russian Federation (Tuttle et al., 2008); higher doses were associated
with higher prevalence of RET/​PTC rearrangements in PTCs of atomic
bomb survivors (Hamatani et  al., 2008); and recent data from post-​
Chernobyl thyroid cancer in Ukraine indicate a non-​monotonic rela-
tionship between I-​131 dose and RET/​PTC or PAX8/​PPARγ-​positive
tumors and dose, with increased risk at low-​to moderate doses and
decreased risk at high doses (Leeman-​Neill et al., 2013).
A genome-​ wide comparison of somatic copy number alterna-
tions (CNAs) between age-​and residence-​ matched exposed and
non-​exposed PTC patients from Chernobyl observed a copy number
gain of chromosome bands 7q11.22-​11.23 in a higher proportion of
radiation-​exposed versus unexposed individuals, with specific m-​RNA
overexpression of the CLIP2 gene located within this band (Hess
et al., 2011). While a positive dose-​response relationship was observed
between I-​131 dose and binary CLIP2 typing for young PTC cases
(age at exposure less than 5 years), this relationship was not observed
for those exposed at age ≥5  years (Selmansberger et  al., 2015), and
these results have yet to be confirmed in other populations.
As with studies of germline DNA, advances in DNA sequencing
technology in the last decade have yielded many insights into somatic
mutations from tumor tissue, largely driven by findings from The
Cancer Genome Atlas (TCGA) and the International Cancer Genome
Consortium (ICGC). These projects characterize the genome, as well
as various aspects of the transcriptome and epigenome, to give a
fuller understanding of how genes contribute to tumorigenesis. Over
30 distinct human tumor types have been analyzed to date through
large-​ scale genome sequencing and integrated multidimensional
analyses, yielding insights into both individual cancer types and
across cancers, particularly with respect to the accurate molecular
classification of tumors (Chin et al., 2011). While most of these dis-
coveries have focused on the genome rather than associated environ-
mental factors, a recent paper examining 4,938,362 mutations from
7042 cancers identified strong mutational signatures in tumor tissue
marking exposure to tobacco carcinogens and ultraviolet (UV) irra-
diation (Alexandrov et al., 2013). The tobacco signal was most evi-
dent in cancers that are known to be tobacco-​related (lung, head and
neck, and liver); and the UV irradiation signal was observed mainly
in malignant melanoma and squamous carcinoma of the head and
neck. A recent study identified potential radiation-​associated muta-
tional signatures in a small number (n = 17) of radiation-​associ-
ated second malignancies (Behjati, 2016). Similar studies to detect
 243
Ionizing Radiation 243
a radiation signature, whereby tumors caused by ionizing radiation
exposure could be discriminated from their sporadic counterparts,
are currently underway in populations environmentally exposed to
high doses of ionizing radiation. The best target populations for these
studies are those with a high proportion of cancers likely to be attrib-
utable to radiation and well-​characterized doses. Results of these
studies are expected over the next few years.
ESTIMATED ATTRIBUTABLE FRACTION
As ionizing radiation is an established carcinogen, it is appropriate
to estimate the potential fraction of cancers that may be attributable
to radiation from various sources, including medical, natural back-
ground, and nuclear accidents in exposed populations. Some estimates
come directly from the study populations, such as the LSS of the
Japanese atomic bomb survivors. For low-​dose exposures such as resi-
dential radon or diagnostic radiation exposure, attributable risks can
be estimated, under certain assumptions, using indirect risk projection
methods. Because radiation has been shown to increase cancer risk for
at least 50 years after exposure (Preston et al., 2007), attributable risk
estimates should be based on studies with very long-​term follow-​up or
life-​table methods, with adjustment for competing risks.
Environmental Radiation Exposure
Indirect risk modeling estimates suggest that 5% of leukemia in
England at any age, and about 15% of childhood leukemias, could
be related to background radiation (Kendall et al., 2011). Residential
radon is estimated to be responsible for about 3% of lung cancers in
the United Kingdom (Parkin and Darby, 2011). The Chernobyl acci-
dent is estimated to be responsible for 3%–​4% of cancer deaths in the
most highly exposed groups: cleanup workers, residents, and evacuees
(WHO, 2006). Radioactive fallout in Europe, by comparison, is esti-
mated to be related to only 0.01% of cancers (Cardis et al., 2006).
After 60 years of follow-​up in the LSS of the Japanese atomic bomb
survivors, it is estimated that about 10% of the solid cancers were
related to the radiation exposure (Preston et al., 2007).
Medical Radiation
As described earlier, there are relatively few studies of the cancer risks
from diagnostic radiation exposure due to the low doses per procedure.
However, diagnostic radiation is the largest man-​made source of radia-
tion, and there are concerns about whether doses are always optimized
and procedures always justified. Indirect modeling approaches esti-
mate that in more developed countries between 0.5% (in the UK) and
3% (in Japan) of cancers could be attributable to diagnostic medical
radiation (Berrington de Gonzalez and Darby, 2004). With the dra-
matic increase in CT scans in the United States, the attributable risk
could increase from 1% to 3% if current levels continue (Berrington de
Gonzalez et al., 2009). Not all of these cancers are avoidable because
many of these procedures have important benefits that need to be bal-
anced against the potential risks.
The proportion of second primary cancers that may be related to
the radiotherapy for the first cancer was estimated in the United States
from the SEER cancer registries as 8% overall for adulthood cancer
routinely treated with radiation (Berrington de Gonzalez et al., 2011).
Estimates for the United Kingdom are similar (6% for males and 8%
for females) (Parkin and Darby, 2011). The attributable risk is likely
higher for some childhood and young adulthood cancers with good
survival such as Hodgkin lymphoma, as children are known to be
more radiosensitve, and high relative risks of subsequent cancers have
been reported. Estimates for all Hodgkin lymphoma survivors in the
United Kingdom suggest that 16% of second cancers for males could
be related to radiotherapy, and 19% for females (because of the high
risk of second breast cancer) (Parkin and Darby, 2011). For testicular
cancer the estimate was 11%, and for cervical cancer 17%; both occur
at younger ages, and pelvic radiation exposes a number of organs.
Overall, when all sources of radiation were considered in the UK
population, Darby and Parkin estimated that about 2% of cancers could
be attributable to radiation (Parkin and Darby, 2011). Background
radiation/​
radon and diagnostic X-​ rays contributed approximately
equally, followed by radiotherapy.
OPPORTUNITIES FOR PREVENTION
There are a number of approaches to reduce unnecessary radiation
exposure to the general population. For example, residential radon
exposure can be reduced by a variety of relatively simple and cheap
remediation strategies such as improved ventilation, which should
also be implemented in schools and workplaces. Diagnostic medical
radiation exposure should be limited to clinically justified procedures
where the clinical decision-​making depends on the outcome of the test.
In addition, doses should be kept as low as reasonably possible. There
is increased awareness about dose levels from diagnostic procedures,
and new technologies can monitor or automatically control dose, such
as automated exposure control for CT scans. Treatment-​planning sys-
tems for radiotherapy aim to maximize tumor control and minimize
dose to the surrounding normal tissue. This should reduce the amount
of normal tissue exposed to very high doses. Many of these systems,
such as IMRT, result in increased whole-​body exposure to low levels
of radiation due to scatter and the number of monitor units involved. It
remains uncertain how this impacts the overall risk–​benefit profile of
newer technologies.
The current exceptions are flight crew, who are currently unmoni-
tored, and certain medical workers who perform fluoroscopically
guided procedures or who handle radionuclides. The length and com-
plexity of these procedures and the need for close proximity to the
beam and patient results in radiation exposure to various exposed parts
of the operator’s body, including the hands, lens of the eye, and brain.
Many of the physicians who perform these procedures have limited
training in radiation protection. Heavy protection aprons, gloves, or
glasses can make it more difficult to perform the procedures, and there
is a need for a careful balance between radiation protection and com-
fort and clinical performance. The development of personal protec-
tive technology that does not impede comfort or clinical performance
could help reduce exposures among medical workers. Badge monitors
need to be worn routinely to better monitor the cumulative exposures
to these physicians.
FUTURE RESEARCH DIRECTIONS
As one of the most extensively studied carcinogens, ionizing radiation
is an ideal candidate for cutting-​edge cancer epidemiology, including
searching for molecular signatures, risk-​projection modeling, uncer-
tainty analyses, and comprehensive assessment of critical exposure
periods.
Currently, most of the exposures to the general population are low-​
level doses (effective doses < 10 mSv) from diagnostic medical expo-
sures or background radiation. The magnitude of the cancer risks from
these low-​dose exposures, and protracted or fractionated exposures, is
more uncertain than that from higher, acute doses that have been stud-
ied for many decades in the Japanese atomic bomb survivors. Sample
size, measurement error, and the length of follow-​up needed to evalu-
ate cancer risks from low doses make it a difficult problem to study
using traditional epidemiological methods. The most promising recent
studies have used electronic record linkage with a retrospective study
design, such as the UK natural background radiation case-​control study
(Kendall et al., 2013), pediatric CT studies (Pearce et al., 2012), and
the pooled nuclear workers studies (Schubauer-​Berigan et al., 2015b).
This design facilitates large-​ scale populations with individualized
dose estimates. In the next decade there will be new publications in all
of these areas from large-​scale efforts including EPI-​CT, INWORKS,
the Million Workers Study, the USRT cohort, and the UK natural back-
ground radiation study. The key limitation in many of these studies,
however, is the lack of information on confounding factors, such as
24
244 PART III:  THE CAUSES OF CANCER
smoking in the nuclear worker studies and underlying medical condi-
tions in the CT scan studies. Traditional epidemiology, therefore, may
not be able to provide a definitive answer to the question of the risks
from low-​dose or protracted radiation exposure.
New molecular techniques could, however, provide new insights. In
particular, the search for “signatures” that can identify radiation expo-
sure as a causal factor for a particular tumor could technically provide a
definitive answer to the low-​dose question if the signature were identi-
fied and then shown to be present in tumors after low-​dose exposure
with evidence of no other clear cause of cancer. New epidemiologic
studies of ionizing radiation and cancer will also likely continue to fea-
ture a search for common genetic markers that can identify individuals
susceptible to radiation risk effects. These studies still face many chal-
lenges, including identifying a population with a high attributable risk,
and high-​quality biospesimens, well-​characterized radiation exposure,
and meaningful replication sets. The thyroid tumors from the Chernobyl
Tissue Bank satisfy many of these requirements, and the first sequenc-
ing study is currently in progress. Other populations of interest include
the Japanese atomic bomb survivors and second cancers that occur in or
near the radiation field. The integrated characterization of germline and
somatic alterations as genotyping and analysis methods evolve rapidly
in the next decade could be a promising avenue of research.
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PMC3887280.
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 249
14 Ultraviolet Radiation
ADÈLE C. GREEN AND DAVID C. WHITEMAN
OVERVIEW
Ultraviolet (UV) radiation is the principal cause of over 95% of kera-
tinocyte cancers (basal cell carcinomas and squamous cell carcinomas
of the skin), the most common cancers in white populations world-
wide; it also causes the majority (estimated 60%–​90%) of cases of
cutaneous melanoma, the cancer of the skin’s pigment-​ producing
cells. In addition, UV radiation is the major cause of many eye dis-
eases, including ocular cancers and cataract, the most common cause
of blindness, and is responsible for the underlying changes in aged
skin on which billions of dollars are spent annually in efforts to repair
the damage. Clinicians first recognized the causal role of sun exposure
in keratinocyte cancer development around the turn of the twentieth
century. The probable role of sunlight in driving high melanoma mor-
tality in populations of European ancestry living at low latitudes was
identified 50 years later.
The sun is the universal source of human exposure to UV radiation,
but artificial sources are also encountered in a wide range of settings,
from medical to industrial, and increasingly from commercial tanning
outlets. A  century ago, high cumulative UV exposure was the prov-
enance of those who worked in outdoor occupations (and in whom
skin cancers were first described), but during the course of the postwar
decades, social customs changed dramatically such that people with pale
skins sought to spend leisure time outdoors to acquire a suntan, and peo-
ple living in temperate climates likewise spent their vacations in sunny
locations and began to patronize tanning salons. By the late twentieth
century, however, the near epidemic increases in skin cancer incidence
in white populations, especially in Australia and New Zealand, stimu-
lated the initiation of skin cancer awareness and prevention campaigns,
including sun protection and legislation to restrict or ban sunbed use, in
an effort to control this growing public health problem.
SOLAR RADIATION AND
THE ELECTROMAGNETIC SPECTRUM
Solar UV radiation, a ubiquitous environmental carcinogen, is part of
the spectrum of electromagnetic radiation emanating from the sun. UV
radiation is also generated by artificial sources encountered in a wide
range of settings. The ultraviolet spectral region spans wavelengths of
10 nm–​400 nm, and is divided into several bands: UVA (320–​400 nm);
UVB (280–​320  nm); UVC (200–​280  nm); far UV (120–​200  nm);
extreme UV (10–​120 nm). Although UV radiation is classified as non-​
ionizing, UV photons are sufficiently energetic to destabilize electron
configurations within molecules such as DNA and to have a biologi-
cal effect. In terms of solar UV radiation, only UVB and UVA have
biological significance, as shorter wavelengths are absorbed by the
atmosphere.
UV radiation is typically absorbed over a surface and is measured
as a radiant exposure. The term irradiation represents the dose of radi-
ant energy delivered to an area within a given time, and is measured
J/​m2. The rate at which UV energy reaches a surface is termed irradi-
ance (units W/​m2). The total irradiance from any given source of UV
radiation is derived by summing the wavelength-​specific irradiances
across the spectrum of wavelengths emitted. A “biologically effective
UV irradiance” (UVeff) for a given source is determined by weighting
the irradiance at each emitted wavelength by its ability to cause the
biological effect of interest (e.g., DNA mutation, erythema), and then
summing these weighted values across all wavelengths.
METHODS OF MEASUREMENT
At the earth’s surface, solar UV radiation is measured by a wide vari-
ety of detector instruments (the most common of which are radiom-
eters), each having different attributes and requirements for calibration
and maintenance (Godar, 2005). In addition, portable monitors and
data-​loggers are increasingly available (Hooke et al., 2014).
Broadband radiometers measure UV irradiance over a broad spec-
tral band, integrated over the wavelengths of radiation known to exert
a particular biological effect (e.g., erythema). The output from broad-
band radiometers is a single number, calculated from the voltage gen-
erated by filtered UV radiation striking a photodiode. These simple
instruments are portable and robust, although relatively insensitive
to changes in irradiance at specific wavelengths. Networks of radi-
ometers were first established during the 1970s and 1980s, often in
remote locations, and subsequently have provided long-​term informa-
tion about levels of biologically effective UV radiation at the earth’s
surface (Frederick et al., 2000; Henderson et al., 2010; Pearson et al.,
2000). Popular early models (e.g., Robertson-​Berger meters) have
been largely replaced by newer models that have less technical error
and are more stable under extremes of temperature, although some
limitations remain (Huber et al., 2002).
Spectroradiometers are more sophisticated instruments that mea-
sure small changes in UV flux at specific wavelengths across the spec-
trum such as occurs following depletions in atmospheric ozone from
time to time (Roy et  al., 1997). Notwithstanding their cost and the
skill required to operate them, networks of spectroradiometers have
been established worldwide to monitor changes in surface irradiance.
For example, the US National Oceanic and Aerospace Administration
(NOAA) and the Environmental Protection Agency jointly manage the
NEU-​Brew network of spectroradiometers (http://​esrl.noaa.gov/​gmd/​
grad/​neubrew). Since 2006, these instruments have measured daily
UV radiation and total column ozone at six locations in the western,
central, and eastern United States (Houston, TX; Table Mountain, CO;
Mountain Research Station, CO; Bondville, IL; Raleigh, NC; Ft. Peck,
MT). This latest generation of instruments replaced an earlier network
of spectroradiometers operated by the EPA from the 1990s until 2004
(UV-​NET; http://​www.epa.gov/​uvnet/​), of which 14 instruments were
located in US National Parks as part of the Park Research and Intensive
Monitoring of Ecosystems Network (PRIMENet). Similar networks
of UV spectroradiometers have been established in many other coun-
tries, contributing to a global network coordinated by the World
Meteorological Organization to monitor UV irradiance (World Ozone
and Ultraviolet Radiation Data Centre, administered by Environment
Canada, http://​www.woudc.org/​home.php/​). Historical UV data from
global locations can be downloaded from this site for analysis.
DETERMINANTS OF SOLAR IRRADIANCE
AND SOLAR DOSE
The irradiance at the surface of the earth is much less than in the
upper atmosphere due to absorption by stratospheric ozone of all
249
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250 PART III:  THE CAUSES OF CANCER
UVC and a large proportion of UVB before reaching the earth. The
thickness of the ozone mantle varies according to season, latitude,
and meteorological conditions and by levels of chlorofluorocarbons
and other gases generated by human activities that can destroy ozone
(Rowland, 2006). International agreements like the Montreal Protocol
aimed to reduce the emission of chlorofluorocarbons (Weatherhead
and Andersen, 2006), and monitoring shows that increases in terres-
trial UVB have been modest (Williamson et  al., 2014). However, it
is uncertain whether subsequent small improvements in ozone levels
are due to a decline in the amount of ozone-​depleting substances in
the Earth’s atmosphere or if they reflect the high natural variability in
ozone levels related to the solar cycle and recent changes in global air
transport and temperature that make it unlikely that ozone will stabi-
lize at levels observed before 1980 (Weatherhead and Andersen, 2006;
Williamson et  al., 2014). UV irradiance, especially UVB, increases
with decreasing latitude, increasing altitude, in summer, and in the
middle hours of the day, and decreases with heavy cloud cover. UVA
levels are less affected than UVB by atmospheric factors and are more
stable throughout the day. By the end of the twenty-​first century rela-
tive to the present decade (2010–​2020), it is expected that projected
decreases in ozone-​depleting gases and changes in cloud cover will
lead to relatively small decreases in UVB, while reductions in reflec-
tivity of melting Arctic sea ice will lead to decreases of up to 10%. On
the other hand, expected improvement of air quality and in particular
reductions of aerosols over densely populated areas of the Northern
Hemisphere are expected to result in increases in UVB of 10%–​20%,
with even higher projected increases over China (Bais et al., 2015).
The UV Index
The standardization of UV information to the public through the UV
Index (UVI) was introduced and endorsed by multiple international
agencies in the 1990s. UV Index values are available throughout the
world from satellite instruments, ground-​based measurements, and
modeled forecasts (Zaratti et al., 2014), and are scaled from 0 to 11+,
with 11+ classified as “extreme.” Increasing levels of sun protection
are recommended with increasing UVI values to 11+. However, a
recent call for modification of the UV Index (Zaratti et al., 2014) was
based on the bias that exists toward European skin types in the cur-
rently depicted UV Index and its failure to properly account for the
most extreme values of the UV Index, over 20, experienced by popula-
tions living close to the equator and at high altitudes, such as in the
Altiplano region of South America.
MEASURING PERSONAL EXPOSURE
TO SOLAR RADIATION
Humans are exposed to sunlight on a daily basis, yet accurate and
reproducible methods for measuring the dose of solar radiation
received by an individual have only been developed in the past few
decades. In epidemiologic studies, human sun exposure has been mea-
sured in a variety of ways, ranging from dosimetry to personal recall
of past exposure.
Dosimetry
Dosimeters are portable units designed to measure personal, incident
exposure to solar UV radiation. Historically, the two most common
dosimeters used in human research have been the Bacillus biologi-
cal dosimeter and the polysulfone badge, both of which estimate
total doses of sun exposure over relatively short periods (Green and
Whiteman, 2006). The biological dosimeter comprises Bacillus sub-
tilis spores immobilized on a polyester sheet, which are inactivated in
a dose-​dependent manner upon exposure to UV radiation (Quintern
et  al., 1992). Dosimeters of this type were used in diverse settings,
including schools (Munakata et al., 1998), mountains (Moehrle et al.,
2003), and the Arctic (Cockell et al., 2001). Polysulfone is UVR-​sen-
sitive polymer that has an action spectrum closely approximating the
erythemal response of human skin when formulated as a film 30–​45
µm thick (Diffey, 1987). These dosimeters have been useful in field
studies as they are inexpensive, stable, and easy to apply, all of which
contribute to high rates of compliance in large-​scale studies (Sun et al.,
2014). However, they do become saturated at relatively modest doses
of UVR, requiring participants in exposure studies to periodically
change badges.
More recently, electronic dosimeters have been developed that
comprise miniature battery-​powered UV detectors that can be worn
on the wrist or other exposed body sites (Allen and McKenzie, 2005;
Heydenreich and Wulf, 2005). These dosimeters have the advantage
of logging UV radiation data at specified intervals, thereby provid-
ing investigators with information about time-​dependent aspects of
sun exposure, such as dose rates and maximum exposure intensity
(Seckmeyer et al., 2012). In addition, electronic dosimeters are able
to be reused, do not saturate after short intervals, and their response to
UVR exposure is linear rather than logarithmic (Allen and McKenzie,
2005; Seckmeyer et al., 2012).
While these various approaches to measuring personal UVB expo-
sure provide a degree of objectivity, there is attendant measurement
error when compared with gold standard measures of UV radiation as
determined by spectroradiometers. It has been suggested that estimates
of UVB exposure from polysulfone badges and electronic dosimeters
may deviate from the gold standard by up to 26% and 15%, respec-
tively (Seckmeyer et  al., 2012). In addition to issues of calibration,
the physical location and placement of dosimeters on the body also
cause measurements to vary. Human field studies comparing measure-
ments obtained from dosimeters placed concurrently on various body
sites have shown that maximal readings are obtained from dosimeters
located on the head (almost 90% of ambient UVR), with lower read-
ings obtained from dosimeters on the shoulder (55% of ambient) and
wrist (43%) (Thieden et al., 2000). Given that the aim of UV radiation
measurement in most epidemiologic studies is to rank participants by
relative exposure, the wrist is generally the preferred site of placement
for reasons of convenience, compliance, and reproducibility (Petersen
et al., 2014; Sun et al., 2014; Thieden et al., 2006).
Numerous field studies have deployed dosimeters and data-​loggers
on humans outdoors. Most studies to date have been relatively small in
scale, and of limited duration, and often have been conducted within
a single geographic site, so generalizations must be made cautiously.
Nevertheless, it appears that most people receive a personal dose of
UV radiation less than 5% of daily ambient UV radiation, although
there is wide inter-​individual variability, and the measured dose is
heavily dependent on environmental, behavioral, and occupational
factors, as well as personal characteristics and the anatomic site of the
dosimeter. As earlier, higher proportions of ambient radiation may be
received on horizontal skin surfaces (such as the vertex of the head,
the top of the shoulders), with lower doses at other sites (Weihs et al.,
2013). Movement, body position, and orientation with respect to the
sun all greatly affect the dose received at any given site (Weihs et al.,
2013). The level of ambient UV radiation is the strongest influence on
a person’s received dose; however, the influence of ambient UV radia-
tion on average doses when compared across populations is modified
by latitude and season. In most non-​equatorial parts of the world, the
average daily levels of ambient UV radiation are higher in summer
than winter, and the magnitude of seasonal difference increases with
latitude. One might therefore predict that seasonal fluctuations in per-
sonal UV radiation doses would follow a similar temporal course to
ambient UVR, with higher doses being received in summer than in
winter months. However, dosimetry studies of “free-​living humans”
conducted over a range of latitudes report discordant seasonal trends
for different geographic locations. In temperate climates at mid-​to
high latitudes, average daily personal UV radiation doses tend to rise
in spring and peak in summer in line with ambient UV radiation levels
(Sun et al., 2014; Thieden et al., 2004b), whereas in subtropical and
tropical locations, higher personal UVR doses are observed in winter
than in summer (Sun et al., 2014). The accepted explanation is that the
intensity of heat and solar radiation in summer months at low latitudes
discourages fair-​skinned residents from outdoor activities, particularly
during the middle part of the day. Conversely, the mild temperatures
 251
Ultraviolet Radiation 251
and less intense levels of ambient UV radiation during winter months
in tropical settings are more conducive to outdoor work and recreation,
resulting in higher levels of personal sun exposure on average.
Few studies have investigated correlations between host character-
istics and personal UV radiation; the scant available evidence suggests
that people with sun-​sensitive phenotypes (such as red or light-​colored
hair, a tendency to sunburn, or poor tanning ability) typically receive
lower average daily doses of UV than those without these character-
istics (Cahoon et  al., 2013; Thieden, 2008). Studies from the high-​
latitude Nordic countries have reported higher average daily personal
UV radiation doses in women than in men (Thieden et  al., 2004a),
whereas studies from mid-​to low-​latitude Australian settings report
the opposite (Xiang et  al., 2015). Within any given population, the
highest doses of UV radiation are experienced during outdoor activi-
ties. Very high UV doses have been recorded among outdoor workers
in diverse settings, including alpine environments and the Canadian
Arctic (Cockell et  al., 2001). As epidemiologic studies often seek
information on past exposures to the sun, it is interesting to note that
a Danish study observed high levels of intra-​individual concordance
for personal UVR doses measured at two time points up to 7  years
apart (Thieden et al., 2013), suggesting that individual patterns of sun
exposure tend to be relatively stable over time.
Biomarkers
The use of biomarkers seeks to overcome the inherent limitation of
the dosimeters described earlier, namely that while dosimeters mea-
sure the amount of ambient UV radiation to which individuals are
personally exposed, they do not measure the mutagenic effects of sun
exposure of interest to cancer epidemiologists. UV radiation induces
specific types of DNA lesions in the nuclei of skin cells (see later dis-
cussion), including thymine dimers, and these lesions tend to accu-
mulate in a dose-​dependent manner. These lesions can be detected
readily in DNA harvested from skin biopsies, but such invasive meth-
ods of sample collection are unsuitable for most epidemiologic stud-
ies. Moreover, such samples provide a measure of UV-​induced DNA
damage at specific anatomical sites only, which may not correlate with
a global measure of mutagenesis. Recently, non-​invasive urine tests
have been developed to measure the burden of UV-​specific mutations
in human subjects.
During the exquisitely refined process of DNA repair (see later dis-
cussion), the damaged segments of nucleic acid containing thymine
dimers are excised and are replaced with a new segment of DNA.
The excised fragments of damaged DNA are secreted from the skin
cells into the bloodstream, to be excreted by the kidney in the urine
(Cooke et al., 2013). Although presently a labor-​intensive procedure,
it is possible to quantify the amount of thymine dimers in the urine
in a reproducible manner using radio-​labeled high-​performance liq-
uid chromatography (Kotova et al., 2005). Kinetic studies demonstrate
that urinary thymine dimer levels reach a maximum 3–​4 days post-​UV
exposure. In field studies among indoor workers in Sweden, thymine
dimers were undetectable in urine samples taken in winter, but fol-
lowing typical working weeks in summer, about 20% of such peo-
ple exhibited measurable levels of thymine dimers (Liljendahl et al.,
2013). Levels of urinary thymine dimers are strongly correlated with
increased UV exposure. These effects have been demonstrated in chil-
dren and adults in outdoor settings in Sweden (Liljendahl et al., 2012),
as well as in Danish skiers, and Danish and Spanish sun-​seekers in a
subtropical beach setting (Petersen et al., 2014). At the present time,
thymine dimers have not been used as measures of UV exposure in
epidemiologic studies with skin cancer endpoints.
Personal Recollection
Because dosimeters and biomarkers measure current or recent solar
exposure, they cannot be used in epidemiologic studies that seek to
capture past exposure. Accurate recall of past sun exposure is diffi-
cult; nevertheless, epidemiologists have attempted to estimate past sun
exposure in two main ways (Whiteman et al., 2001).
The first approach has been to estimate an individual’s average
exposures to solar UV radiation during defined time periods according
to places of residence, since ambient solar UV radiation increases with
proximity to the equator (Godar, 2005). Epidemiologists have com-
monly used these ambient exposure measures when conducting eco-
logical studies, such as comparing the incidence of melanoma among
native residents and migrants with contrasting experiences of past sun
exposure. Although place of residence is a relatively crude measure of
personal sun exposure, it is a good proxy for solar dose when compar-
ing populations (Diffey et  al., 1996; Diffey and Gies, 1998; Godar,
2005) and has the practical advantage of being easy to recall.
The other approach has been to ask study participants to recall salient
exposures, such as numbers of sunburns, time spent outdoors in sum-
mer, or recreational activities associated with high levels of sun exposure
(English et al., 1998). An episode of sunburn is an integrated measure of
acute solar dose, and thus the number of sunburns a person experiences
gives an indication of accumulated acute exposures to intense solar UV
radiation (Green et al., 1985; Whiteman and Green, 1994). Recall of past
sunburn episodes is reasonable, with most studies suggesting moderate
repeatability (kappa scores 0.5–​0.7) (Jennings et al., 2013; Morze et al.,
2012; van der Mei et al., 2006; Veierod et al., 2008). The number of sun-
burns experienced by a person is due not only to the intensity or dura-
tion of sun exposure, but also to host characteristics including skin type
and pigmentations. Other recalled measures of UV exposure that are not
completely independent of host characteristics include time spent out-
doors, vacations in sunny locations, use of tanning salons and outdoor
occupations, most of which have moderate to high levels of agreement
when subjected to test-​retest reliability studies (Jennings et  al., 2013;
Morze et al., 2012; van der Mei et al., 2006; Veierod et al., 2008).
Phenotypic Markers of UV Exposure
Because of the challenges in measuring past sun exposure by ques-
tionnaire-​based methods, and because dosimetry and biomarkers are
limited to recent or current UV exposures, researchers have sought
“objective” measures of historical sun exposure based on biological
changes that correlate with exposure. Photoaging encompasses a range
of visible and microscopic changes to the skin associated with chronic
exposure to UV radiation. Silicone-​rubber skin casts capture a record
of the loss of visible surface architecture. These casts have several epi-
demiologic virtues: they can be obtained rapidly; they are inexpensive,
safe, and painless to participants; and they can be stored indefinitely.
Moreover, graders can be trained easily to make reliable assessments
of photoaging (kappa values > 0.90) that correlate well with histologi-
cal measures of photoaging (Battistutta et al., 2006).
ARTIFICIAL SOURCES OF UV EXPOSURE
While most people’s only UV exposure comes from sunlight, artificial
UV sources may contribute to a material proportion of total UV expo-
sure for some. In particular, the prevalence of exposure to artificial
UV radiation for cosmetic tanning has increased markedly in recent
decades, with users attaching considerable personal and social impor-
tance to tanned skin (Grange et al., 2015; Lake et al., 2014). A sys-
tematic review and meta-​analysis in 2013 showed the large extent of
ever-​exposure to indoor tanning in Western countries, especially in the
young (Wehner et al., 2014), with summary prevalences of 36% for
adults, 55% for university students, and 19% for adolescents.
Although the indoor tanning industry generally implies to users
that their use of tanning parlors complying with regulations is safe
and might have health benefits (Autier et al., 2011), several reviews
show the high risks of ill effects on eyes and skin, including melanoma
and other skin cancers (Boniol et al., 2012; International Agency for
Research on Cancer, 2012; Wehner et al., 2012). Surveys have indi-
cated variable compliance by the sunbed industry with guidelines
(Chandrasena et al., 2013), and exposure to tanning units can still result
in high UV doses (Khazova et al., 2015; Nilsen et al., 2011), similar
to exposures received while sunbathing in summer at a Mediterranean
resort. Measured UV irradiance from a large number of Norwegian
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252 PART III:  THE CAUSES OF CANCER
solaria (sunbeds and stand-​up cabinets) in 2008 showed that overall
compliance had increased since 1998–​1999 but total UV irradiance
had not decreased, mainly because of higher UVA irradiance (Nilsen
et al., 2011). A recent survey in the United Kingdom showed that an
increase in sunbed emissions had occurred in the last decade, with
UVB irradiance of over 0.3 W m–​2 in more than 85% of all tested
solaria, though exposure per session appeared not to have increased
(Khazova et al., 2015).
Other sources of artificial UV exposure are found in occupational
and medical settings. In occupational settings, workers are normally
shielded from material UV radiation, though prolonged exposure to
intense UV radiation from arc welding is hazardous to both eyes and
skin (International Agency for Research on Cancer, 1992, 2012). In
clinical usage, different UV dose regimens influence the occurrence
of long-​term carcinogenic side effects. Applications such as PUVA
photochemotherapy that combines UVA with photosensitizing pso-
ralens to treat skin diseases such as psoriasis, have been used widely.
A  systematic literature review of the carcinogenic risks of psoralen
UVA therapy versus narrowband UVB therapy, also commonly used
for chronic plaque psoriasis, concluded that there is an increased risk
of skin cancer following PUVA shown by both US and European
studies, with a greater risk seen in US studies, likely to be partly
explained by higher average UVA doses and lighter phototypes of
treated patients (Archier et  al., 2012). There were insufficient pro-
spective studies in psoriasis patients treated with UVB to assess the
associated carcinogenic risk.
BIOLOGIC MECHANISMS FOR UVR CARCINOGENESIS
DNA Damage
The principal mechanism of UV carcinogenesis at the molecular level
is DNA damage. DNA damage may arise directly through highly
energetic UV photons interacting with chemical elements of the dou-
ble-​helix, or indirectly through the transfer of energy from photons
through endogenous photosensitizers to DNA. Most DNA damage is
repaired with very high fidelity by specific enzymes before the cell
replicates. If repair fails, then the damaged nucleotide can be replaced
by an incorrect nucleotide in the DNA of the daughter cell, resulting
in a permanent change in the sequence known as a mutation. Drawing
a distinction between DNA damage (including lesions, adducts, and
photoproducts) and mutation is critically important in establish-
ing the temporal relationship along the pathway to carcinogenesis
(Brash, 2015).
The chemical structure of DNA, particularly the density of pyrim-
idine bases (thymine [T]‌and cytosine [C]), renders the molecule
a potent absorber of UV photons (Pfeifer and Besaratinia, 2012).
Incident UVB radiation directly damages the integrity of DNA by
inducing bulky lesions (cyclobutane pyrimidine dimers [CPDs] and
[6–​4] photoproducts) between adjacent pyrimidine nucleotide bases
that interfere with essential genomic functions such as transcription
and replication. If these lesions are not repaired, then characteris-
tic mutations occur, most frequently base substitutions of C by T
at dipyrimidine sites, and less commonly, CC to TT tandem base
substitutions (Ikehata and Ono, 2011). Such is the specificity of these
mutations for sunlight exposure that they are termed UV signature
mutations. Recently there has been renewed appreciation that UV
damage causes many other nonspecific DNA mutations. Whether
or not UV photodamage results in a signature mutation depends on
the precise sequence of nucleotides at the target site, as well as the
presence of other chemical elements in close proximity at the time
of photon strike (Brash, 2015). It follows that the absence of a UV
signature mutation in a cancer gene of interest does not mean that the
mutation was not caused by sun exposure.
While DNA is a major chromophore for UVB radiation, it absorbs
photons in the UVA spectrum poorly. Thus UVA induces DNA dam-
age indirectly. For many years, it was held that UVA interacted with
sensitizers, both endogenous (e.g., bilirubin, porphyrins) and exog-
enous (e.g., medications, cosmetics, sunscreens) to produce reactive
oxygen species that result in characteristic lesions such as 8-​oxo-​7,8
dihydroxyguanine (8-​oxodGuo). Recent experiments have demon-
strated that erythemal doses of UVA actually induce more CPDs
than 8-​oxodGuo in human skin (Mouret et  al., 2006), although in
relative terms, the amount of CPD damage induced by UVA is about
five-​fold less than an erythemally equivalent dose of UVB (Tewari
et al., 2012). For any given dose of UVA, however, the yield of CPDs
is greater in the cells of the basal epidermis than in more superfi-
cial layers, whereas the potency of UVB diminishes with increas-
ing depth (Tewari et al., 2012). These findings are important, since
cells in the basal layer include the stem cells and transitional cells
that are likely to be the progenitors of keratinocyte cancers (Halliday
and Cadet, 2012). Given that around 95% of the daily UV irradiance
falls in the UVA range, the realization that UVA also causes CPDs in
measurable quantities in the dividing cells of the basal epidermis has
potential ramifications for primary prevention strategies, which have
focused mainly on the hazards arising from UVB wavelengths. As
yet, it is too early to determine how these laboratory findings might
affect public health advice; larger scale field studies are required to
address the relative importance of UVA and UVB at a population
level.
The mechanism through which UVA causes CPDs appears to
involve melanin, the complex pigment produced by melanocytes
that shields nuclear material from UV radiation (Abdel-​Malek and
Cassidy, 2015). Following UVA exposure, various classes of enzymes
are induced that generate large intracellular quantities of nitric oxide
and superoxide. At the same time, UVA sufficiently solubilizes mela-
nin polymers into small fragments that are able to enter the nucleus of
cells. Once exposed to nitric oxide and superoxides, the melanin frag-
ments undergo electrolysis in an electrolytic reaction, releasing similar
energy to a UV photon, sufficient to generate CPDs when in close
proximity to DNA (Premi et al., 2015). This mechanism is thought to
explain the observation that induction of CPDs by UVA in skin cells
containing melanin peaks several hours after exposure (with so-​called
dark CPDs), unlike UVB, for which maximal photodamage is almost
instantaneous. Of note, it underscores the potential hazards to DNA
integrity from UVA light sources (such as tanning salons) (Abdel-​
Malek and Cassidy, 2015).
DNA Repair
Terrestrial organisms have evolved highly efficient mechanisms to
repair DNA damaged by UV radiation. Enzymatic nucleotide exci-
sion repair (NER) is the only pathway through which UVB-​induced
photoproducts are removed in placental mammals (Vermeulen and
Fousteri, 2013). NER operates through two mechanisms, called
global genome NER (GG-​ NER) and transcription-​coupled NER
(TC-​NER), respectively (Marteijn et al., 2014). Other types of DNA
photodamage induced by UVR are repaired by different mecha-
nisms; for example, oxidative lesions are removed by base excision
repair.
In GG-​NER, the entire genome is scanned for distortions to the dou-
ble-​helix caused by destabilizing DNA lesions. The XPC protein plays
a central role in recognizing DNA damage, and in the specific case
of CPDs, recognition is enhanced by UV-​DDB (UVR-​DNA damage
binding protein). Once detected, a cascade of proteins acts to verify the
lesion (XPB and XPD, encoded by ERCC3 and ERCC2 genes, respec-
tively), excise the damaged DNA fragment of about 22–​30 nucleotides
(XPF and XPG), and then synthesize the sequence and ligate it to the
preserved single strand.
The GG-​NER process is relatively slow, however, and it is not
uncommon that photoproducts remain unrepaired at the time of
transcription or cell replication. Stalled transcription can have lethal
consequences for cells, and so the TC-​NER pathway has evolved to
remove stalled complexes and to ensure that damaged segments can
be repaired and transcribed in a timely fashion. The precise sequence
of events is the subject of intense research scrutiny, but it appears
that the key trigger for TC-​NER is when RNA polymerase II reaches
a bulky DNA photolesion and is unable to proceed with RNA syn-
thesis. This initiates a complex cascade of verification and excision
proteins, which remove the damaged DNA fragment and synthesize
 253
Ultraviolet Radiation 253
a new sequence. The fidelity of the transcription-​ coupled repair
process seems to vary according to conditions, however, with both
error-​free and error-​prone repair pathways known to exist (Ikehata
and Ono, 2011). Overall, it is estimated that about 90% of CPD dam-
age is repaired by GG-​NER, with the remainder repaired by TC-​NER
(Vermeulen and Fousteri, 2013).
The importance of DNA repair pathways has been shown in people
with xeroderma pigmentosum (XP), who lack enzymes that specifi-
cally repair UV-​induced lesions (Kiss and Anstey, 2013). These indi-
viduals manifest extreme sun sensitivity, premature development of
multiple skin cancers, and early death. Even within the population
at large, there is considerable variation in DNA repair efficiency,
prompting investigations of whether people with less efficient DNA
repair mechanisms are at higher risk of UV-​associated cancers, with
conflicting findings to date (Han et al., 2005; Mocellin et al., 2009;
Ruczinski et al., 2012). Actively transcribed genes are repaired more
quickly than infrequently expressed genes, and since the pattern of
transcriptional activity differs by cell type, so too will the distribution
of mutations.
UV Radiation Mutagenesis
Mutations occur when DNA repair mechanisms fail to restore the
original sequence of nucleotides that existed prior to photodamage.
There is consensus that certain photolesions confer a higher probabil-
ity of erroneous repair than others, and hence have higher mutagenic-
ity (Pfeifer and Besaratinia, 2012). CPD photoproducts account for the
majority of mutations in mammalian cells, as they are incurred more
commonly than 6–​4 photoproducts following UVR exposure, and are
repaired much more slowly. Even for CPDs, however, it appears that
TT sequences are repaired with higher fidelity than TC sequences and
that methylated dipyrimidine sites are particular “hot spots” for UVR
mutations. DNA damage arising from oxidative stress is also muta-
genic, causing G to A mutations.
It has long been known that mutations in key regulatory genes are
the hallmarks of cancer. Early work focused on the role of tumor sup-
pressor genes, so named because loss-​of-​function mutations confer
increased risks of cancer in experimental models. TP53 is one such
gene, whose protein product (p53) plays a central role in cell cycle
regulation, apoptosis, and DNA repair (Lane, 1992). When this func-
tion is lost through mutation or deletion, cells have a reduced capacity
to repair DNA damage, facilitating cell transformation. Early research
showed that UVR signature mutations in TP53 were detectable in about
50% of basal cell carcinomas (BCC) and more than 90% of squamous
cell carcinomas (SCC) in humans (Brash et al., 1991; Campbell et al.,
1993; Rady et al., 1992).
Of epidemiological importance has been recent research docu-
menting the high prevalence of UV signature mutations in non-​can-
cerous “normal” human skin. Careful mapping studies have revealed
that up to 30% of skin cells on the eyelid carry non-​silent driver
mutations in known skin cancer genes including NOTCH1, NOTCH2,
TP53, and FAT1 (Martincorena et  al., 2015), suggesting that “pre-
neoplastic clones” are extremely common in sun-​exposed human epi-
dermis. Understanding how sunlight and genes interact to promote
tumor development and establishing how the process can be halted
or reversed once initiated are the focus of intense research (Viros
et al., 2014).
UV Radiation and Gene Expression
Exposure to UV radiation invariably leads to DNA damage in kera-
tinocytes. Upon detection of damage, p53 is stabilized to halt kerati-
nocyte replication and allow the damage to be repaired. At the same
time, p53 activates the transcription of pro-​opiomelanocortin, which is
then cleaved to alpha-​melanocyte stimulating hormone (α-​MSH) and
released by keratinocytes. α-​MSH binds to the melanocortin-​1 receptor
(MC1R) on the cell membrane of neighboring melanocytes, launching
an intracellular cAMP-​signaling cascade, culminating in increased
production of melanin pigments for distribution back to keratinocytes.
This is the tanning response induced by sun exposure (Chen et  al.,
2014). From the perspective of cancer epidemiology, it is important to
recognize that there are two types of melanin, the brown/​black eumela-
nin and the red/​yellow pheomelanin, and the relative abundance of
each is determined largely by MC1R genotype (Garcia-​Borron et al.,
2014). MC1R is a highly polymorphic gene with more than 200 vari-
ants recorded. MC1R variants associated with red hair color represent
a loss-​of-​function mutation that results in the production of pheomela-
nin. In addition to its central role in the tanning response, MC1R is
now understood to protect against the adverse effects of UVR through
non-​pigmentary mechanisms (Robinson et al., 2010), including DNA
repair (Swope et al., 2014).
Immunosuppression
UV radiation suppresses immunity in humans and animals; however,
the extent, duration, and type of immunsuppression depend on many
factors (extrinsic and intrinsic) and are subject to complex regulatory
control (Halliday et al., 2012; Hart et al., 2011). Both UVA and UVB
induce immune suppression of the skin, probably by different mecha-
nisms (Damian et al., 2011). The molecular mediators of UV-​induced
local immunosuppression include DNA damage, cis-​urocanic acid,
and reactive oxygen species (Schwarz and Schwarz, 2011).
At the cellular level, UV exposure causes Langerhans cells, the den-
dritic antigen-​presenting cells of the skin, to migrate to draining lymph
nodes and activate T and B regulatory cells (Halliday et  al., 2012).
Other cell types demonstrated to play a role in UV-​induced immuno-
suppresion of the skin include mast cells (Byrne et al., 2008), natural
killer cells (Fukunaga et al., 2010), and effector and memory T-​cells
(Rana et al., 2008). UV radiation can also suppress immune responses
systemically at sites distant from the skin, including lower levels of
activity of memory T-​cells in bone marrow and spleen.
The evidence that immune surveillance plays a role in protecting
against skin cancer development is indirect, derived mainly from the
high incidence of skin cancers in organ transplant patients treated with
immunosuppressive drugs, an effect that is amplified in immunosup-
pressed patients who experience high sun exposure (Euvrard et  al.,
2003; Vajdic and van Leeuwen, 2009).
Vitamin D Synthesis
UVB radiation is necessary for the conversion in the skin of 7-​dehy-
drocholesterol to cholecalciferol (vitamin D3), the precursor to the
biologically active form of vitamin D.  When measured by dosim-
etry, personal UV exposure contributes modestly (about 8% of the
variance explained) to serum vitamin D concentrations (Kimlin
et  al., 2014)  after controlling for related factors like latitude and
seasonal factors, use of vitamin D supplements, race, body mass
index, and physical activity (Freedman, 2013; Kimlin, 2014; Millen,
2010). Observational studies have suggested that people with low
serum concentrations of vitamin D have increased risks of cancers
at various sites (particularly colon and breast) when compared with
people who have higher concentrations of vitamin D. At the present
time, however, the observational evidence regarding vitamin D and
cancer falls short of causality (IARC, 2008; Manson and Bassuk,
2015) and is not supported by the findings of clinical trials (Bolland
et al., 2014).
CANCERS ASSOCIATED WITH UV EXPOSURE
Keratinocyte Cancers
There is a large body of observational and experimental evidence
that UV radiation is the principal environmental cause of keratino-
cyte cancers (basal cell carcinomas and squamous cell carcinomas of
the skin) (International Agency for Research on Cancer, 1992, 2012;
Olsen et al., 2015) (see Chapter 58). Salient points are that keratino-
cyte cancers are more common among those living in areas of high
solar irradiance, and residents of regions with low solar irradiance
254
254 PART III:  THE CAUSES OF CANCER
develop more lesions when they migrate to areas with higher ambient
UV radiation. Both BCC and SCC of the skin occur almost exclusively
on sun-​exposed body sites among fair-​skinned populations and are fre-
quent in patients with constitutional genetic deficiencies preventing
the repair of UVB-​specific DNA mutations. Field trials have demon-
strated that regular use of sunscreen reduces the incidence of actinic
keratoses (AK) (Darlington et al., 2003; Thompson et al., 1993) and
SCC tumors in humans (Green et al., 1999). Finally recent meta-​analy-
ses have shown that sunbed use significantly increases risks of BCC
and SCC (Wehner et al., 2012).
The era of high-​throughput genomics has revealed the full extent
of UV-​induced mutations for each of the common types of skin can-
cer. Sequencing studies have shown that the total mutational loads for
BCC and SCC far exceed those of other common cancers, with up to
75 mutations per megabase (Mb) of DNA for BCC and 35 per Mb for
SCC (Jayaraman et al., 2014; South et al., 2014). Overwhelmingly,
the most prevalent mutations in the somatic genome of these tumors
are the classic UVR signatures—​C to T substitutions at dipyrimidine
sites (Hodis et al., 2012; South et al., 2014). The key challenge, how-
ever, has been to separate the small number of critically important
mutations that drive tumor development from the thousands of pas-
senger mutations scattered throughout the genome that are acquired
as the tumor evolves. For SCC, driver mutations appear restricted
to a relatively small subset of genes:  NOTCH1, NOTCH2, TP53,
CDKN2A, NRAS, and KRAS (Durinck et al., 2011; South et al., 2014;
Wang et al., 2011); these mutations typically carry UVR signatures.
Driver mutations appear similarly restricted to a small number of
genes for BCC (PTCH, TP53) (Jayaraman et  al., 2014). For both
types of keratinocyte cancers, other genes have been identified as
candidate drivers at lower frequency, and these await confirmation
in larger studies.
Melanoma
Cutaneous melanoma is a cancer of the pigment-​producing cells of the
skin. The causal role of UV exposure is complex and is determined
by phenotypic, genotypic, and behavioral factors (Whiteman et  al.,
2011) (see Chapter 63). The evidence linking UV exposure with cuta-
neous melanoma is similar to that for keratinocyte cancer, namely that
melanomas develop more commonly among fair-​skinned migrants to
high UV environments than among the population of origin (Whiteman
et al., 2001); and sun-​exposed sites, such as the face and ears, are the
most commonly affected (per unit area of skin), but intermittently
exposed sites, such as the trunk and proximal limbs, are also often
affected (Green et al., 1993). Estimates of the population fraction attrib-
utable to sun exposure range from 60% to 95% (Olsen et al., 2015).
UV-​ induced mutations are highly prevalent throughout the
somatic genome of cutaneous melanomas (at around 14 per Mb),
both as drivers and passengers, as described earlier (Hodis et  al.,
2012). Key genes affected in melanoma include BRAF, NRAS,
PTEN, TP53, CDKN2A, and MAP2K1 (Hodis et  al., 2012). Unlike
SCC and BCC, however, not all driver mutations for melanoma have
the classical UVR signature. The most prevalent somatic mutation
in melanoma, occurring in around 50% of tumors, occurs in BRAF
and involves a T to A transversion at position 1799 (resulting in the
substitution of valine for glutamine at codon 600, hence the abbre-
viation BRAFV600E). There is conjecture about whether UVR could be
responsible for such a mutation, since BRAFV600E mutations are also
commonly found in internal cancers (Davies et al., 2002). The most
favored explanation is that this pattern is consistent with oxidative
damage in the target cell, for which UVR is one such source (Denat
et al., 2014). Converging lines of evidence support this theory, since
melanin (particularly pheomelanin) is a potent producer of oxy-
gen radicals when exposed to UVR (Napolitano et  al., 2014), and
experimental studies indicate that UVA alone induces melanoma in
pigmented but not albino mice through oxidative damage (Noonan
et al., 2012). It is also possible that pheomelanin induces melanoma
independently of sun exposure (Mitra et  al., 2012), although this
remains to be established in human studies.
Finally, mouse models support observational human studies showing
that sun exposure in early life has particularly adverse effects (Noonan
et al., 2001, 2012; Viros et al., 2014). Numerous epidemiologic studies
have examined the possible association of UV with ocular melanoma,
and it appears that occupational sun exposure, especially farming and
welding, is associated with higher risks of melanoma of the choroid
and ciliary body (Vajdic et al., 2002, 2004).
Other Cancers
There has been speculation that exposure to UV radiation may indi-
rectly affect a person’s risk of developing cancers at sites other
than skin, but evidence from large prospective studies that have
tested this hypothesis directly is scarce. The larger of two relevant
cohort studies, the National Institutes of Health (NIH)-​AARP Diet
and Health Study, linked ambient erythemal UV exposure esti-
mated from satellite Total Ozone Mapping Spectrometer data to
the Census 2000 record of baseline residence for 450,934 white,
non-​Hispanic subjects and examined their cancer outcomes after
9  years of follow-​up using cancer registries. After accounting for
confounding factors, ambient UV exposure was associated with sig-
nificant decreases in non-​Hodgkin’s lymphoma, colon, squamous
cell lung, pleural, prostate, kidney, and bladder cancers (Lin et al.,
2012). On the other hand, a Scandinavian cohort study of 49,261
women found no evidence of an association between any measure
of personal cumulative UV exposure at ages 10–​39 and overall can-
cer occurrence after 15 years follow-​up, though sunbathing at ages
10–​29 was related to reduced breast cancer and cancer overall, ≥ 2
sunburns/​year was related to reduced lung cancer, and solarium use
was also inversely associated with breast cancer (Yang et al., 2011).
On balance, there is insufficient strong evidence available to draw
firm conclusions.
OPPORTUNITIES FOR PREVENTION
Reducing Sun Exposure
Many health promotion and health education strategies have been
developed to change knowledge, attitudes, and behaviors to reduce
susceptible people’s sun exposure. Behavioral interventions aim to
improve personal sun protection through use of clothing, hats, sun-
screen, and sunglasses, staying in shade, and avoiding exposure during
peak UV hours. This section provides a broad overview of approaches
to reduce exposure to UV radiation. A more detailed discussion of
practical issues regarding the implementation of these approaches is
provided in Chapter 62.4.
Preventive interventions can be delivered through a variety of
means including education, counseling by healthcare providers,
policy and environmental changes, and community-​wide engage-
ment through media or social media campaigns (NICE, 2007), or
by combining several of these approaches (Saraiya et  al., 2004).
A  systematic review of the evidence for behavioral counseling to
prevent skin cancer conducted for the US Preventive Services Tasks
Force (Lin et  al., 2011)  resulted in recommendations to counsel
children, adolescents, and young adults aged 10–​24  years who
have fair skin to minimize UV exposure to reduce skin cancer risk
(Moyer, 2012), but claimed insufficient evidence to assess the bal-
ance of benefits and harms of counseling adults over 24 about skin
cancer prevention, despite several successful field trials in adults
(Green et  al., 2012). Another systematic review of the evidence
for reducing UV radiation exposure among outdoor workers found
men more likely to wear hats and protective clothing and women
more likely to use sunscreen, but found little evidence concerning
education and prevention policies in the outdoor workplace (Glanz
et al., 2007).
Multiple-​level community-​wide interventions have been devel-
oped by cancer agencies in many countries. Australia led the way
from the 1980s with mass-​media campaigns to increase the public’s
knowledge about the link between sun exposure and skin cancer
 25
Ultraviolet Radiation 255
and to reduce high levels of recreational sun exposure. Beginning
with the “Slip, Slop, Slap” Campaign with a logo that encouraged
people to “slip on a shirt, slop on some sunscreen and slap on a
hat,” successive campaigns targeted specific groups, for example,
adolescents, outdoor workers, and schoolchildren (Iannacone and
Green, 2014). These campaigns have been conducted predomi-
nantly by state Cancer Councils under a “SunSmart” license, rein-
forced by policies to adopt supportive environments such as shade
in schools and access to quality sun-​protection products (Iannacone
and Green, 2014). In New Zealand, campaigns have been similar in
their history, with the New Zealand Cancer Society first conduct-
ing campaigns with an emphasis on children, parents, and teachers,
and later on other sections of the community, informed by quali-
tative research (Watts, 2002). A  formal school accreditation pro-
gram for sun protection has had positive results (Reeder, 2012).
Countries in the Northern Hemisphere with lower skin cancer rates
have also conducted comprehensive community-​based campaigns,
but with lower levels of intensity and investment of resources
(Hiom, 2010)  and often lacking national coordination (Lazovich
et al., 2012). For example, the SunWise campaign was launched in
2000 by the US Environmental Protection Agency, and its school
program had modest early success (Geller et al., 2003). Economic
analysis indicated that if the SunWise school program continued
to 2015 it should avert nearly 11,000 skin cancer cases and 960
quality-​adjusted life-​years (undiscounted) among its participants
(Kyle et al., 2008). For every dollar invested in SunWise, between
approximately $2 and $4 in medical care costs and productivity
losses could be saved, depending on funding levels (Kyle et  al.,
2008). In the United Kingdom, primary prevention efforts com-
menced in the 1990s with the government-​supported national skin
cancer prevention campaign Sun Know How. Since 2003, Cancer
Research UK, commissioned by the UK Health Departments, has
run the SunSmart campaign with varying levels of subsequent
funding (Hiom, 2010), supported by campaigns conducted by der-
matologists and other charities.
Reducing Exposure to Artificial UV for Tanning
A review of the trends in legislation to restrict access to indoor tan-
ning found that the number of countries with such legislation increased
from two countries in 2003 to 11 countries in 2011 (Pawlak et  al.,
2012). Brazil has subsequently banned tanning salons (in 2009) and
Australia in 2015.
Legislated restrictions of the tanning industry have been fewer in
the United States, but in 2014, based on the accumulated evidence
of harmful health effects of indoor tanning for cosmetic reasons,
the US Food and Drug Administration reclassified tanning lamps
from a class I (low risk) medical device to a class II (moderate risk)
device, with the added requirement for black-​box labeling warn-
ing minors about the harms of using tanning lamps (Ernst et  al.,
2015). Also in 2014, the Surgeon General of the US Department of
Health and Human Services issued his “Call to Action to Prevent
Skin Cancer,” which inter alia included the call to “reduce harms
from indoor tanning” (US Department of Health & Human Services,
2014). It has been noted that some 44 US states now have some kind
of law or regulation related to indoor tanning, though with varying
strength of state laws and compliance enforcement, and some states
have no laws related to indoor tanning (Pan and Geller, 2015; US
Department of Health & Human Services, 2014).
FUTURE RESEARCH
Use of new technologies, including social media, is now being
researched to reduce deleterious sun exposure. Implementation and
evaluation programs of behavioral interventions, especially among
men, adolescents, children, and their caregivers, are high research
priorities.
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 259
15 Electromagnetic Fields
MARIA FEYCHTING AND JOACHIM SCHÜZ
OVERVIEW
This chapter focuses on the carcinogenic effects of exposure to elec-
tromagnetic fields, mainly power frequency and radiofrequency fields/​
microwaves. It discusses current knowledge on interaction mecha-
nisms of relevance for carcinogenicity, describes exposure sources,
and reviews the available epidemiological studies. The chapter com-
ments on the strengths and weaknesses of the data available, and dis-
cusses sources of bias of concern for the interpretation of the findings.
Based on current evidence, electromagnetic fields are not regarded as
carcinogenic to humans, but there are open scientific questions that
merit further research, as will be outlined.
INTRODUCTION
Electromagnetic fields in the non-​ionizing radiation spectrum are an
integrated part of modern life, with an ever-​increasing number of
applications. The properties of electromagnetic fields and their inter-
action with the human body are determined by their frequency and
wavelength, with the wavelength inversely related to the frequency.
Electromagnetic fields generate energy, which is directly proportional
to the frequency. In the non-​ionizing part of the electromagnetic spec-
trum (Figure 15–1), the generated energy is too weak to break chemi-
cal bonds, and ions cannot be formed. The low frequency end of the
spectrum includes static fields (0 Hz) and fields related to the pro-
duction, transmission, and use of electricity (usually at 50–​60 Hz).
At higher frequencies within the non-​ionizing spectrum are radiofre-
quency fields (RF) and microwaves, including applications such as
radio and television, mobile telephony, radar, and microwave heating.
Further up the frequency range are infrared light, visible light, and UV
radiation. This chapter focuses on the frequencies from above 0 Hz to
300 GHz, mainly power frequency and RF fields/​microwaves, as this
has been the focus of the research on potential carcinogenic effects of
electromagnetic fields during the past decades.
Extremely low frequency fields (ELF) have a very long wavelength
(6000 km at 50 Hz), and electric and magnetic fields are separated.
The electric field strength is measured in volts per meter (V/​m), while
magnetic fields are usually measured as the magnetic flux density in
tesla (T), and in the human environment usually in microtesla (µT). At
these low frequencies the energy is too low to cause heating, and the
magnetic fields pass through the body. The established mechanism of
interaction between ELF fields and the human body is the induction of
electric currents. Induced electric currents may cause acute neurologi-
cal effects, and current exposure guidelines are set to protect against
these acute effects. The research on the potential carcinogenicity of
ELF magnetic fields has focused on exposures that are orders of mag-
nitude below the current guidelines (ICNIRP, 2010; IEEE, 2002).
Radiofrequency fields associated with mobile phone technology
have wavelengths of a few centimeters, depending on the frequency
used for communication. They are characterized by their power den-
sity (i.e., the electromagnetic energy per unit area), which is measured
as watts per meter squared (W/​m2). Except for near-​field exposure
(i.e., very close to the source), there is a direct relation between the
power density, the electric field (V/​m), and the magnetic field (A/​m),
and measurement of either the electric or magnetic field is sufficient
to estimate the other quantities (AGNIR, 2012). At these frequencies,
energy is deposited and can cause heating (cf. microwaves). Heating
of tissue is the established mechanism of interaction with the human
body at these frequencies, and current exposure guidelines protect
against excessive heating of tissue, at both localized and whole body
exposures (ICNIRP, 1998; IEEE, 2005). The energy absorption inside
the body is estimated as the specific absorption rate (SAR), expressed
in watts per kilogram (W/​kg). It is, however, not possible to directly
measure tissue heating inside the body; therefore SAR values are esti-
mated through measurements in phantoms and theoretical modeling
(AGNIR, 2012; IARC, 2013). Use of a mobile phone is an example of
localized near-​field exposure, and energy is absorbed to a depth of a
few centimeters within the head.
Potential Mechanisms of Carcinogenicity
Despite considerable research efforts, there is currently no known bio-
logical mechanism for a carcinogenic effect of electromagnetic fields
at the exposure levels encountered in the general population or in
occupational settings. In vitro studies of ELF fields indicate genotoxic
effects at exposure levels of 100 µT or higher, which is far above what
is encountered in the human environment for longer than short dura-
tions, while in vivo studies do not provide evidence that ELF fields
cause tumors or enhance tumor growth (SCENIHR, 2015). It is impor-
tant to note, however, that an appropriate animal model for childhood
leukemia has not previously been available, and the recent develop-
ment of such a model (Hauer et al., 2014; Martin-​Lorenzo et al., 2015)
has not yet provided new evidence.
For RF fields, studies in cells do not consistently show effects on
genotoxicity, cell transformation, or cell proliferation, and occasional
positive findings have not been replicated in independent studies.
Similarly, studies in experimental animals have not shown compelling
evidence of a carcinogenic effect, including several long-​term rodent
bioassays, studies in transgenic animals, and studies of co-​carcino-
genic effects (AGNIR, 2012; SCENIHR, 2015). Independent studies
attempting to replicate a few positive findings for RF field exposure,
such as an increased lymphoma incidence in the transgenic Eμ-​Pim1
mouse model (Repacholi et al., 1997), have not been able to confirm
the original findings. One exception is a recent replication of an earlier
pilot study of a co-​carcinogenic effect of RF fields in mice exposed in
utero to ethylnitrosourea (ENU) (Tillmann et al., 2010). The replica-
tion study found an increased occurrence of tumors in mice exposed in
utero to ENU, and to one of four RF exposure levels (sham, 0.04, 0.4,
or 2 W/​kg), but no evidence of dose–​response pattern (Lerchl et al.,
2015). Tumor types with increased occurrence in the replication study
were lung, liver, and lymphoma, while the original study found an
increase in lung tumors. Discovery of a Helicobacter hepaticus infec-
tion among the mice made results for liver tumors uninterpretable
(Tillmann et al., 2010). None of the studies found increases in brain
tumors. Replication of these findings is warranted.
The largest and most comprehensive animal study within this area is
in the process of being published, and was conducted by US National
Toxicology Program (National Toxicology Program, 2014). Selected
results have just been made available as a partial report, reporting
increased occurrence of two tumor types in male rats (mainly schwan-
nomas of the heart and, somewhat weaker, gliomas in the brain), at
exposures of 1.5, 3, and 6 W/​kg compared to non-​exposed sham con-
trols. The partial report indicates that no positive findings were seen
259
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260 PART III:  THE CAUSES OF CANCER
Power lines and
electric appliances
10 103
0 100 104
Low frequency
Non-ionizing radiation Cellular Telephones
Figure 15–1.  The electromagnetic spectrum.
for female rats, or male and female mice, or for any other tumor type in
any kind of animal. In addition, survival was significantly lower in the
sham exposed rats, and tumor occurrence was lower than observed his-
torically in sham exposed rats. While a full assessment of the implica-
tions from this major study has to await the publication of the complete
set of results, the already shared findings may renew interest in look-
ing into mechanistic pathways. Given the inconsistency across animal
sexes and species, the high exposure levels and duration compared to
common exposures in humans, the main finding in a rare cancer type,
and the lower survival in sham exposed controls, limits the applicabil-
ity of the findings to what this means for real life exposures in humans.
The available epidemiological evidence on potential cancer risks
associated with exposure to ELF and RF fields, respectively, is sum-
marized in the two following sections.
EXTREMELY LOW FREQUENCY MAGNETIC
AND ELECTRIC FIELDS
First, notably, it must be stressed that there is no “zero” exposure to
ELF magnetic fields; due to the electrification of the modern world,
everyone is exposed to ELF fields to various extents, with typical daily
average background levels of less than 0.05 µT but possibly slightly
higher in urban areas. Sources of exposures to ELF magnetic fields
above background levels can be roughly subdivided into three types.
Exposures exceeding 0.2 µT are related to either the transmission or
distribution of power (fields from high-​voltage power lines, lower-​
voltage distribution lines, underground cables, transformers, indoor
wiring) (type 1:  residential exposures), the use of electrical devices
(such as hair dryer, vacuum cleaner) (type 2:  exposure from use of
electrical appliances), or working in electrical occupations (such as
electricians, welders) (type 3:  occupational exposures). Magnetic
fields are produced by the flow of the current; thus exposure is deter-
mined by the current and distance to the source. Electric devices may
emit magnetic fields of several mT in their immediate vicinity, but
only during use; therefore they are sources of high but intermittent
very short-​term exposure. In certain occupations, when working close
to electric motors, for example, average exposures of 1–​10 µT are pos-
sible, and exposure may span over the whole working day. Residential
exposures are usually at background level, but if elevated, then they
result in rather continuous exposure. Magnetic fields of > 0.2 µT to
a few µT may be reached within distances of less than 50–​200 m to
nearby high-​voltage power lines (> 200 kV, depending on their power
load), distances of less than 20–​50 m to medium-​voltage power lines
or other installations (> 10 kV), less than 5–​10 m to low-​voltage power
lines, their roof connections to buildings, or to transformers (< 1 kV),
or in homes with unbalanced currents in indoor wiring or by current
produced by ELF fields on closed metallic loops. Even taken together,
however, these exposure situations are rather uncommon. It is esti-
mated that only a few percent (1%–​3%) of residences in Europe and
potentially slightly more (1%–​10%) in North America have average
Visible
light
AM TV
radio FM radio Radar Infrared UV-light Gamma rays
X-rays
105 107 109 1011 1013 1015 1017 1019 1021
Hz
106 108 1010 1012 1014 1016 1018 1020 1022
Radio waves Micro waves
Ionizing radiation
(900–2100 Mhz)
residential exposures exceeding 0.2 µT (Maslanyj et al., 2009), and the
exposure prevalence of averages > 0.5 µT is below 1%.
ELF electric fields are produced wherever there is electric potential,
and they are directly related to the voltage, irrespective of whether any
current flows. Hence, high exposures are experienced mainly in occu-
pational settings or in the vicinity of high-​voltage installations, such
as overhead power lines or substations. In contrast to magnetic fields,
which are not perturbed by most materials (and especially not by tis-
sue and therefore penetrating the body), electric fields are shielded
by most materials. This is why it is extremely difficult to measure or
predict electric field exposures. Distance to the source alone is not a
good surrogate measure, as other buildings or trees may be between
the source and the home and may distort the electric field. Normally,
electric field levels in homes are a few V/​m, but can become as high
as several kV/​m in homes in close vicinity and with an unobstructed
path to high-​voltage power lines and in certain occupational situations.
Most epidemiological studies have investigated magnetic field
exposures, and here either residential or occupational exposures. After
approximately 40 years of epidemiological research on cancer effects
of ELF electric and magnetic field exposures, most notable evidence is
an association between residential ELF magnetic fields and a modestly
increased risk of leukemia in children (about 1.5-​to 2-​fold), observed
in a large number of studies with some degree of consistency. For other
exposure and cancer outcome combinations, there are either fewer
studies, rather exploratory studies, or the studies are inconsistent or
mostly showing no association. Therefore the remainder of this section
provides a detailed review of the childhood leukemia evidence and
only brief summaries of the other evidence.
Exposure Assessment
Exposure assessment of ELF magnetic fields is challenging. Various
methods have been used to assess residential exposures. Residential
exposures are used as surrogates of the individual’s exposure, assum-
ing that total exposure is mostly determined by exposure at home. This
has shown to be reliable in especially young children given how much
time they spend at home, but may lead to some exposure misclassi-
fication in adults due to exposures and time spent at the workplace
and elsewhere (Forssen et  al., 2002). Personal monitors, carried by
the individual, which constantly record magnetic field levels and pro-
vide the most accurate estimate of contemporary exposure, do exist.
However, studies of residential exposures are almost exclusively case-​
control studies requiring an accurate estimate of past exposures. This
is better achieved by residential measurements, as exposure tends to
be more stable over time in cases of elevated field levels, while per-
sonal monitoring is more influenced by personal behavior. A person’s
behavior is likely to change over time, especially when having a cancer
diagnosis, but also by the aging of the subject, so that contemporary
exposure is not a good predictor of past exposures. Exposure assess-
ment methods and their features are summarized in Table 15–1.
 261
Electromagnetic Fields 261
Table 15–1.  Main Exposure Assessment Methods Used in Epidemiological Studies of Residential Exposures to Extremely Low-​Frequency Magnetic Fields
Method Description
Personal dosimetry Device carried by study participant over 1 or several
days, recording the magnetic field level several times
per minute
Long-​term stationary Device placed in study participant’s home over 1 or
measurement several days, recording the magnetic field level
several times per minute; either used stationary in
the bedroom or at several places in the home for
calculation of time-​weighted average according
to how much time the participant spends at each
measurement location
Spot measurements As above, but measurements taken only for usually
several minutes up to a few hours, at several locations
within the home but sometimes only outside the
residence
Calculated fields Estimation of magnetic field levels from overhead
high-​voltage power lines based on distance from line
to home, historic power load of the line, and other line
characteristics
Wire code Estimation of magnetic field levels from overhead power Can be used for retrospective assessment; surveys show some variability on
lines and other electrical installations similar to the
preceding method, but rather based on characteristics
of the source and no data on power load
Distance to power line Measuring or estimating the distance between the home Weakest surrogate of magnetic field exposure; works well in very close
and nearby overhead high-​voltage power lines or other
electrical installations
Exposure assessment methods for occupational settings range from
categorizations of job titles, to expert ratings of job-​related tasks (Hug
et al., 2010), to the development of more complex quantitative job-​expo-
sure matrices (JEMs) based on measurement surveys (Bowman et al.,
2007). While the latter is believed to be the most reliable approach,
exposure misclassification remains a problem, due to the large exposure
variation within jobs and the usually relatively small number of available
measurements per job category (Gobba et al., 2011; Greenland et al.,
2016). Exposure from electrical appliances is usually assessed through
interviews, with self-​reported type and frequency of use of devices, and
distance to the source (e.g., for television), and exposure estimates are
therefore prone to both random and systematic error. Electric field expo-
sures are even more difficult to estimate. Similar approaches to those
used with magnetic fields were used in occupational studies, especially
using job categorizations by experts. Measurements of residential expo-
sures as reported in a few studies (e.g., McBride et al., 1999) must be
interpreted with care, as it is questionable how well they predict past
exposures. In the example of Canadian children, most time-​weighted
average exposures to electric fields were below 20 V/​m (McBride et al.,
1999), although in some instances they exceeded 50 V/​m.
Childhood Cancer
Childhood Leukemia
ELF magnetic fields have been studied as a potential risk factor for
childhood leukemia since the late 1970s, when Wertheimer and Leeper
published a case-​control study from Denver, Colorado, observing a
three-​fold increased risk for children living in houses assigned to the
highest exposure category using the wire code exposure assessment
method, a crude categorization of exposure based on proximity of
the residence to certain electrical installations, such as power lines of
Advantages/​Disadvantages
Most precise picture of magnetic field exposure of the individual, especially
when combined with activity diary; rarely used in cancer epidemiology, as
too expensive for large cohorts and limited use in case-​control studies, as
activity patterns change when having cancer and by the aging of subjects
(especially in children) so that contemporary exposure is not a good
predictor of past exposures.
Most precise picture of magnetic field exposure in the home environment;
surveys show good correlation in repeated measurements so that method
appears to be a good surrogate of exposure in retrospective studies; good
exposure surrogate in children spending most of their time at home; in
adults, time spent at other places or occupational exposures may influence
the individual exposure more than the home measurement.
May be as accurate as longer term measurements with stable magnetic
field conditions, but much lesser so when fields vary strongly over time;
especially outdoor measurements have shown rather poor correlation in
repeated measurements.
Accurate retrospective estimation of long-​term magnetic field exposure in
the home environment caused by high-​voltage power lines; neglects other
sources of magnetic field exposures in the home environment and when
not at home; can only be estimated when the respective historic power load
data are available, which is often not the case (used almost exclusively in
the Nordic countries and the UK).
how well the method predicts actual magnetic field exposures in the home
environment depending on the local conditions, which makes it difficult to
judge how well the method worked in the individual studies; neglects other
sources of magnetic field exposures in the home environment and when not
at home; mostly used in North America.
proximity (50 m) to the power lines in countries where power lines are
usually run with high power load, but leads to gross misclassification of
exposure in the home environment otherwise; may also be surrogate for
other living conditions and therefore raises issue of confounding.
different voltages (Wertheimer and Leeper, 1979). At present, more
than 30 epidemiological studies have investigated this topic. Most of
these were conducted in the late 1980s to early 2000s, and used vari-
able sample sizes and design features. As the studies differ greatly in
exposure assessment, exposure indices, and exposure categorizations,
as well as analytical strategies, direct comparison is difficult and may
even be misleading.
Therefore, the most informative evidence comes from systematic
reviews or meta-​ analyses. Authoritative hazard identifications or
health risk assessments were prepared by the International Agency
for Research on Cancer (IARC) program on the evaluation of car-
cinogenic risks to humans, the World Health Organization (WHO)
Environmental Health Criteria, and the evaluation of the European
Commission’s Scientific Committee on Emerging and Newly Identified
Health Risks (SCENIHR). In 2001, the IARC classified ELF magnetic
fields as possibly carcinogenic to humans, based on limited evidence
from human (epidemiological) studies and inadequate evidence from
studies in experimental animals, including studies published before
2001 (IARC, 2002). WHO confirmed the IARC assessment, stating
that evidence from the more recent studies does not alter the classifica-
tion as possible carcinogen (WHO, 2007). SCENIHR also confirmed
that the evidence of possible carcinogenicity remains unchanged, most
recently in their update in 2015 (SCENIHR, 2015).
What was considered the strongest evidence in all risk assess-
ments stems from the pooled analyses of the original studies, which
allowed to some extent the harmonization of the different study
features and was therefore more informative than a comparison of
the individual studies. Greenland et al. pooled most of the available
studies at the time (Greenland et al., 2000), irrespective of exposure
assessment method, which is why they had to combine various expo-
sure indices into a single metric. The combined relative risk estimate
was 1.7 (95% confidence interval [CI] 1.2–​2.3) in children exposed
26

262 PART III:  THE CAUSES OF CANCER

Table 15–2.  Pooled Analyses of Epidemiological Studies on Residential Exposure to Extremely Low Frequency Magnetic Fields and the Risk
of Childhood Leukemia

Ahlbom et al., 2000 Kheifets et al., 2010a Greenland et al., 2000 Schüz et al., 2007

Study base 9 studies (Canada, Denmark, 6 studies (Brazil, Germany, Japan, 12 studies; 8 as in Ahlbom et al. 4 studies (Canada, Germany,
Finland, Germany, New Italy (2), UK); not included in (except UK), 4 additional ones UK, US); all included in
Zealand, Norway, Sweden, Ahlbom et al./​Greenland et al. (2nd from Sweden, other UK, Ahlbom et al. or Kheifets et al.
UK, US) except partly the German study 2nd and 3rd from US) (Germany)
Inclusion Population-​based case-​control As Ahlbom et al., 2000 Inclusive; no restriction but Exposure during the night had
criteria of studies; exposure either delivery of original data to be extractable from the
studies assessed through long-​term exposure measurement
stationary measurements or
calculated fields
Exposure Long-​term stationary As Ahlbom et al., 2000 Measurements (personal, long-​term Long-​term stationary
assessment measurements or calculated or spot), calculated fields measurement
fields
Exposure Average magnetic field level, As Ahlbom et al., 2000 Average magnetic field level, Average exposure during
indices in µT in µT, albeit from different nighttime (10 pm–​6 am), in µT
measurement methods
Numbers of 3247 cases, 10,400 controls 10,818 cases, 12,806 controls 2656 cases, 7084 controls 1842 cases, 3099 controls
subjects
Main result Reference < 0.1 µT Reference ≤ 0.1 µT Reference ≤ 0.1 µT Reference < 0.1 µT
0.1–​< 0.2: OR 1.08, > 0.1–​≤ 0.2: OR 1.07, > 0.1–​≤ 0.2: OR 1.01, 0.1–​< 0.2: OR 1.11,
CI 0.89–​1.31 CI 0.81–​1.41 CI 0.84–​1.21 CI 0.91–​1.36
0.2–​< 0.4: OR 1.11, >0.2–​≤ 0.3: OR 1.16, >0.2–​≤ 0.3: OR 1.06, 0.2–​< 0.4: OR 1.37,
CI 0.84–​1.47 CI 0.69–​1.93 CI 0.78–​1.44 CI 0.99–​1.90
≥ 0.4: OR 2.00, CI 1.27–​3.13 > 0.3: OR 1.44, CI 0.88–​2.36 > 0.3: OR 1.68, CI 1.23–​2.31 ≥ 0.4: OR 1.93, CI 1.11–​3.35
Further results Increase of 15% per 0.2 µT (CI Using ≥ 0.4 µT as highest category Included pooling of 8 studies having Virtually no difference between
4–​27%); small heterogeneity gives OR of 1.46 (CI 0.80–​2.68); wire code data (all from Canada, ORs for nighttime exposure
across studies, although most large overall numbers come from Mexico, or US), with an OR of only and whole-​day exposure;
of the excess cases came from UK study (9665 cases, 9677 1.65 (CI 1.15–​2.35) for highest linear increase in risk with
US study controls), but only few are exposed exposure category, but some increasing exposure
> 0.3 µT (2 cases, 2 controls) heterogeneity across studies

Abbreviations: OR (odds ratio), CI (95% confidence interval), µT (micro-​Tesla).

to average magnetic fields > 0.3 µT compared with those exposed
≤ 0.1 µT. Ahlbom et al. pooled studies that fulfilled certain criteria,
such as a defined population base for case ascertainment and control
recruitment, as well as having used longer term measurements or
calculated fields for exposure (Ahlbom et al., 2000); the main find-
ing was a relative risk estimate of 2.0 (CI 1.3–​3.1) for exposures
≥ 0.4 µT compared with exposures < 0.1 µT. While the studies dem-
onstrated a high degree of consistency, a major contribution to the
overall excess risk came from a large US study (Linet et al., 1997),
and no association was seen in a large study in the United Kingdom
(UKCCS, 1999). Despite the large number of studies, the numbers
of exposed children were too small to reliably predict the shape of
a dose–​response function. Hence, trends are compatible with mon-
otonic increases, thresholds at 0.3/​0.4 µT, plateauing at higher mag-
netic field levels, as well as no significant increase at all. Kheifets
and colleagues (2010a) used the approach of Ahlbom et al. (2000) to
update the evidence, pooling only the more recent studies, and over-
all confirming the modest association (though somewhat weaker than
in the earlier studies). In another pooled analysis of four studies, the
focus was exposure during the night, driven by hypotheses that there
may be less exposure misclassification as the measurement better
captures the time when the child is really at home or that nighttime
exposure may be of more biological relevance. The result was that
using nighttime exposure did not yield relative risk estimates differ-
ent from the results when using whole-​day exposure (Schüz et  al.,
2007). Summaries of these four influential pooled analyses are pro-
vided in Table 15–2 and Figure 15–2.
In summary, based on a large number of studies, a modest asso-
ciation (1.5-​to 2-​fold) between residential ELF magnetic fields and
childhood leukemia was observed, with—​especially when account-
ing for differences in study design features—​a quite high degree
of consistency across studies carried out in different parts of the
world, at different times, and by different investigators. On the other
hand, despite the large number of studies, the number of exposed
children remained small; for instance, combining the pooled data
sets utilized by Greenland et al. (2000) and Kheifets et al. (2010a),
only 125 of 13,474 leukemia cases (0.9%) had exposures > 0.3 µT.
While the consistency of studies and indication of a dose–​response
trend may favor a causal interpretation, chance and bias cannot be
ruled out with reasonable confidence as alternative explanations, so
that together with the lack of supportive experimental evidence and
plausible mechanistic hypotheses, the overall evidence was classi-
fied as possibly carcinogenic (IARC, 2002; SCENIHR, 2015). With
respect to confounding, no candidate exposure has been identified
yet (Schüz, 2007); traffic density, use of pesticides in the vicinity
of power lines, and environmental tobacco smoke are among those
that were considered. Because of the low prevalence of elevated
magnetic field exposure, the confounding factor would have to be
a strong risk factor itself and, at the same time, be strongly corre-
lated with magnetic field strengths from all sources. Hence, while
confounding by an unknown factor is always a possibility, it seems
to be an unlikely explanation. With regard to exposure assessment
methods, there is potential for exposure misclassification. However,
as it is unlikely that the magnitude of misclassification from most
of the exposure assessment methods was associated with disease
status, the expected bias would rather be in the direction of dilut-
ing an association (Schüz, 2007). With regard to selection bias, the
low participation rates in many studies were of concern, especially
in those studies using measurements. Data suggested that families
with a lower socioeconomic status were particularly under-​repre-
sented among controls, resulting in an underestimation of exposure
prevalence in controls (Schüz, 2007). The studies using calculated
magnetic fields were not affected by selection bias (Feychting
et al., 1995; Tynes and Haldorsen, 1997; Verkasalo et al., 1993), as
no contact with the families was necessary. While they also show
an association, this is based on much smaller numbers of exposed
 263
Electromagnetic Fields 263
Childhood Leukemia Childhood Leukemia Childhood Brain Tumors
studies before 2000 studies after 2000
(Ahlbom et al., 2000) (Kheifets et al., 2010a) (Kheifets et al., 2010b)
10 10 10
1 1 1
0.1 0.1 0.1
By exposure categories of < 0.1 µT, 0.1–0.2 µT, 0.2–0.4 µT, and ≥ 0.4 µT
children (Ahlbom et  al., 2000; Kheifets et  al., 2010a). Taking all
these considerations into account, selection bias alone is perhaps
not sufficient to explain the entire association, but a combination of
selection bias, confounding, and chance cannot be ruled out as an
alternative explanation for the observed association.
Recently, it was suggested that if ELF magnetic fields would
increase the risk of developing leukemia, they may also increase the
risk of a relapse after initial treatment, leading to a lower survival in
exposed leukemia patients (Foliart et al., 2006). Pooling six studies
totaling 3073 children with acute lymphoblastic leukemia, however,
did not show any association between ELF magnetic field exposure
and overall or event-​free survival from leukemia (Schüz et al., 2012).
Some studies also investigated paternal exposure to ELF magnetic
fields and the risk of childhood leukemia in their offspring, hypothe-
sizing a genetic alteration of the sperm. Meta-​analysis of those studies
showed a combined relative risk estimate of 1.35 (CI 0.95–​1.91), but
at the same time there was some evidence of publication bias (Hug
et al., 2010). Less data are available for maternal exposures, mainly
because occupational exposure is much less common than in fathers.
Other Childhood Cancers
There are much fewer studies on other childhood cancers, includ-
ing lymphoma, perhaps because those cancers are less frequent in
children than leukemia. The only exception is tumors of the central
nervous system (CNS)/​brain. Thirteen studies were combined in a
literature-​based meta-​analysis, separately analyzing studies based on
distance, wire codes, calculated fields, and measurements. For the
latter, four studies were available and showed a combined relative
risk estimate of 1.14 (CI 0.65–​2.00) for exposures ≥ 0.2 µT compared
to < 0.2 µT (Mezei et al., 2008). A recent pooling study having access
to original data of 10 studies (in Denmark, Finland, Germany, Japan,
Norway, Sweden, UK [2]‌, US [2]) showed relative risk estimates of
0.95 (CI 0.65–​1.41), 0.70 (0.40–​1.22), and 1.14 (CI 0.61–​2.13) for
ELF magnetic field exposures of 0.1–​< 0.2 µT, 0.2–​< 0.4 µT, and
≥ 0.4 µT, compared to < 0.1 µT (Kheifets et al., 2010b; Figure 15–2).
Taken as a whole, those results were interpreted as providing little
evidence for an association between residential ELF magnetic field
exposure and childhood brain tumors, suggesting that the observed
association with an increased risk may be specific to childhood
leukemia.
Cancer in Adults
Studies on EMF exposures and cancer risk in adults included residential
and more often occupational studies. Especially the latter often did not
All studies
Figure  15–2. Pooled analyses of epidemiological studies
on residential extremely low frequency magnetic fields and
the risk of childhood leukemia (studies published before and
after 2000) and the risk of brain tumors; pooled relative risk
estimates for three exposure categories compared to the refer-
ence category of average magnetic fields < 0.1 µT.
distinguish between electric and magnetic field exposures. Most studies
investigated the risks of leukemia, brain tumors, or breast cancer.
In 2008, Kheifets et al. published a meta-​analysis of studies of occu-
pational EMF, including 47 studies of brain cancer and 56 of leuke-
mia (Kheifets et al., 2008). For brain cancer, the pooled relative risk
estimate was 1.14 (CI 1.07–​1.22), and for all leukemia it was 1.16
(CI 1.11–​1.22). There was little variation by diagnostic subtypes, and
the associations seen in the more recent studies were slightly weaker
than in those from the more distant past. Although similarly small
elevations in risk were seen for both outcomes, the apparent lack of
a clear pattern of exposure and risk detracts from a causal interpre-
tation. Studies were of varying quality, especially when it comes to
exposure assessment; however, restricting the meta-​analysis to only
studies that were considered of better design quality by the authors
of the meta-​analyses did not show substantially different results. In
a recent multicenter case-​control study in seven countries (InterOcc
study) involving 1939 cases of glioma, 1822 cases of meningioma,
and 5404 controls, in which a JEM based on workplace EMF surveys
was applied (Bowman et al., 2007), no association was seen overall
between the ELF magnetic field estimate and brain tumor risk (for
cumulative exposure in µT-​years in the highest exposure category, the
odds ratios were 0.80 [CI 0.63–​1.00] for glioma and 0.89 [CI 0.70–​
1.12] for meningioma [Turner et  al.,  2014]). In analyses looking at
different time windows of exposure, there was an increased risk of
glioma with a dose–​response trend for exposures 1–​4  years before
diagnosis, while there was no association in both the 5–​9 years before
diagnosis or 10+ years before diagnosis time windows; this may sug-
gest a role of EMF in tumor promotion, but too little data are available
yet to draw firm conclusions.
Residential exposures were also investigated in some studies, but
mainly based on distance to nearby high-​voltage power lines, which
for adults may introduce substantial exposure misclassification. In a
large UK record-​linkage-​based case-​control study using distance to
power lines as well as calculated fields as exposure metrics, cases of
leukemia or of brain cancer did not have increased risks compared to
cancers not assumed to be related to EMF exposures (used as con-
trols) (Elliott et al., 2013). With the potential to calculate historic expo-
sures from power load of power lines (see Table 15–1), studies from
the Nordic countries are particularly informative. No increased risks
of either brain tumors or leukemias have been observed in Finland
(Verkasalo et al., 1996). In Norway, leukemias showed little evidence
of an association (Tynes and Haldorsen, 2003), and for brain tumors
the overall risk was 1.6 (CI 0.9–​2.7), but there was an inverse associa-
tion with occupational exposures (Klaeboe et al., 2005). In Sweden,
risks were slightly elevated for two subtypes of leukemia but not others
and not for brain tumors (Feychting and Ahlbom, 1994).
264
264 PART III:  THE CAUSES OF CANCER
It has also been hypothesized that exposure to ELF magnetic fields
may increase the risk of female breast cancer, assuming that the ELF
magnetic fields would affect nocturnal melatonin production (as light
at night does) and that melatonin is protective against breast cancer
(Stevens, 1987), mainly by acting as potent antioxidant (Reiter, 1995).
Several studies addressed the question, looking at occupational expo-
sures, residential exposures, and use of electric bed heating as expo-
sure sources, reviewed in 2006 (Feychting and Forssen, 2006). While
some early smaller studies were inconsistent but showed some positive
associations, the more recent studies reported were mostly negative. In
a meta-​analysis of almost 25,000 cases and > 60,000 controls from 15
studies published between 2000 and 2009, there was no evidence of an
association with a combined relative risk estimate of 0.99 (CI 0.90–​
1.09) (Chen et al., 2010). Combining results from 23 studies published
from 1990 to 2010, however, showed an overall combined relative risk
estimate of 1.07 (CI 1.02–​1.13), with the association restricted to pre-​
menopausal breast cancer (Chen et al., 2013). New studies continue to
appear, such as another well-​conducted occupational study in textile
workers in China (Li et al., 2013) showing no increased risk, suggest-
ing the accumulation of evidence against an association.
Several of the studies were addressing various cancer types as out-
come, but overall much fewer studies are available for other cancers
in adults than the ones mentioned earlier. For none of the cancers did
any consistent picture emerge (SCENIHR, 2015). Among the most
recent cohort studies, no increased risk was seen for leukemia, brain
cancer, and breast cancer in Danish electric utility workers (Johansen
et al., 2007). In the prospective Netherlands cohort study, among pre-​
selected cancers (namely lung, breast, and brain cancer), as well as
hematological malignancies, no increases were seen for lung, breast,
and brain cancer, but among hematological malignancies there was an
increased risk of acute myeloid leukemia with ever higher exposures
and an increased risk of follicular lymphoma with both ever and cumu-
lative exposures (Koeman et al., 2014).
Future Research Needs
Whether the observed association between residential ELF magnetic
fields and childhood leukemia is causal remains an open question that
merits further research. Given the consistency of results from epidemi-
ological studies, combined with their difficulty of further reducing the
potential of bias and confounding to a level that would address the con-
cerns of having created a spurious association, it is unlikely that further
case-​control studies of similar design would provide any new insights.
Promising advancements were recently made in experimental set-
tings with the development of a mouse model that better mimics leu-
kemia development in children (Hauer et  al., 2014; Martin-​Lorenzo
et al., 2015); application of this model is underway. If the results are
positive, this may provide insights into mechanisms, perhaps suggest-
ing the existence of particularly susceptible children, which could in
turn be addressed by epidemiology. If the results are negative, it adds to
the evidence that the epidemiological studies may show a non-​causal
association and will be a general warning of how cautious the inter-
pretation of epidemiological studies investigating the combination of
rare exposures and rare diseases must be. If the association was causal,
due to the rarity of relevant exposure levels, the preventive potential
is limited; only a small proportion of childhood leukemias would be
attributable to ELF magnetic field exposure, recently estimated to be
< 1%–​2% in European countries (Grellier et al., 2014) and possibly
slightly higher in North America (Greenland and Kheifets, 2006).
For adults, any future studies should be based on better expo-
sure measures, alongside testable plausible mechanistic hypotheses.
Further studies linking job titles or other EMF surrogates with can-
cer outcomes will not provide additional insight. “Better” exposure
measures need to be validated with respective measurements and
comprehensive analyses of their direction and magnitude of potential
exposure misclassification. “Testable” hypotheses should be described
by plausible or novel scenarios. Candidates not sufficiently addressed
are co-​exposures of EMF with known carcinogens (such as chemi-
cals or ionizing radiation). Like for childhood leukemia, if there were
consistent associations observed in experimental animals, future epi-
demiological studies may be better guided by addressing a particular
mechanistic scenario.
RADIOFREQUENCY FIELDS
Exposure Sources
Currently, the most prevalent sources of radiofrequency (RF) field
exposure in the general population are related to wireless communica-
tion, and can be grouped into personal (near-​field) and environmen-
tal (far-​field) exposures. The so-​called bag-​phones and car phones
that were introduced in the early 1980s had the antenna far from the
human body, giving rise to far-​field exposure; handheld mobile phones
with the antenna in the handset became available in the late 1980s,
resulting in near-​field localized exposure to the head. The RF expo-
sure decreases rapidly with distance to the exposure source; thus use
of a wired hands-​free device reduces the RF exposure to the head by
approximately 90%. The first handheld mobile phones used the ana-
logue system, which had maximum average radiated powers typi-
cally at 0.6 W (IARC, 2013). In the early 1990s, digital phones were
introduced, which have lower radiated power (maximum average at
0.1–​0.25 W). Development of the technologies for more efficient uti-
lization of the cellular networks has resulted in even lower exposure
levels during actual use through the introduction of adaptive power
control (APC), by which mobile phones reduce their output power to
the level sufficient to maintain a good quality contact with the base
station, and discontinuous transmission (DTX), which means that the
mobile phone transmits only when the user is talking. Through this,
average RF field levels from mobile phones have decreased consider-
ably (AGNIR, 2012). The third generation of mobile phones has the
same maximum average output level as the second generation, but
the actual output power in real use is about 10 times lower than that
of second-​generation mobile phones when in use. Another source of
near-​field exposure is cordless phones used within homes, with DECT
phones being the most successful technology (i.e., wireless handsets
connected to the landline phone through a DECT base station in the
home). As the DECT phone only transmits to a base station that is a
few meters away, exposure is considerably lower, with average pow-
ers 10 or more times smaller than those from mobile phones at their
highest power level.
Sources of environmental, or far-​field, exposure include, for exam-
ple, mobile phone base stations and radio and television transmitters,
DECT phone base stations, and wireless local area networks (Wi-​Fi),
which give rise to exposures that are only a fraction of the exposure
guidelines and less than 1% of the exposure to the head from a hand-
held mobile phone (AGNIR, 2012). Similarly, devices such as baby
monitors and smart meters used to measure electricity consump-
tion also generate very low RF fields. These technologies have also
changed over time; for example, analog television has been replaced
by digital television broadcasting, which in most cases has resulted in
decreased total output power (AGNIR, 2012).
Occupational settings may be associated with higher exposures than
are found in the general population. Workers in occupations involving
the use of dielectric heaters or induction heaters (e.g., PVC welders)
are among the highest exposed group. Other examples are operators of
surgical and other medical diathermy devices or magnetic resonance
imaging (MRI), workers near radar equipment, or those involved in
the maintenance of transmitters such as base stations and radio and
television towers (AGNIR, 2012). Applications with sometimes inten-
tionally relatively high exposures to the general public are anti-​theft
devices, such as those used in retail stores, but the time that humans
stay in the close vicinity of those sources is usually very short.
Mobile Phone Use
During the last 15 years, studies of RF exposure associated with wire-
less communication have focused on mobile phone use, which is the
source that gives the highest localized RF exposure. Consequently,
 265
Electromagnetic Fields 265
the main studied outcomes have been tumors in the head and neck
region, as they are located in the areas of the body where most of the
energy is absorbed during a mobile phone call (i.e. glioma, meningi-
oma, and acoustic neuroma). Systematic reviews of the scientific evi-
dence have continuously been conducted by international and national
bodies such as the SCENIHR, IARC, and the Independent Advisory
Group on Non-​ionizing Radiation (AGNIR) of Public Health England
(AGNIR, 2012; IARC, 2013; SCENIHR, 2009, 2015). The WHO is
currently working on an update of the Environmental Health Criteria
document on RF fields. All reviews identify considerable method-
ological limitations and inconsistencies in the available epidemio-
logical studies, which prevent firm conclusions. In 2011, the IARC
classified RF fields as possibly carcinogenic to humans, based on
limited evidence in humans from epidemiological case-​control stud-
ies of mobile phone use and limited evidence from animal studies
(IARC, 2013). AGNIR, however, concluded in 2012 that the “accu-
mulating evidence on cancer risks … is increasingly in the direction
of no material effect of exposure” (AGNIR, 2012), also based on the
epidemiological studies of mobile phone use, combined with infor-
mation from incidence trend studies. Based on even more recent data,
the SCENIHR review concludes that the evidence for an effect on
glioma has become weaker since the IARC evaluation (SCENIHR,
2015). It was noted in all those assessments that conclusions could
not be drawn about longer latencies than up to 15  years since first
mobile phone use.
Methodological Limitations
Most of the available studies are case-​control studies with retrospec-
tive assessment of mobile phone use history through structured per-
sonal interviews or self-​administered questionnaires. This method has
the advantage that detailed information can be collected, such as the
preferred ear when using the phone and use of hands-​free devices,
but it is prone to exposure misclassification, both non-​differential and
differential, where the former would more likely lead to a dilution of
an effect should there be a true association, and the latter would more
likely lead to reports of overestimated or even spurious effects. The
early studies of mobile phone use and cancer risk were conducted at
a time period when use of handheld mobile phones was uncommon
in the general population, and the technology had only been available
for a few years. Thus, these studies could only inform about effects
after short exposure duration, which are not expected for the type of
outcomes studied. This review focuses on studies that include induc-
tion periods of at least 5  years for glioma and meningioma, and at
least 10 years for acoustic neuroma. The changes over time of mobile
phone technologies, the considerably reduced costs associated with
buying and using the devices, and the development of new applica-
tions (e.g., the introduction of smartphones) have all led to a sub-
stantial increase in mobile phone use over time; at the same time,
as illustrated earlier, the output power of the devices has decreased
substantially with each new technology. This combination is a consid-
erable challenge for the retrospective assessment of mobile phone use
histories in case-​control studies. Furthermore, studies of brain tumors
are faced with the additional complication that the tumor itself may
affect memory function.
Validation studies conducted as part of the Interphone study, a large
international collaborative study including 16 study centers (Cardis
et  al., 2007), have shown considerable exposure misclassification
when healthy volunteers were asked to report their amount of mobile
phone use 6 months earlier (Vrijheid et al., 2006). Moreover, it was
found that cases tended to overestimate their mobile phone use to
a greater extent the further back in time they were reporting about
(Vrijheid et al., 2009a), which was not observed among controls (the
study covered recall approximately 4 years back in time). A study of
self-​reported year when first starting to use a mobile phone also found
considerable misclassification (Pettersson et al., 2015), which was also
found in responses to a seemingly simple question like preferred side
of the head during mobile phone use (Kiyohara et al., 2015). The few
cohort studies available have either collected exposure information
from subscriber registers, or prospectively collected questionnaires.
When collected prospectively, as in the UK Million Women study
(Benson et al., 2013), questionnaire information will not be affected by
recall bias, but non-​differential exposure misclassification may be sub-
stantial because of the difficulty in reporting accurately about mobile
phone use among healthy volunteers as well, as described previously.
Information obtained from mobile phone operators, if unequivocally
linked to a specific person, will reduce non-​differential exposure mis-
classification considerably. A  Danish cohort study identified mobile
phone users through the subscription registers held by mobile phone
operators during a period when mobile phone use was still uncom-
mon in the general population (Frei et al., 2011; Johansen et al., 2001;
McCarthy et al., 2011; Schüz et al., 2006b). With this approach, non-​
differential exposure misclassification could be limited, but no infor-
mation was available about the amount of mobile phone use. Thus,
the study would not be able to detect an increased risk in a small sub-
group of heavy users. Currently, one cohort study with more elabo-
rated exposure information from mobile phone operators is underway
(Schüz et al., 2011a).
Selection bias may also occur in case-​control studies caused by
non-​participation related to the exposure. Investigation of non-​
response in the Interphone study showed that mobile phone users
among both cases and controls were more likely to participate than
subjects who did not use a mobile phone (Vrijheid et al., 2009b). As
non-​response was more common among controls than cases, selec-
tion bias was introduced, leading to a reduction of the risk estimates
by approximately 10% for ever regular use of a mobile phone. The
cohort studies have used population-​based cancer registers for case
identification, and follow-​up could be made independently of study
participants (Benson et  al., 2013; Frei et  al., 2011; Johansen et  al.,
2001; Schüz et al., 2006b).
Mobile Phone Use Results
There are now many publications on mobile phone use and brain
tumors (e.g., AGNIR, 2012; Ahlbom et  al., 2009; SCENIHR, 2015;
Swerdlow et al., 2011). Several studies are published in multiple pub-
lications, and have also been included in pooled analyses. Most of the
studies have focused on glioma and acoustic neuroma, and somewhat
fewer on meningioma. In most studies, the main analyses were of
exposure, defined as time since first mobile phone use. Table 15–3
includes the original publication of studies with longer induction peri-
ods, and displays results for glioma and acoustic neuroma. Amount of
use in cumulative hours or cumulative number of calls were analyzed
in several of the studies.
Time Since First Mobile Phone Use.  For glioma, most of the
epidemiological evidence does not indicate an increased risk associated
with time since first mobile phone use, regardless of how long a time
the phone had been used. None of the cohort studies with prospective
information on mobile phone use found indications of an increased
glioma risk, examining exposure durations of more than 13 years since
first mobile phone subscription in the Danish study (Frei et al., 2011)
and more than 10 years in the UK cohort (Benson et al., 2013, 2014).
Exceptions to this pattern are two case-​control studies conducted in
Sweden by Hardell and coworkers (Hardell et al., 2006, 2013), which
reported moderately increased risks of malignant brain tumors already
after a short period of mobile phone use, and substantially increased
risk estimates after longer exposure durations. The Interphone study,
on the other hand, reported risk estimates for glioma that were consist-
ently below unity, which could, at least partly, be explained by selec-
tion bias caused by non-​participation (Interphone Study Group, 2010;
Vrijheid et al., 2009b). For meningioma, one study reported a doubling
of the risk after more than 10 years of use of an analogue mobile phone
(Hardell et al., 2005), while most other studies reported risk estimates
close to or below unity (e.g., Interphone Study Group, 2010; Lahkola
et al., 2008). A recent French study reported a non-​significantly raised
risk of meningioma after 10 years of mobile phone use (Coureau et al.,
2014).
For acoustic neuroma, the pattern is very similar to the glioma find-
ings. The Hardell group reported considerably increased risks already
after less than 5 years of mobile phone use (Hardell et al., 2002, 2005),
while other studies found no association between acoustic neuroma
26

Table 15–3.  Epidemiological Studies of Mobile Phone Use and Risk of Malignant Brain Tumors and Acoustic Neuroma That Present Results for at
Least 10 Years Since First Start of Mobile Phone Usea

Location, Time Relative Risk/​SIR

Reference Period, Design Source Outcome Exposure (95% CI)

Schüz et al., 2006 Denmark 420,095 mobile phone Brain and nervous Time since first subscription
1982–​2002 subscribers; the whole system < 1 year 0.90 (0.67–​1.18)
Cohort study Danish population 1–​4 years 1.03 (0.91–​1.17)
5–​9 years 0.96 (0.84–​1.09)
≥ 10 years 0.66 (0.44–​0.95)
Frei et al., 2011 Denmark 358,403 mobile phone Glioma Men
1990–​2007 subscribers; subset Time since first subscription
Cohort study of previous study 1–​4 years 1.20 (0.96–​1.50)
with information on 5–​9 years 1.05 (0.87–​1.26)
socioeconomic status ≥ 10 years 1.04 (0.85–​1.26)
10–​12 years 1.06 (0.85–​1.34)
≥ 13 years 0.98 (0.70–​1.36)

Women
Time since first subscription 0.87 (0.43–​1.75)
1–​4 years 1.02 (0.60–​1.72)
5–​9 years 1.04 (0.56–​1.95)
≥ 10 years
Schüz et al., 2011b Denmark 2,883,665 Danes Acoustic neuroma Mobile phone subscription
1998–​2006 included in the ≥ 11 years
Cohort study CANULI cohort Men
No 1.0
Yes 0.87 (0.52–​1.46)
Women
No No exposed case, 1.6
Yes expected
Benson et al., 2013, UK 791,710 women Glioma Duration of use
2014 1999–​2005—​followed participating in 875 cases < 5 years 0.96 (0.75–​1.23)
through 2011 the UK Million 5–​9 years 0.86 (0.72–​1.02)
Cohort study Women Study, who ≥ 10 years 0.77 (0.62–​0.96)
answered a base-​ Acoustic neuroma Duration of use
line questionnaire 126 cases < 5 years 0.94 (0.53–​1.66)
1999–​2005 5–​9 years 1.46 (0.94–​2.27)
≥ 10 years 1.17 (0.60–​2.27)
Hardell et al., 2002a, Sweden Population-​based Malignant brain Mobile phone use, analog
2002b 1997–​2000 tumors > 1–​6 years 1.09 (0.68–​1.75)
Case-​control study 588 cases > 6 years 1.17 (0.75–​1.81)
Acoustic neuroma Mobile phone use, analog
159 cases > 1–​5 years 3.0 (1.0–​9.3)
> 5–​10 years 3.8 (1.4–​10.2)
> 10 years 3.5 (0.7–​16.8)
Hardell et al., 2005, Sweden Population-​based Malignant brain Mobile phone use, analog
2006 2000–​2003 tumors > 1–​5 years –​
Case-​control study 359 cases > 5–​10 years 1.8 (0.9–​3.5)
> 10 years 3.5 (2.0–​6.4)
Mobile phone use, digital
> 1–​5 years 1.6 (1.1–​2.4)
> 5–​10 years 2.2 (1.4–​3.4)
> 10 years 3.6 (1.7–​7.5)
Acoustic neuroma Mobile phone use, analog
84 cases > 1–​5 years 9.9 (1.4–​69)
> 5–​10 years 5.1 (1.9–​14)
> 10 years 2.6 (0.9–​8.0)
Mobile phone use, digital
> 1–​5 years 1.7 (0.9–​3.5)
> 5–​10 years 2.7 (1.3–​5.7)
> 10 years 0.8 (0.1–​6.7)
 267

Electromagnetic Fields 267
Table 15–3. Continued

Location, Time Relative Risk/​SIR

Reference Period, Design Source Outcome Exposure (95% CI)

Hardell et al., 2013 Sweden Population-​based Malignant brain tumors Mobile phone use, analog
2007–​2009 593 cases > 1–​5 years –​
Case-​control study > 5–​10 years 0.6 (0.1–​3.1)
> 10–​15 years 1.4 (0.7–​3.0)
> 15–​20 years 1.4 (0.7–​2.7)
> 20–​25 years 2.1 (1.1–​4.0)
> 25 years 3.3 (1.6–​6.9)
Mobile phone use, digital
> 1–​5 years 1.8 (1.01–​3.4)
> 5–​10 years 1.6 (0.97–​2.7)
> 10–​15 years 1.3 (0.8–​2.2)
> 15–​20 years 2.1 (1.2–​3.6)
> 20–​25 years –​
> 25 years –​
Interphone Study Group, Interphone Population-​based Glioma Time since first regular use
2010, 2011 13 countries 2708 cases 1–​1.9 years 0.62 (0.46–​0.81)
2000–​2004 2–​4 years 0.84 (0.70–​1.00)
Case-​control study 5–​9 years 0.81 (0.60–​0.97)
≥ 10 years 0.98 (0.76–​1.26)
Acoustic neuroma Time since first regular use
1105 cases 1–​1.9 0.73 (0.49–​1.09)
2–​4 years 0.87 (0.69–​1.10)
5–​9 years 0.90 (0.69–​1.16)
≥ 10 years 0.76 (0.52–​1.11)
Lahkola et al., 2007; Nordic-​UK Interphone Population-​based Glioma Time since first regular use
Schoemaker centers, broader 1496 cases 1.5–​4 years 0.77 (0.65–​0.92)
et al., 2005 age range 5–​9 years 0.75 (0.62–​0.90)
(Partly overlapping with 2000–​2004 ≥ 10 years 0.95 (0.74–​1.23)
the Interphone study) Case-​control study Acoustic neuroma Time since first regular use
676 cases 1.5–​4 years 0.8 (0.7–​1.0)
5–​9 years 0.9 (0.7–​1.2)
≥ 10 years 1.0 (0.7–​1.5)
Han et al., 2012 Pittsburg, US Hospital based Acoustic neuroma Years of mobile phone use
1997–​2007 343 cases < 10 years 0.79 (0.45–​1.37)
Case-​control study ≥ 10 years 1.29 (0.69–​2.43)
Coureau et al., 2014 France Population-​based Glioma Time since first regular use
2004–​2006 190 cases 1–​4 years 1.04 (0.64–​1.69)
Case-​control study 5–​9 years 1.45 (0.91–​2.33)
≥ 10 years 1.45 (0.68–​3.08)
Pettersson et al., 2014 Sweden Population based Acoustic neuroma Time since first regular use
2002–​2007 451 cases 1–​4 years 1.04 (0.72–​1.52)
Case-​control study 5–​9 years 1.40 (0.98–​2.00)
10–​12 years 1.10 (0.68–​1.76)
≥ 13 years 1.12 (0.72–​1.73)

a
Studies with only short-​term mobile phone use are not included in the table (in total 7 studies, published in multiple papers).

risk and time since starting mobile phone use, not even after more than
13 years of mobile phone use (Pettersson et al., 2014).
Most studies did not take cordless phone use into consideration in
the exposure assessment, which could potentially cause non-​differen-
tial exposure misclassification. Hardell et al. report increased risks of
brain tumors associated with cordless phone use in the same order of
magnitude as for mobile phone use (Hardell et al., 2006, 2013). No
associations were observed with cordless phone use in two national
Interphone studies (Lonn et al., 2005; Schüz et al., 2006a). In addi-
tion, when Hardell and colleagues included cordless phone users in
the unexposed category to mimic the analyses in the Interphone study,
the results were virtually unchanged (Hardell et al., 2011). Thus, cord-
less phone use does not appear to explain the differences in results
between the studies by Hardell and colleagues and other studies.
The few reported risk increases appear implausible for several rea-
sons. First, glioma incidence time trends have been stable since the
introduction of mobile phone technologies, as shown in incidence
studies from many parts of the world (Barchana et al., 2012; de Vocht
et  al., 2011; Deltour et  al., 2012; Dobes et  al., 2011; Kohler et  al.,
2011; Little et al., 2012); this was particularly so for middle-​aged and
younger persons, which are the more relevant age groups in relation
to mobile phone use, while an incidence increase in the elderly, which
was observed to start even before the introduction of mobile phone
technologies, is believed to be due to improved and more readily
available diagnostic imaging techniques (especially MRI). Simulation
studies have demonstrated that risk increases after short duration of
mobile phone use are incompatible with the observed incidence trends
(Deltour et  al., 2012; Little et  al., 2012). More details are provided
later in this chapter (section on “Incidence Studies”). Second, recall
bias is indicated by the findings of the strongest effects among per-
sons reporting to have started mobile phone use at least 25 years prior
to diagnosis when handheld mobile phones had only been available
in Sweden 23 years or less at the end of the data collection (Hardell
et al., 2013).
268
268 PART III:  THE CAUSES OF CANCER
Also for acoustic neuroma, incidence time trends do not support
an effect of mobile phone use (Benson et al., 2013; Larjavaara et al.,
2011a), although fewer data are available. Acoustic neuroma is a slow-​
growing tumor, and one would not expect an effect on the tumor occur-
rence after a short latency period. It is likely that most of the acoustic
neuroma tumors diagnosed within 5 years after first mobile phone use
were already present when the person started to use a mobile phone
(Thomsen and Tos, 1990).
Amount of  Mobile Phone Use. If high intensity of
mobile phone use is required for effects on tumor development,
results based on time since first mobile phone use would be less
informative, and estimates of amount of use would be needed.
Available studies with analyses of amount of mobile phone use
have used different exposure cutoff points, most often based on
the exposure distribution among controls. In the Interphone study,
cumulative hours of mobile phone use were categorized with cut-
off points approximately at the deciles of hours of use among
controls. As shown in Figure 15–3, no trends of increasing risk
with increasing amount of use were observed for glioma, acous-
tic neuroma, or meningioma (Interphone Study Group, 2010;
2011). In the highest category of cumulative hours (> 1640 h),
a slight risk increase was observed for all three outcomes, 1.40
for glioma, 1.15 for meningioma, and 1.32 for acoustic neuroma
(although not statistically significant for the latter two). It is note-
worthy that the risk estimates in the 9th decile (735–​1639 h) were
among the lowest observed: 0.71 for glioma, 0.76 for meningioma,
and 0.48 for acoustic neuroma. With a 5-​year latency period for
acoustic neuroma, the risk estimate in the 10th decile was statisti-
cally significant, but the risk estimate in the 9th decile was still the
lowest of all categories. For glioma and meningioma, the highest
risk increase associated with heavy mobile phone use was observed
within 1–​4 years after starting to use a mobile phone, for acoustic
neuroma among long-​term users. No associations were observed
with cumulative number of calls.
In the first two studies by the Hardell group (Hardell et al., 1999,
2002), no consistent associations between cumulative hours of
mobile phone use and brain tumor risk were found, but the last
two studies observed considerable risk increases, also after hav-
ing accumulated relatively few hours; for example, > 80 hours of
analog phone use were associated with a four-​fold risk increase
of malignant brain tumor, and > 64 hours of digital phone use
with a two-​fold risk increase. Associations were also observed
for meningioma and acoustic neuroma. Several other studies
have analyzed higher amounts of use than these, for example two
early studies from the United States (around 500 h as the high-
est cutoff point; Inskip et  al., 2010; Muscat et  al., 2000), and
national Interphone studies (> 500 h; Lahkola et  al., 2007, 2008;
Lonn et  al., 2005; Schoemaker et  al., 2005). None of these stud-
ies found increased risks at such low cumulative levels of use. In
the most recent study by the Hardell group (Carlberg et al., 2013;
Hardell et al., 2013), four categories of cumulative hours of phone
use were analyzed, and risk estimates for malignant brain tumors
were raised in all four categories, but in some categories of bord-
erline statistical significance. In the highest exposure category
(> 2376 h), an almost eight-​fold risk increase was observed for
analog and a three-​fold risk increase for digital phone use. Also for
meningioma, considerable risk increases were found in the high-
est category of analog and digital mobile phone use, respectively,
while acoustic neuroma was not analyzed separately in this study.
A recent French case-​control study also reported raised risk esti-
mates at considerably fewer hours of mobile phone use than the
Interphone study (Coureau et  al., 2014). The odds ratio for glioma
after 339–​895 hours of phone use was 1.78 (95% CI 0.98–​3.24, and
after at least 896 hours it was 2.89 (95% CI 1.41–​5.93). For menin-
gioma, an increased risk was observed only in the highest exposure
category, with an odds ratio of 2.57 (95% CI 1.02–​6.44).
Only one cohort study with prospectively collected information
on amount of mobile phone use is currently available (Benson et al.,
2013, 2014). The highest exposure category was “daily use,” and the
risk estimates for daily users did not differ from the overall results of
no associations.
The very high risk increases at quite low amounts of mobile phone
use reported in the studies by Hardell et al. are implausible in the
light of the stable incidence time trends. The findings in the French
case-​control study would also have resulted in increased incidence
trends (Deltour et al., 2012). The results of the Interphone study are
difficult to interpret, considering the lack of a dose–​response pat-
tern. For acoustic neuroma, there were indications of a downward
trend until the 10th percentile. The cases included in the Interphone
study were diagnosed in the early 2000s, at which time approxi-
mately 10% of the controls had cumulated at least 1640 hours of
mobile phone use. Now, about 15 years later, a considerably larger
proportion of the population in many countries would have accu-
mulated this amount of use and more, but so far, no corresponding
increase in the brain tumor incidence has been observed. In addi-
tion, implausibly high cumulative hours of phone use were more fre-
quent among cases than controls in the Interphone study (Interphone
Study Group, 2010). As mentioned earlier, the results from the vali-
dation study provide empirical evidence that recall bias is likely to
have affected the findings (Vrijheid et al., 2009a), but the question is
whether it can explain the small risk increase in heavy users entirely.
The cohort study with prospectively collected exposure informa-
tion, unaffected by recall bias, did not support the hypothesis of an
increased tumor risk with more frequent mobile phone use, but the
highest exposure category was limited to “daily use” (Benson et al.,
2013, 2014).
Laterality of  Phone Use and Tumor Localization.  RF
exposure to the head is highly localized during mobile phone use,
and reaches only a few centimeters deep into the brain. Therefore, if
the exposure is causally related to brain tumor risk, one would expect
to find an increased risk on the same side of the head as the phone
was usually held, and a risk close to unity on the opposite side. Self-​
reported laterality of mobile phone use is, however, highly uncertain
(Kiyohara et  al., 2015). Information about laterality of phone use
has so far only been collected retrospectively in case-​control studies,
and there is a possibility that cases are affected by their knowledge
about the side of the tumor location when reporting the preferred side
used during mobile phone calls prior to diagnosis, and they might
tend to more often report ipsilateral use (Schüz, 2009). Controls will
of course report independently of the fictive “tumor” side assigned
to them by the researchers, as they do not even know which side of
their head is the one relevant in the analysis. Results in the case-​
control studies indicate that recall bias may indeed be a problem, as
several studies found an increased risk of brain tumors on the same
side of the head as the phone was reported to be held, and at the
same time a reduced risk on the opposite side and/​or among subjects
for whom laterality data were missing (Ahlbom et al., 2009; Schüz,
2009; Swerdlow et  al., 2011). Overall, there are strong indications
that recall bias may have affected results where laterality was taken
into consideration.
Another way to take the localized exposure into consideration is
to conduct separate analyses of tumors localized in different lobes of
the brain. The temporal lobe absorbs the highest energy during mobile
phone calls, but studies have often grouped the different areas of the
brain differently, which hampers comparability. Most studies did not
find higher risk estimates for glioma located in the temporal lobe than
in other locations. One exception is the Interphone combined analysis,
where the glioma risk was slightly higher in the temporal lobe among
long-​term users and in the highest category of cumulative hours of use,
but not overall (Interphone Study Group, 2010). For meningioma, the
overall analysis found a lower risk estimate for tumors in the tempo-
ral lobe than in other locations. The four studies conducted by Hardell
and colleagues grouped tumor locations differently in all studies, and
small numbers probably prevented analyses of temporal lobe tumors
separately in the two first studies. The fourth study reported somewhat
stronger risk estimates for temporal lobe locations combined with over-
lapping lobes (Hardell et al., 2013). The recent French study reported
risk estimates in the same order of magnitude for glioma with temporal
 269

Electromagnetic Fields 269
Glioma
hours cases controls RR (95% CI)

–4 141 197 0.70 (0.52, 0.94)

5–12 145 198 0.71 (0.53, 0.94)

13–30 189 179 1.05 (0.79, 1.38)

31–60 144 196 0.74 (0.55, 0.98)

61–114 171 193 0.81 (0.61, 1.08)

115–199 160 194 0.73 (0.54, 0.98)

200–359 158 194 0.76 (0.57, 1.01)

360–734 189 205 0.82 (0.62, 1.08)

735–1639 159 184 0.71 (0.53, 0.96)

1640+ 210 154 1.40 (1.03, 1.89)

.5 .7 .8 1 1.5 2

Acoustic neuroma
hours cases controls RR (95% CI)

–4 58 144 0.77 (0.52, 1.15)

5–12 63 129 0.80 (0.54, 1.18)

13–30 80 136 1.04 (0.71, 1.52)

31–60 66 131 0.95 (0.63, 1.42)

61–114 74 137 0.96 (0.66, 1.41)

115–199 68 128 0.96 (0.65, 1.42)

200–359 50 144 0.60 (0.39, 0.91)

360–734 58 126 0.72 (0.48, 1.09)

735–1639 49 126 0.48 (0.30, 0.78)

1640+ 77 107 1.32 (0.88, 1.97) Figure 15–3.  Results from the Interphone
study for cumulative hours of mobile
phone use, categorized in deciles. The
reference category is non-​regular mobile
.5 .7 .8 1 1.5 2 phone use.

lobe location as for “other locations,” while risk estimates for frontal
lobe tumors were lower (Coureau et al., 2014). Taken together, the evi-
dence does not consistently suggest stronger associations with tumors
in the temporal lobe.
Two studies have further developed analyses of tumor localization
beyond lobe of the brain by using information about the exact local-
ization of the tumor based on radiological images (Cardis et al., 2011;
Larjavaara et al., 2011b). The study by Larjavaara and colleagues used
a case-​case design based on the assumption that gliomas in mobile
phone users on average are located closer to the exposure source (i.e.,
where the mobile phone handset is held) than tumors in cases who
were not regular mobile phone users. This type of design eliminates
potential selection bias caused by non-​participation among controls,
and if the preferred side for phone use is not included, it may also
reduce the effect of recall bias. Analyses were based on 873 glioma
cases, and no major difference in distance between the tumor location
and a hypothetical mobile phone was found between cases who were
regular mobile phone users and those who were non-​users; if anything,
the distance was somewhat shorter for non-​users.
The other study estimated the total RF dose at the tumor location
or a corresponding location for the controls (Cardis et  al., 2011).
The total RF dose was estimated based on retrospective self-​reported
information on cumulative hours of mobile phone use, preferred side
of the head, frequency band, communication system, and network
characteristics. Self-​reported cumulative hours of use and tumor loca-
tion were the only significant predictors of RF dose (43% and 13%
of the variation, respectively). Complete information for estimation
of RF dose were available for a subset of the subjects, and results for
glioma were almost identical in this subset when based simply on self-​
reported cumulative hours of use as when the more elaborated expo-
sure estimate was used, contrary to what would have been expected if
there were a causal association between RF dose and glioma risk. The
study design did not attempt to reduce recall bias, and the addition of
more technical details about the mobile communication system did not
seem to reduce non-​differential exposure misclassification. The inves-
tigators also made a case-​case analysis, similar to the analysis in the
Larjavaara study, but based on somewhat fewer cases (N = 556). They
found that > 10 years since first mobile phone use were associated with
270
270 PART III:  THE CAUSES OF CANCER
an increased risk of glioma in the brain region with the highest expo-
sure, but they also found a reduced risk for those with 5–​9 years since
first mobile phone use, and no consistent dose–​response pattern with
cumulative call time.
Children.  Currently there is only one study available on mobile
phone use and brain tumor risk in children and adolescents in the age
range 7–​19  years (Aydin et  al., 2011). It used a case-​control design
with exposure information collected through interviews with the
parents and children. Information from mobile phone operators was
available for a small subgroup of participants who were able to report
their children’s current and previous mobile phone numbers. Overall,
a risk estimate close to unity was observed, and risk did not increase
with amount of use or by location of the tumor. Having had a mobile
phone subscription > 2.8 years prior to diagnosis was associated with
an increased brain tumor risk, but these results were based on only
about one-​third of the data. Furthermore, this finding was not compat-
ible with the stable incidence trends observed. Thus, the study does not
support the hypothesis of an increased risk of brain tumors, but it also
does not provide strong evidence against a risk increase.
Other Tumors.  For other tumor types (e.g., parotid gland tumors,
ocular melanoma, pituitary tumors, leukemia, lymphoma, and tes-
ticular cancer), the available data are fewer than for brain tumors.
Currently, no consistent evidence suggests that mobile phone use
is associated with an increased risk of these tumors (AGNIR, 2012;
Ahlbom et al., 2009; SCENIHR, 2015).
Incidence Studies
Normally, incidence time trend studies would not be regarded as
informative for inferences about etiology because exposure informa-
tion at the individual level is not available, and there is no information
about potential confounding factors. In addition, changes in clinical
practices and new diagnostic procedures may affect incidence time
trends without any real change in disease occurrence (as it does
indeed for brain tumors, with the detection of smaller tumors follow-
ing the introduction of computed tomography and later MRI) (Fisher
et al., 2007; Helseth, 1995). Nevertheless, the situation with mobile
phone use and brain tumor risk is somewhat different. Brain tumors
are not related to lifestyle factors like smoking or alcohol consump-
tion; the only established environmental risk factor is ionizing radia-
tion, which explains only a small fraction of the occurrence. During
the last decades there has been a rapid increase in the prevalence of
mobile phone use in the general population in many countries, from a
few percent at the end of the 1980s to near 100% in some age groups
by the middle of the first decade of the 2000s. If RF exposure from
mobile phone use increases the risk of brain tumors, one would expect
to see an increasing brain tumor incidence in many countries, in the
age groups that first adopted mobile phone technologies, unless the
latency period is longer than the present risk time, or the risk increase
is restricted to a small subgroup of the population. As mentioned
earlier, brain tumor incidence studies have been published in many
countries, including the Nordic countries, the United Kingdom, the
United States, and Australia (Ahlbom and Feychting, 2011; de Vocht
et  al., 2011; Deltour et  al., 2009, 2012; Dobes et  al., 2011; Kohler
et al., 2011; Little et al., 2012). They have all reported on malignant
brain tumors or gliomas specifically. The time periods included differ
between the incidence studies, but the majority cover the incidence
until 2007 or 2008, and one covers the period until 2009. All stud-
ies report stable incidence trends in age groups where mobile phone
use has become prevalent, with no indications of increasing incidence
after the introduction of mobile phones. In the oldest age groups,
however, where mobile phone use has not been prevalent, an increas-
ing brain tumor trend can be observed, which started before the intro-
duction of mobile phones (Deltour et al., 2009; Dobes et al., 2011).
Two studies used simulations to predict the shape of the glioma inci-
dence trend over time under assumptions of different risk scenarios
related to mobile phone use (Deltour et al., 2012; Little et al., 2012).
The aim was consistency checks, that is, to investigate whether the
risk of malignant brain tumors reported in some of the case-​control
studies would have been detected in incidence time trends. Both stud-
ies concluded that strong risk increases, such as reported in the studies
by Hardell et al., would have been detected in incidence time trends.
The Nordic incidence time trend study also had statistical power to
detect smaller risk increases and would most likely also have detected
an increased risk after 1640 cumulated hours of mobile phone use
(Deltour et  al., 2012), which was the risk increase observed in the
Interphone study. No such incidence increase was observed.
Several studies reported brain tumor incidence time trends for chil-
dren and adolescents separately (Aydin et  al., 2011; de Vocht et  al.,
2011; Dobes et al., 2011; Inskip et al., 2010; McKean-​Cowdin et al.,
2013). None of these studies found increases in the brain tumor inci-
dence after the introduction of mobile phones.
A few incidence studies of acoustic neuroma and parotid gland
tumors have also been published (Benson et al., 2013; de Vocht, 2011;
Larjavaara et al., 2011a; Shu et al., 2012; Stangerup et al., 2010). None
of them reports changes in incidence trends that could be linked to the
introduction of handheld mobile phones.
Environmental Exposure
Studies of cancer risk associated with RF exposure from environmen-
tal sources have usually focused on radio and television transmitters
or mobile phone base stations. Several studies were conducted as a
result of public concern, and used an ecological design with expo-
sure simply measured as distance to the nearest transmitter. These
studies are not included in this review, as distance alone is too crude
to measure RF exposure accurately. Two studies have assessed RF
exposure from radio and television transmitters on an individual level,
using elaborated modeling with detailed information about important
exposure determinants, such as frequency, field strength, and other
relevant information (Bethke et al., 2008; Ha et al., 2007; Merzenich
et al., 2008; Schüz et al., 2008), and one study focused on exposure
from mobile phone base stations, also with elaborated modeling to
assess exposure (Elliott et al., 2010). None of the studies found any
indications of increased risk for any types of tumors among children
in relation to environmental RF exposure from transmitters. Taken
together, the evidence does not suggest that environmental RF expo-
sure from transmitters affects cancer risk, but few data are currently
available.
There are currently no epidemiological studies available on poten-
tial effects on cancer risk from exposures emanating from sources
such as Wi-​Fi, smart meters, and other low-​level RF-​emitting devices.
Although these exposure sources are now ubiquitous in society, the
level of exposure to individuals from these devices is very low, far
below current exposure guidelines (AGNIR, 2012; Tell et al., 2013),
and considerably lower than the exposure during a mobile phone call,
for example.
Occupational Exposure
Epidemiological research on occupational exposure to RF fields has
not evolved in the same way as for ELF fields. Accurate assessment
of occupational RF exposure remains a key concern in these studies,
as they have usually been limited to job title alone, with no actual
knowledge about the exposure levels for the workers in the particu-
lar occupations, to expert assessment, for example by occupational
hygienists when no objective measurements were available, or by
restricting the exposed group to specific areas, such as militaries in the
navy. Exposure assessment has not been conducted on an individual
level, and information on potential confounding factors is lacking.
Many exposed occupations are also exposed to low frequency fields,
such as radio and television repairmen and radio and telegraph opera-
tors. Most occupational studies focused on the risk of cancer overall,
and leukemia and brain tumors (AGNIR, 2012; Ahlbom et al., 2004).
No consistently increased risks were reported, but findings were often
based on small numbers, and exposure misclassification is likely to
be considerable. A  few risk increases were observed, generally in
studies with severe methodological shortcomings. The largest studies
 271
Electromagnetic Fields 271
with the most sophisticated exposure assessment provide little support
for an association (Groves et al., 2002; Morgan et al., 2000). Groves
et al. reported higher leukemia mortality among groups with the high-
est potential for radar exposure, with a risk estimate of 1.48 (95%
CI 1.01–​2.17), but also a reduced brain cancer mortality in the same
group, with a risk estimate of 0.65 (95% CI 0.43–​1.01). Morgan and
colleagues reported risk estimates below unity for both leukemia and
nervous system tumors, but results were based on small numbers of
exposed cases (Morgan et al., 2000). Overall, the data do not suggest
an increased cancer risk associated with occupational RF exposure,
but the evidence is not sufficient to exclude the possibility of a risk
increase.
CONCLUSIONS
Overall, the epidemiological evidence does not suggest that exposure
to RF fields increases cancer risk, taking into consideration the meth-
odological limitations in the case-​control studies of mobile phone use
and brain tumor risk, lack of associations in the cohort studies, and
the stable brain tumor incidence time trends in the age groups that
have been frequent mobile phone users for a long time. Some uncer-
tainty remains regarding the heaviest mobile phone users, although
the proportion of the population that has reached the highest cumula-
tive hours of mobile phone use investigated thus far is likely to be
substantial by now. Mobile phone use during the more recent years
is, however, likely to be associated with considerably lower average
RF exposure levels, as the third-​generation mobile phone technology
has become more widespread. Experimental studies, including ani-
mal studies with long-​term exposure, have not found consistent evi-
dence of a carcinogenic effect (AGNIR, 2012), and despite the large
amount of research performed, a plausible biological mechanism has
still not been suggested. Thus, the mounting evidence speaks increas-
ingly against a carcinogenic effect of exposure to low-​level radiofre-
quency electromagnetic fields. However, neither cohort, case-​control,
nor incidence time trend studies performed to date would be able to
detect a risk increase after an induction period exceeding 20  years,
and limited data are available on potential effects in children.
FUTURE RESEARCH NEEDS
Although brain tumor incidence time trends have remained stable
since the introduction of mobile phones, and recall and selection bias
in available case-​control studies are likely explanations for observed
risk increases after moderate and short-​term mobile phone use, the
uncertainty regarding the most intensive mobile phone use and the
widespread use of mobile phones throughout society and in all age
groups, with an increasing amount of time spent using the technology,
make further research warranted.
A continued monitoring of brain tumor incidence time trends in
various age groups is recommended, provided that well-​established
high-​quality cancer registries are available. Further case-​control
studies with retrospective self-​reported exposure information are
unlikely to add useful knowledge. Highly recommended are stud-
ies that use a cohort design with prospectively collected exposure
information, preferably from independent sources such as mobile
phone operator registers, combined with prospective questionnaire
information that covers important aspects that may modify expo-
sure levels, such as use of hands-​free devices, preferred side of the
head, and DECT phones and other wireless technologies. Access
is also needed to population-​based sources for complete follow-​up
of cancer occurrence, and studies must cover long enough expo-
sure durations and be of sufficient size to provide statistically sta-
ble risk estimates. Such an approach would address the sources of
bias identified in currently available epidemiological studies. Focus
on mobile phone use is warranted, as it is still the main source of
RF exposure in the general population, while exposure levels from
mobile phone base stations, smart meters, and other far-​field sources
are considerably lower.
Few data are available on mobile phone use and cancer risk in chil-
dren, and although the single available case-​control study of brain
tumors in children and adolescents did not indicate an increased risk,
and brain tumor incidence time trends in this age group have been sta-
ble during the last decades, further studies focused on children are rec-
ommended. These must, however, be able to overcome potential bias
from differential recall and selection bias. Prospective cohort studies
would overcome these limitations and could also enable follow-​up into
adult life. To address cancer risk in children, adolescents, and young
adults, however, these cohorts need to be extremely large because of
the rarity of the diseases, which is an obstacle for the feasibility of
such studies. Exposure assessment among children poses additional
challenges, as they do not have mobile phone subscriptions in their
own name, and may more often share a mobile phone. In addition,
exposure patterns have changed considerably with the introduction of
smartphones, which are more frequently used for texting and surfing
than making phone calls.
Studies of occupational RF exposure would allow investigation of
higher levels of exposure, but to be informative, exposure assessment
needs to be improved considerably, to be on an individual level, and to
be properly validated. In addition, information on potential confound-
ing factors must be collected. An obstacle is that exposed occupational
groups are small in numbers, and to achieve sufficient statistical power
international collaboration is necessary.
Numerous studies of genotoxic or carcinogenic effects of RF fields
in experimental animals have been conducted, but have not shown
consistent effects at exposure levels below guideline levels. Studies of
RF fields as a co-​carcinogen have been mostly negative, or have had
methodological limitations. The recent finding of increases in tumors
of the lung and liver, and lymphoma in ENU-​treated mice exposed to
RF fields, but with no dose response, warrants replication.
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Electromagnetic Fields 273
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16 Occupational Cancer
KYLE STEENLAND, SHELIA HOAR ZAHM, AND A. BLAIR
OVERVIEW
Occupational cancer was one of the earliest areas of cancer research,
as astute clinicians observed clusters of cancer in workers exposed to
high levels of workplace toxins. These early observations were fol-
lowed by some of the earliest epidemiologic cohort studies, beginning
after World War II, which followed the leads from the early clusters.
Many of today’s recognized carcinogens were discovered via occu-
pational studies, including classic carcinogens such as asbestos and
arsenic, as well as more recently established carcinogens, such as
silica and diesel fumes. The earlier discoveries were characterized by
high exposures and high risks; later discoveries of agents with lower
exposure and lower risks have required a multiplicity of large studies
to establish causality, and to provide sufficient data for risk assessment
to be performed by regulatory agencies. It is likely that this pattern
will continue, with cancer risks from more difficult to characterize
exposures like shift work, currently considered a probable but not defi-
nite carcinogen, requiring a large body of evidence before acceptance.
Most occupational exposures recognized in the past were of a chemi-
cal or particle nature. A more expansive view of occupational expo-
sures today should consider a broader range of infectious, medical,
behavioral, and physical factors that might impact cancer, such as shift
work, sedentary behavior, or workplace stress.
Occupational carcinogen discovery has always been controversial
because such findings have economic as well as public health impli-
cations. Consequently, decision-​making and action may involve more
political activity than findings in other epidemiologic areas. The exam-
ple of diesel exhaust, recently declared a definite carcinogen by the
International Agency for Research on Cancer (IARC) after 25 years of
controversy, is a good example (see later discussion in this chapter).
In this chapter we summarize the past history of occupational can-
cer epidemiology, and indicate which occupational exposures are pres-
ently considered to be definite or probable carcinogens. We describe
the basic study designs of occupational cancer research, which are
similar to the designs of non-​occupational studies, but which have
their own peculiarities, particularly in regard to exposure assessment.
We discuss the type of evidence that has stimulated occupational can-
cer studies and how data generated by occupational cancer studies are
used in risk assessment for workplace regulations, and the calculation
of attributable fractions to quantify the burden of occupational cancer.
Finally, we discuss some current controversies and propose likely
future directions for occupational epidemiology. These include a focus
on “exposures” like shift work and sedentary work habits, which are
not traditional toxins. In addition, it will be important to document the
carcinogenic effects of established occupational carcinogens in less
developed countries where they have not been studied, as a means to
affect policy and ensure safe workplaces.
INTRODUCTION
Studies of workplace exposures have provided a wealth of information
regarding the causes of cancer from early (Ramazzini, 1713) to recent
times (Siemiatycki, 2014). Approximately 40% of the factors classified
as sufficient, probable, or possible human carcinogens by the IARC
were initially investigated as occupational exposures (Siemiatycki
et al., 2004). There are many practical and disease prevention benefits
of studies of cancer in the workplace. Exposures in the workplace are
often considerably higher than those in the non-​occupational setting.
Occupational exposures can often be measured more precisely than
non-​occupational exposures because of the availability of production
records, personal and area measurements, and operating procedures,
which provide information that can be used to characterize exposures.
Occupational studies are needed to protect workers from workplace
hazards. Many workers have little flexibility regarding how tasks are
performed, equipment and ingredients used, and the location of work,
and thus have relatively little individual control over their personal
exposures. Occupational exposures are, therefore, largely involun-
tary. Although the excesses of cancer from occupational exposures
may occur in worker groups of relatively small size, the high level of
exposure can result in large relative risks. Because of this, over three
decades ago Doll and Peto (1981) noted that “detection of occupational
hazards should therefore have a higher priority in any program of can-
cer prevention than their proportional importance might suggest.” This
conclusion is still true today. It should be noted that many occupational
exposures also occur in non-​occupational settings and have adverse
impacts beyond the workplace (e.g., arsenic, diesel fumes, polychlo-
rinated biphenyls [PCBs], dioxins, polycyclic aromatic hydrocarbons,
and pesticides).
Despite the many established links between occupational expo-
sures and cancer, much remains unknown. A starting place for a list of
needed studies could be those occupational exposures already classified
as possible or probable human carcinogens by the IARC. These often
have limited or no epidemiologic information, but are already suspect,
and clarity is needed. The selection priority for the agents on this list
would depend upon factors such as number of workers exposed, typical
levels of exposure, likely magnitude of relative risk, opportunities for
high-​quality investigations, and the possibility of exposures outside the
workplace. In addition, there are many occupations or industries where
cancer excesses have been noted, but specific agents that might be
involved have not been clearly identified. Despite the obvious need for
additional investigations (Blair et al., 2011; Siemiatycki, 2014; Straif,
2012; Ward et al., 2010), the number of publications on cancer in the
workplace is decreasing and is now only about one-​third the number of
just a decade ago (Raj et al., 2014). Explanations for this decline are not
clear, but may include a change in the political/​social climate that no
longer supports this type of health research, a decrease in heavy indus-
try in high-​income countries, a weakening of labor unions which have
encouraged research, cycles of focus and popularity in public health
research, a belief that control of hazardous occupational exposures has
been accomplished because of previous successes, and the failure in
recent times to find occupational exposures with such dramatic impacts
on cancer as previously identified agents such as asbestos, benzidine,
vinyl chloride, benzene, and chromium (Blair et al., 2011; Raj et al.,
2014; Siemiatycki, 2014).
Most recognized occupational carcinogens have been identified
through studies of men in high-​income countries (Hohenadel et al.,
2015; Zahm et al., 1994, 1999). The inclusion of women in studies
of the workplace has increased since the early 1990s, but studies
of men still predominate and typically have more detailed analyses
on men than on women, possibly due to small numbers or a lower
priority placed on investigating risks among women (Hohenadel
et al., 2015). Furthermore, in the past few decades, low-​and mid-
dle-​income countries have assumed a larger and larger fraction of
275
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276 PART III:  THE CAUSES OF CANCER
the world’s production in many industries, but there does not yet
appear to have been a comparable increase in investigations of occu-
pational exposures in most low-​income countries (Raj et al., 2014).
Studies are particularly needed in low-​and middle-​income countries
because exposures may be less well controlled (Siemiatycki, 2014).
HISTORY
The era of modern occupational epidemiology, with systematic assem-
bling and follow-​up of occupational cohorts, did not begin until after
World War II. Most early identification of the occupational origin of
some cancers was done by astute clinicians seeing cancer in clear
excess (i.e., clusters) among workers who were exposed at the time.
Perhaps the earliest identification of occupational cancer was particu-
larly prescient. Bernardo Ramazzini, the father of occupational medi-
cine, noted in 1713 that nuns, who can be considered members of a
specific occupation, were more likely to have breast cancer than other
women. He speculated that this might be due to a lack of sexual activ-
ity (Olson, 2002). Today we know that Ramazzini was right about the
phenomenon but (partly) wrong about the cause, which we now attri-
bute to nulliparity and increased exposure of the breast to estrogen.
Ramazzini also described diseases among miners, painters, weavers,
and printers.
Another famous clinician who identified occupational cancer was
Percival Pott, who noted in 1775 that chimney sweepers in London had
an excess of scrotal cancer, which he attributed to soot accumulation in
the scrotum (Dobson, 1972; Pott, 1775; Waldron, 1983). Subsequently
there were other reports of scrotal cancer among other workers exposed
to soot, also known as coal tar. Coal tar can be considered the first rec-
ognized occupational carcinogen, for which workmen’s compensation
was given in England as of 1907 (Waldron, 1983). Another clinician
who identified an early occupational carcinogen was Ludwig Rehn,
who reported a cluster of bladder cancers among aniline dye workers
in 1895 (Dietrich and Dietrich, 2001). In the 1920s, mineral oil was
also recognized as a cause of scrotal cancer, and other skin cancers,
due to a cluster of cases among cotton spinners (Waldron, 1983).
Kuroda and Kawahata identified a cluster of lung cancer among
workers exposed to coal gas in steel mills in Japan in 1935 (Takahashi
and Ishii, 2013). In one of the earliest examples of calculation of stan-
dardized mortality ratios (SMRs) using death certificates and census
data by occupation, Kennaway and Kennaway (1936) showed that coal
gas workers in England had excess cancer of the lung (coal gas was
later replaced by coke in steel mills, which also caused lung cancer)
(Lloyd, 1971). Other notable clusters included bone and blood cancer
in radium dial painters, identified by Harrison Martland in New Jersey
in 1931 (Loutit, 1970), and lung cancer in nickel refinery workers in
Wales, identified by Bridge in 1933 (Bridge, 1933). There were also
several German case reports of lung cancer among chromate workers
in the 1930s (Hayes et al., 1988).
After World War II, occupational epidemiologists, primarily in
England, systematically began using retrospective cohort studies
based on industry records to study cancer mortality. Defining the
study population as all workers in a particular job or industry and
following them over time, instead of studying case series or clusters
among current workers only, allowed the inclusion of cancers occur-
ring after leaving work, and allowed statistical comparisons of cancer
rates in exposed workers versus low-​or non-​exposed referents. Most
of the previously observed clusters were confirmed in such studies,
including bladder cancer in dye workers (Case et al., 1954), arsenic
and lung/​skin cancer (Hill and Faning, 1948), chromates and lung
cancer (Machle and Gregorius, 1948), nickel refining and lung can-
cer (Doll, 1958), and coal gas and lung cancer (Doll, 1952). Radium
decays into radon gas, and after World War II investigators linked
radon in uranium miners to lung cancer (Wagoner et al., 1965). All
of these studies were retrospective cohort mortality studies, with two
exceptions. In the case of arsenic and nickel, investigators did not have
access to plant records, and instead conducted studies of proportional
mortality in the areas where the plants were located, compared with
other areas in England.
Asbestos had been known to cause asbestosis since before World
War II. There were case reports of lung cancer among asbestos work-
ers, and some published literature began to draw links between the
two before the war (Greenberg, 1999). However, the first solid epide-
miologic evidence came from the landmark cohort mortality study of
asbestos workers by Doll in 1955, which showed the lung cancer risk
among men employed for 20 or more years to be 10 times that of the
general population (Doll, 1955). The first strong epidemiologic evi-
dence for a link between asbestos and mesothelioma followed in 1960
among asbestos miners in South Africa (Wagner et al., 1960). Wagner
et al. (1960) described a case series of 33 cases living near or working
in crocidolite asbestos mines (i.e., a cluster). The fact that the tumor
was so rare and did not occur elsewhere in South Africa provided com-
pelling evidence of a link. The evidence of the relationship is now so
strong that mesothelioma is considered a sentinel tumor or marker for
asbestos exposure (Friedman, 2011).
Following these classic early studies, subsequent cohort studies
found excess cancer associated with a large number of occupational
exposures, including dioxin, radon in mines, ethylene oxide, silica,
vinyl chloride, diesel fumes, cadmium, benzene, beryllium, PCBs,
wood dust, acid mists, and others all of which are classified as IARC
Group 1 (definite) human carcinogens, as detailed in the next section
of this chapter. Ionizing radiation, beyond the radon that caused lung
cancer among miners (Darby et  al., 1995; IARC, 2012d), has also
been identified as an occupational carcinogen. Long-​term follow-​up
of nuclear workers from three countries, exposed primarily to γ-​radia-
tion, showed the risk of developing leukemia, particularly chronic
myeloid leukemia, to be linked to the protracted low doses of radiation
(Leuraud et  al., 2015). Nuclear weapons workers exposed to pluto-
nium had increased risk of lung cancer, liver cancer, and bone sarcoma
(Gilbert, et al., 2000, 2004; IARC, 2012d; Koshurnikova et al., 2000).
Workers involved in cleanup after the Chernobyl nuclear accident
were exposed to X-​and γ-​radiation and have excess risk of leukemia,
including chronic lymphocytic leukemia (Kesminiene et  al., 2008;
Zablotska et al., 2013).
Several of the carcinogens mentioned in the preceding paragraph
are also present in the general environment at lower levels (e.g.,
dioxin, diesel fumes, PCBs, indoor radon). In addition, two occupa-
tions, painting and foundry work, have been identified by the IARC as
increasing cancer risk (Group 1), without being able to specify which
specific carcinogens are responsible.
While most occupational carcinogens have been discovered via
retrospective cohort studies, large population-​ based case-​ control
studies have often confirmed these findings, using self-​reported job
histories and assessment of potential occupational exposures by indus-
trial hygienists. Perhaps the most important model for this approach
has been the numerous studies in Montreal by the group led by Jack
Siemiatycki (Siemiatycki et al., 1991, 1997). Siemiatycki’s team elic-
ited detailed job histories through a semi-​structured questionnaire
with supplementary questionnaires for selected occupations, followed
by comprehensive review by chemists and industrial hygienists, who
translated each job into a list of potential exposures using a checklist
of 294 agents.
ACCEPTED HUMAN OCCUPATIONAL CARCINOGENS
Several groups regularly convene expert panels to evaluate the car-
cinogenicity of agents, with the most long-​standing being the IARC,
an agency of the World Health Organization. The IARC Monograph
Program assembles interdisciplinary working groups to evaluate epi-
demiologic, experimental, exposure, and mechanistic data to classify
agents, mixtures, or exposure circumstances as carcinogenic (Group 1),
probably carcinogenic (Group 2A), possibly carcinogenic (Group 2B),
not classifiable (Group 3), or probably not carcinogenic (Group 4) to
humans. Although there are some critics of the IARC process who
 27

Table 16–1.  Agents, Occupations, and Industries Classified by IARC as Human Carcinogens (Group 1) That Are Primarily Occupational Exposures

Agent Cancer Main Industry or Use

Acid mists containing sulfuric acid, strong Larynx Chemical

inorganic
4-​Aminobiphenyl Bladder Rubber
Arsenic and arsenic compounds Lung, skin, bladder Glass, metals, pesticides
Asbestos (all forms) Larynx, lung, pleura, ovary Insulation, construction, renovation
Benzene Leukemia Chemical production, solvent, fuel
Benzidine Bladder Dye/​pigment manufacture
Benzo(a)pyrene N/​A* Coal liquefaction and gasification, coke
production, coke ovens, roofing, paving,
aluminum production
Beryllium and beryllium compounds Lung Aerospace industry, metals
Bis(chloromethyl) ether; chloromethyl Lung Chemical intermediate/​byproduct
methyl ether
1,3-​Butadiene Leukemia, lymphoma Plastic, rubber
Cadmium and cadmium compounds Lung Dye/​pigment manufacture, batteries
Chromium (VI) compounds Nasal cavity, lung Metal plating, dye/​pigment manufacture
Coal tar pitch Skin, lung Construction, electrodes
1,2-​Dichloropropane Biliary tract Chemical, paint stripping, printing
Diesel engine exhaust Lung Transport, mining
Erionite Pleura Hydrocarbon cracking, agriculture
Ethylene oxide N/​A* Chemical, sterilant
Fission products, including strontium-​90 Leukemia, lymphoma Nuclear workers
Formaldehyde Nasopharynx, leukemia Plastics, textiles
Gallium arsenide N/​A* Semiconductors
Ionizing radiation (all types, including Thyroid, leukemia, salivary gland, lung, Radiology, nuclear industry, underground mining
radon-​222 Progeny) bone, esophagus, stomach, colon, rectum,
skin, breast, kidney, bladder, brain
Leather dust Nasal cavity Leather industry
4,4′-​Methylenebis (2-​chloroaniline) (MOCA) N/​A* Rubber
Mineral oils, untreated and mildly treated Skin Lubricant
β-​Naphthylamine Bladder Pigment
Nickel compounds Nasal cavity, lung Metal alloy
3,4,5,3′,4′-​Pentachlorobiphenyl (PCB-​126) N/​A* Electrical components
2,3,4,7,8-​Pentachlorodibenzofuran N/​A* Incineration, smelting, refining
Polychlorinated biphenyls Skin Electrical components
Polychlorinated biphenyls (“dioxin-​like”) N/​A* Electrical components
Shale oils Skin Lubricant, fuel
Silica dust, crystalline, in the form of Lung Construction, mining
quartz or cristobalite
Solar radiation Skin Outdoor workers
Soot Skin, lung Chimney sweeps, masons, firefighters
Sulfur mustard Lung War gas
2,3,7,8-​Tetrachlorodibenzo-​p-​dioxin N/​A* Chemical
Tobacco, secondhand Lung Restaurant and bar workers, offices
Ortho-​Toluidine Bladder Pigment
Trichloroethylene Kidney Solvent, dry cleaning
Ultraviolet radiation Skin, eye Outdoor workers
Vinyl chloride Liver Plastic
Wood dust Nasal cavity Wood, furniture

Occupation or Industry Cancer Main Industry or Use

Acheson process Lung Graphite and silicon carbide production

Aluminum production Lung, bladder Dye manufacture
Auramine, production of Bladder Dye manufacture
Coal gasification Skin, lung, bladder Power plants, chemical industry
Coal-​tar distillation Skin Coke oven plants
Coke production Skin, lung, kidney Coke oven plants
Hematite mining, underground Lung Mining
Iron and steel founding Lung Iron and steel founding
Isopropyl alcohol manufacture Nasal cavity Chemical
using strong acids
Magenta production Lung, bladder Painting
Painter (occupation as) Lung, bladder Painting
Rubber manufacturing industry Leukemia, lymphoma, bladder, lung, stomach Rubber

Source: Benbrahim et al., 2014; Boyle and Levin, 2008; Grosse et al., 2014; Guyton et al., 2015; IARC, 2013, 2014a, 2014b, 2015c, 2015d, 2015e; Stewart and Wild, 2014.
** N/​A—​Not applicable (agent classified in Group 1 on the basis of mechanistic evidence).
278
278 PART III:  THE CAUSES OF CANCER
claim the reviews have not sufficiently taken into account potential
methodological weaknesses in epidemiologic data in general and may
be biased by working group members with vested interests, there is
very broad involvement of the scientific community in the IARC
Monograph Program, overwhelming support for the scientific rigor
of the process, and ongoing international agreement with its decisions
(Pearce et al., 2015)
The IARC does not systematically indicate which carcinogens are
occupational, and thus lists of occupational carcinogens may vary
depending on the criteria used. Table 16–1 presents the agents classi-
fied by IARC as Group 1 carcinogens that we consider to be mostly
occupational exposures. Note that occupational exposures can
involve a broad range of infectious, medical, behavioral, and physi-
cal factors, in addition to the long-​recognized toxic chemicals. For
example, chemotherapeutic medications are an occupational expo-
sure for some healthcare workers. Medical radiation workers have
excess leukemia and cancers of the skin and breast related to their
occupational exposure (Linet et  al., 2010; Yoshinaga et  al., 2004).
Tobacco, in the form of secondhand smoke, is an occupational expo-
sure for bar and restaurant workers, resulting from the failure to
ban smoking in these workplaces in some localities. Restrictions on
smoking in public indoor areas have recently decreased this expo-
sure in some areas and countries, but not all (Schmidt, 2007). Shift
work adversely affects diurnal rhythm (IARC, 2010a). Physical inac-
tivity and sedentary work are the norm in most modern workplaces
(Brownson et  al., 2005). Sunlight is an occupational exposure for
persons who work outdoors (Carey et al., 2014).
Agents classified by the IARC as Group 1 carcinogens must have
sufficient evidence for carcinogenicity in humans, or exceptionally
limited evidence in humans but sufficient evidence of carcinogenic-
ity in animals, along with strong evidence in exposed humans that
the agent acts through a mechanism relevant to human carcinogenic-
ity (IARC, 2015a). Ethylene oxide, which is used as an intermedi-
ate in the production of several industrial chemicals, as a fumigant,
and as a sterilant for medical equipment and supplies, was classified
as a carcinogen based on limited evidence from humans, sufficient
evidence from animals, and compelling genotoxicity data from stud-
ies of exposed workers (IARC, 2012f). Similarly, mechanistic data
on the presence of DNA adducts, sister chromatid exchanges, and
micronuclei among workers exposed to 4,4'-​Methylenebis (2-​chlo-
roaniline) (MOCA) resulted in its classification as a known human
carcinogen (IARC, 2010b), despite limited human evidence. 2,3,7,8-​
Tetrachlorodibenzo-​p-​dioxin, which is a byproduct of the synthesis
of chlorophenols or chlorophenoxy acid herbicides, waste incinera-
tion, metal production, and wood combustion, was also classified as
a Group 1 carcinogen based on limited human data, sufficient animal
data, and evidence that TCDD acts through a mechanism involving
the Ah receptor, which is involved in normal cell homeostasis and is
present in both humans and animals. Other occupational agents clas-
sified as carcinogens based on limited human evidence, but sufficient
animal data and mechanistic data, include 2,3,4,7,8-​pentachlorod-
ibenzofuran, “dioxin-​like” polychlorinated biphenyls, dyes metabo-
lized to benzidine, and benzo(a)pyrene.
Table 16–2 presents the occupational agents classified as probable
carcinogens (Group 2A), generally based on limited evidence of car-
cinogenicity in humans and sufficient evidence of carcinogenicity in
experimental animals. In some cases, agents are classified Group 2A
based on lower levels of evidence of carcinogenicity in humans, but
with strong evidence that the carcinogenesis is mediated by a mecha-
nism that also operates in humans or that the agent clearly belongs,
based on mechanistic considerations, to a class of agents for which
one or more members have been classified as Group 1 or Group 2A.
Agents on this list have considerable potential for human carcinoge-
nicity, so those with widespread human exposure have a high prior-
ity for research to resolve the uncertainty in their classification (Ward
et al., 2010).
These lists (Tables 16–1 and 16–2) include some exposure scenar-
ios that have been linked to cancer, but for which the specific agents
responsible have not been identified. These include exposures asso-
ciated with the Acheson process (synthesis of graphite and silicon
carbide), iron and steel founding, isopropyl alcohol production by the
strong-​acid process, magenta production, working as a painter, frying
(emissions from high temperatures), working as a hairdresser or bar-
ber, spraying and applying non-​arsenical insecticides, petroleum refin-
ing, and shift work that involves circadian disruption. The exposures
associated with these processes and occupations could change over
time or by geographic location, and change the cancer risk previously
associated with them. For example, if the cancer risk associated with
occupation as a hairdresser were due to exposure to hair dyes, changes
in the formulations of hair dyes might cause the risk to change over
calendar time or geographic region.
Table 16–3 presents the most common types of occupational cancer;
these are lung cancer, bladder cancer, mesothelioma, and leukemia,
although occupational exposures have been linked to many cancer
sites (IARC, 2015b).
In 2008–​2009, the IARC held six working group meetings during
which expert panels reviewed the evidence for substances and factors
that the IARC had classified as known (Group  1) carcinogens in the
past. This re-​review reaffirmed the earlier Group 1 classifications, and
added new cancer sites for some agents. For example, formaldehyde
had originally been classified in 2006 as a human carcinogen based
on excess risk of nasopharyngeal cancer, but the recent review in 2009
added leukemia, particularly myeloid leukemia, as having sufficient
evidence of carcinogenicity due to formaldehyde (IARC, 2012f). To
date, the accumulation of additional evidence has never caused the
IARC to downgrade an agent that was previously classified as a known
carcinogen, although some agents classified as possible carcinogens
(Group 2B, possibly carcinogenic to humans) have been downgraded
to Group 3 (inadequate evidence), such as amitrole, atrazine, and eth-
ylene thiourea.
EVIDENCE STIMULATING EPIDEMIOLOGIC STUDIES
OF OCCUPATIONAL CANCER
There are several types of evidence that by themselves have suggested
the presence of occupational cancer hazards and have stimulated epide-
miologic studies of occupational exposures or groups. These informa-
tive approaches include investigations of cancer clusters, searches for
explanations of unusual geographic patterns, whole animal cancer bio-
assays, Ames testing, and animal and human biomarker and mechanistic
studies.
A cancer cluster is the apparent excess of cancer cases among a
relatively small group of people. As noted earlier, occupational can-
cer clusters have led to the identification of carcinogens and in-​depth
epidemiologic studies dating back centuries. In the modern era after
World War II, a plant physician noted three cases of angiosarcoma
of the liver among workers exposed to vinyl chloride monomer in a
polymerization operation at a chemical plant (Creech and Johnson,
1974). The extremely rare nature of angiosarcoma, and the fact
that three cases came from the same workplace, contributed to the
ability of the physician to recognize the excess cancer incidence.
Epidemiologic investigations confirmed the excess of angiosarcoma
of the liver and discovered that vinyl chloride also caused hepatocel-
lular carcinoma, a more common cancer that would be less likely to
be noted as excessive among an occupational group without a formal
study (IARC, 2012f).
A similar story of discovery occurred in 2013 with the observation
of 11 male patients with intrahepatic or extrahepatic biliary tract cancer
(cholangiocarcioma) among workers exposed to 1,2-​dichloropropane
among 62 male workers at a printing company in Japan (Kumagai et al.,
2013). The rarity of cholangiocarcioma, the very high relative risk, the
young ages of the patients, the absence of non-​occupational risk fac-
tors, and the intensity of the exposure, along with sufficient evidence of
carcinogenicity among experimental animals, led the IARC to classify
1,2-​dichloropropane as a known human carcinogen (Benbrahim-​Tallaa
et al., 2014; Kubo et al., 2014; Kumagai et al., 2013).
Geographic patterns of cancer occurrence have provided clues to
occupational carcinogens. Publication of the first US cancer mortality
atlas in 1975 revealed a string of counties along the southeast Atlantic
 279

Occupational Cancer 279
Table 16–2.  Agents, Occupations, Industries, and Occupational Circumstances Classified by IARC as Probable Human Carcinogens (Group 2A) That
Are Primarily Occupational Exposures

Agent Cancer Main Industry or Use

Acrylamide –​ Plastics
Bitumens (combustion products during roofing) Lung Roofing
Captafol –​ Pesticide
α-​Chlorinated toluenes –​ Pigment, chemical
4-​Chloro-​o-​toluidene Bladder Pigment, textile
Cobalt metal with tungsten carbide Lung Hard metal production
Creosotes Skin Wood
Diazinon Lymphoma, lung Agriculture, pest control
Dibenz[a,j]acridine –​ Mastic asphalt worker
Dichloromethane (methylene chloride) Biliary tract, lymphoma Plastics, solvent, paint stripping
Diethyl sulfate –​ Chemical
Dimethycarbamoyl carbide –​ Chemical
1.2-​Dimethylhydrazine –​ Research
Dimethysulfate –​ Chemical
Epichlorhydrin –​ Plastic
Ethylene dibromide –​ Fumigant
Glycidol –​ Pharmaceutical industry
Glyphosate Lymphoma Agriculture, forestry
Indium phosphide –​ Semiconductors
Lead compounds, inorganic Lung, stomach Metals, pigments
Malathion Lymphoma, prostate Agriculture, pest control
Methyl methanesulfonate –​ Chemical
6-​Nitrochrysene –​ Transportation, underground mining
1-​Nitropyrene –​ Transportation, underground mining
2-​Nitrotoluene –​ Dye production
Non-​arsenical insecticides Leukemia Agriculture
Polybrominated biphenyls –​ Flame retardants, plastics
1,3-​Propane sultone –​ Chemical, batteries
Silicon carbide whiskers Lung Plastics
Styrene-​7,8-​oxide –​ Plastic
Tetrachloroethylene Liver, lymphoma Solvent, dry cleaning
Tetrafluoroethylene –​ Chemical
1,2,3-​Trichloropropane –​ Solvent
Tris(2,3-​dibromopropyl)phosphate –​ Plastic, textile
Vinyl bromide –​ Plastic, textile
Vinyl fluoride –​ Chemical

Occupation, Industry, or Occupational Circumstance Cancer Main Industry or Use

Art glass, glass containers, and pressed ware, manufacture Lung, stomach Glass manufacture
Carbon electrode manufacture Lung Carbon electrode manufacture
Food frying at high temperature Lung Restaurant
Hairdresser or barber Bladder, lung Cosmetology
Petroleum refining Leukemia, skin Petroleum refining
Shift work that involves circadian disruption Breast Health care, manufacturing, custodial work

Source: Benbrahim et al., 2014; Boyle and Levin, 2008; Grosse et al., 2014; Guyton et al., 2015; IARC, 2013, 2014a, 2014b, 2015c, 2015d, 2015e; Stewart and Wild, 2014.

coast with markedly elevated rates of lung cancer (Mason et al., 1975).
A series of case-​control studies conducted in the areas found that the
excess lung cancer was due to asbestos exposures associated with
short-​term shipyard work that took place largely during World War
II (Blot et al., 1978, 1979b, 1980; Tagnon et al., 1980). Many of the
shipyards had been closed for years.
In recent time, a common motivation for an epidemiologic study of
a suspect occupational carcinogen is demonstration of cancer among
experimental animals. Animal bioassays have characteristics that must
be considered when extrapolating the results to humans, such as ani-
mal/​human species metabolic differences, typically greater doses to
animals than are experienced by humans, different routes of exposure,
fewer concomitant exposures that could affect cancer risk, and some
target organs that may not exist in humans (e.g., the rodent Zymbal
glands) or that rarely develop cancer among humans (e.g., the pituitary
gland). However, despite these limitations, the results of long-​term can-
cer bioassays are highly predictive for identifying human carcinogens,
and the overwhelming majority of established human carcinogens have
also been shown to cause cancer in animals (Huff, 1999, 2008). There
are many chemicals that were found to cause cancer in animals before
epidemiologic studies demonstrated effects in humans. Some notable
carcinogens first identified in animal studies and later found to cause
cancer among exposed workers are dioxin (IARC, 1997, 2012f), 1,3-​
butadiene (Melnick and Huff, 1992), and formaldehyde (IARC, 2006).
Concordance overall between animal and human carcinogens, as
well as concordance of the specific affected sites, has improved with
better bioassay methods, such as improved histopathology with more
detailed examination of more organs per test animal, use of vari-
ous routes of administration, and different forms of the compounds
(Maronpot et  al., 2004). For example, arsenic was recognized as a
human carcinogen in 1987, while animal bioassays were negative or
provided limited evidence until many years later, when organic metab-
olites of arsenic were studied and found to be positive (Huff et  al.,
2000; IARC, 2012c).
280

280 PART III:  THE CAUSES OF CANCER

Table 16–3.  IARC Human Carcinogens (Group 1) That Are Primarily Table 16–3. Continued
Occupational Exposures by Cancer Site
Cancer Site Occupational Exposure
Cancer Site Occupational Exposure
Pleura Asbestos
Bladder Aluminum production Erionite
4-​Aminobiphenyl Painter (occupation as)
Arsenic and inorganic arsenic
compounds Skin Arsenic and inorganic arsenic
Auramine production compounds
Benzidine Coal-​tar distillation
Magenta production Coal-​tar pitch
2-​Naphthylamine Mineral oils, untreated or mildly treated
Painter (occupational exposure as) Polychlorinated biphenyls
Rubber production industry Shale oils
Ortho-​Toluidine Solar radiation
X-​ and γ-​radiation Soot
X-​ and γ-​radiation
Bone Plutonium
Radium-​224 and its decay products Stomach Rubber production industry
Radium-​226 and its decay products
Radium-​228 and its decay products Source: IARC, 2015b, 2015f.
X-​ and γ-​radiation
Breast X-​ and γ-​radiation Measures of exposure and biomarkers of effects in humans can also be
Eye Welding critical in assessing and understanding carcinogenesis. They have also
stimulated occupational epidemiologic investigations. Early reports of
Gallbladder and biliary tract 1,2-​Dichloropropane
chromosomal damage from ethylene oxide (Ehrenberg and Hallstrom,
Kidney Trichloroethylene 1967), a sterilant gas, were instrumental in leading to two epidemiologic
X-​ and γ-​radiation studies, which documented excess leukemia (Hogstedt et  al., 1979a;
Larynx Acid mists, strong inorganic Hogstedt et al., 1979b). Animal studies subsequently showed that inhaled
Asbestos ethylene oxide caused leukemia in rodents (Snellings et al., 1984).
Leukemia/​Lymphoma Benzene
1,3-​Butadiene
Fission products, including
DESIGN OF HUMAN STUDIES
strontium-​90
Formaldehyde The role of occupational exposures in the development of cancer has
Rubber production industry been investigated using various epidemiologic designs, including cohort,
X-​ and γ-​radiation case-​control, cross-​sectional, and ecological studies (Checkoway et al.,
Liver Plutonium 2007; Steenland and Moe, 2016). The type of study design has a major
impact on the type and source of information available on occupational
Lung Acheson process exposures as well as potential bias, and thus on the quality of the data
Aluminum production generated by the study and the conclusions that can be drawn.
Arsenic and inorganic arsenic
compounds
Asbestos
Beryllium and beryllium compounds
Cohort Studies
Bis(chloromethyl)ether; chloromethyl In a cohort study, typically exposed and non-​exposed groups are iden-
methyl ether (technical grade) tified and followed over time to ascertain disease outcomes (although
Cadmium and cadmium compounds sometimes highly exposed workers are compared to lower exposed
Chromium (VI) compounds
Coal gasification
workers in an internal analysis). The occurrence of disease among the
Coal-​tar pitch two groups is compared. For many occupational studies, the “non-​
Coke production exposed” group has been the general population of the country or some
Diesel engine exhausts other political entity in which the exposed group is located. Such a com-
Hematite mining parison group is typically selected for practical reasons (i.e., information
Iron and steel founding on the incidence or mortality experience is already available, and no spe-
Nickel compounds cific unexposed population can be assembled without considerable effort
Painter (occupational exposure as) and cost). Although use of a non-​worker referent population has practi-
Plutonium cal advantages, it has a methodological limitation known as the healthy
Radon-​222 and its decay products worker effect. This occurs when the exposed population (i.e., workers)
Silica dust, crystalline
Soot
is made up of relatively healthy individuals, while the referent group
Sulfur mustard includes non-​working people who are not employed because of health
Tobacco smoke, secondhand problems, so the two groups are not comparable (Fox and Collier 1976).
X-​ and γ-​radiation The healthy worker effect can take two forms; one involves the selection
of healthy workers into the workforce, and a second involves healthy
Nasal cavity and paranasal sinus Isopropyl alcohol manufacture using
strong acids workers staying in the workforce while others who develop illnesses
Leather dust leave the workforce early (the latter is called the healthy worker survivor
Nickel compounds effect and is important when considering cumulative exposures). The
Radium-​226 and its decay products healthy worker effect can obscure an increase in disease among work-
Radium-​228 and its decay products ers due to an occupational exposure, which may be offset by the gener-
Wood dust ally healthy nature of the working population. The healthy worker effect
Nasopharynx Formaldehyde is a particular problem for diseases that are disabling and which may
Wood dust occur relatively early in life, such as cardiovascular disease, but it is not
entirely absent for cancer. However, the healthy worker effect wears off
Ovary Asbestos
 281
Occupational Cancer 281
with further follow-​up, when more of the cohort is no longer working,
which is when most cancers occur. When a referent group of workers is
available, its use not only avoids the healthy worker effect, but also has
the advantage that it is likely to be similar to the exposed population
in other often unmeasured ways (e.g., sharing lifestyle factors such as
smoking habits). Thus it can help limit unmeasured confounding.
A cohort study can assess multiple outcomes (e.g., all types of can-
cer), but unless the cohort is extremely large, the number of subjects
with rare diseases will be small. The cohort design is particularly
useful for the study of occupational exposures that would otherwise
be uncommon in most samples of the general population. An increas-
ing challenge, particularly in the United States, is gaining access to
workplaces and to the historical occupational and exposure infor-
mation necessary to conduct cohort studies. In the United States,
until recently most occupational cohort studies ascertained mortality
only, not cancer incidence, which means that some associations with
cancers that have good survival (e.g., bladder, prostate, and breast
cancer) may have been missed. With better coverage of the United
States by cancer registries, more incidence-​ based occupational
cohorts are appearing, such as the study of US firefighters (Daniels
et al., 2014) and the Agricultural Health Study (Blair et al., 2015b).
Countries with national cancer registries, such as Scandinavian coun-
tries, have long been able to study cancer incidence among workers,
such as the studies of dry cleaners in Denmark, Norway, Sweden,
and Finland (Lynge et al., 2006). A retrospective cohort study identi-
fies the exposed and unexposed groups (either some general popu-
lation or a specific unexposed worker population) at some point in
the past and follows them to the present, while a prospective cohort
study identifies the two groups in the present time and follows them
into the future. In general, most occupational studies have been retro-
spective in nature, which must rely upon historically collected expo-
sure information, but provide results more quickly than prospective
studies, which must wait for cancers to develop in the population.
There are some notable exceptions to the almost exclusive use of
retrospective cohort studies to assess occupational carcinogens (Blair
et al., 2015a), including the prospective cohort study of cancer among
Swedish construction workers that began in the mid-​1960s (Bergdahl
and Järvholm, 2003; Järvholm and Englund, 2014), the US Agricultural
Health Study (Alavanja et al., 1996), the French Agricultural and Cancer
(AGRICAN) study (Levêque-​Morlias et al., 2015), studies of Chernobyl
cleanup workers (Kesminiene et al., 2002; Romanenko et al., 2008), and
the recently launched World Trade Center Rescue and Recovery Workers
Study (Solan et  al., 2013)  and the GuLF Study (Sandler et  al., 2014).
Some prospective cohort studies that were initiated primarily to investi-
gate non-​occupational factors have been utilized to evaluate cancer and
occupational cancers as well, such as the Nurses’ Health Study, Shanghai
Women’s Study, EPIC study, and Sister Study (Blair et al., 2015a).
A limitation of most retrospective cohort studies is the lack of
information on important potential confounders, such as occupational
exposures from other jobs besides the one under study and lifestyle
factors such as smoking and alcohol consumption and diet. However,
for smoking, which is usually the potential confounder of most con-
cern, a considerable amount of research based on studies with smoking
data, and based on hypothetical simulations, has been published which
shows that smoking rarely confounds disease risks in occupational
studies, and changes of effect measures (e.g., rate ratios) greater than
20% are extremely unlikely (Axelson and Steenland, 1988; Blair et al.,
2007). It is still preferable to collect smoking data, to control for pos-
sible confounding, but also to assess if smoking modifies the effect of
an occupational exposure, as it does for asbestos (IARC, 2012e) and
diesel exhaust (Silverman et al., 2012). For example, smokers who are
also exposed to asbestos have a risk of developing lung cancer that
is greater than the individual risks from asbestos and smoking added
together, but less than the risks multiplied together (IARC, 2012e).
Proportional Mortality Studies
A variation on the cohort design in which a defined population is
followed over time is a proportional mortality study, which includes
observations on deaths only. Full information on the occupational
group from which the deaths arose is not available. Without enumera-
tion of the population at risk, it is not possible to calculate incidence or
mortality rates and compare them to an unexposed population. Instead,
the proportion of deaths due to a specific cause out of the total number
of deaths among the workers is compared to the proportion in a com-
parison population, often the general population. The statistic used to
express the results, the proportional mortality ratio, is the origin of
the common name for this design, the PMR study. This approach is
most common when a company, union, government agency, or insur-
ance company may have death certificates available for study, but no
records on the identity or work histories for all persons who worked
in the job of interest, regardless of their current employment or vital
status. Examples include the NIOSH National Occupational Mortality
Surveillance (NOMS) system, which has occupation and industry-​
coded death data from 30 US states from over a 20-​year time period
(Robinson et  al., 2015), a study of deaths among unionized plumb-
ers, pipefitters, and allied trades (Lehman et al., 2008), and a study of
deaths among cement workers recorded by a Greek insurance com-
pany (Rachiotis et al., 2012).
Proportional mortality studies are generally inexpensive and quick
to conduct; they have been used as a surveillance tool for routine detec-
tion of any occupational excess and as an inexpensive initial approach
to provide some information on a new issue. However, they may be
biased if the death certificates on hand are not representative of all
deaths that occurred in the occupational group. Often such studies are
based on deaths among active workers or retirees from the company or
union under study, but miss deaths among persons who left employ-
ment with that company or union before death or before becoming
eligible for retirement. Also, because the proportion of deaths for all
causes must total 100%, a higher proportion of deaths from one cause
must be offset by a lower proportion of deaths from another cause, or
vice versa, which can distort results. For example, if aerial pesticide
applicators have a large real excess of deaths due to accidents, the
mathematical requirement that the PMR for all causes combined equal
1.00 may cause some one or other causes of death to appear deficient,
even if their absolute mortality rates are excessive compared to an
unexposed population.
Case-​Control Studies
In a case-​control study, persons with the disease of interest (“cases”)
and persons without the disease (“controls”) are identified and past
exposures are ascertained. The relative occurrence of exposures among
cases and controls is compared. Case-​control studies are of three
types: population-​based, clinic or hospital-​based, and nested within a
cohort. A population-​based case-​control study is the optimal approach
for the study of rare cancers, which would be infrequent in a cohort
study, and allows for ascertainment of important lifestyle factors, such
as smoking, that are not typically recorded in work records, upon
which most occupational cohort studies rely. Case-​control studies can
assess multiple exposures (e.g., all past occupations). Generally, these
studies include subjects with a very wide range of jobs, each held by
a small number of persons (except for a few common occupations),
which can limit the power to evaluate rare exposures and hence limit
the usefulness of this approach for studies of occupational exposures.
Case-​control studies can sometimes restrict the study area to enhance
the proportion of the population exposed, for example, studies of pesti-
cides have been located in rural states, or portions of states, to increase
the proportion of farmers who use pesticides (e.g., Miligi et al., 2003;
Zahm et al., 1990).
Most case-​control studies conduct interviews with study subjects,
and rely upon self-​reported occupational histories. Workers are usu-
ally able to report job title, industry, and dates of employment with
high validity, but often not the actual exposures sustained on the job
(Teschke et  al., 2002). Workers in some occupations do better than
others. Farmers, for example, can provide quite accurate informa-
tion about pesticides used and conditions of handling and application
(Blair et al., 2002). However, for many case-​control studies, specific
28
282 PART III:  THE CAUSES OF CANCER
exposures must be inferred from the job history through assessment by
experts, use of a job-​exposure matrix, or, rarely, biological measure-
ments (Teschke et al., 2002) (see the section “Exposure Assessment”
later in this chapter).
Nested case-​control studies of occupational carcinogens are case-​
control studies conducted within a cohort, and cases are compared to
a set of non-​cases in the cohort. More extensive information on the
occupational exposure or important potential confounders or effect
modifiers can be more easily obtained for the cases and a set of con-
trols than for the full cohort (Rothman et al., 2008).
Cross-​Sectional Studies
In cross-​sectional studies, the exposure and cancer come from approx-
imately the same point in time. The major limitation of this approach
is that the temporal sequence of the exposure and the disease may be
difficult, if not impossible, to determine. For cancer, which has a long
latency, the assumption that current exposure status reflects exposures
when the disease process was initiated may be particularly problem-
atic. Despite this limitation, a series of informative studies of the cor-
relation between the concentration of various industries with cancer
mortality in US counties yielded clues about occupational carcino-
gens, and were followed up with case-​control and cohort studies (Blot
et al., 1979a).
Cross-​sectional studies are often used in the study of biomarkers
related to occupational exposures. For example, cadmium in the urine
of smelter workers has been measured at the same time as urinary pro-
teins beta-​2-​microglobulin and retinol binding protein showing kid-
ney damage (Thun, 1992). Benzene levels in air and urine of exposed
workers were correlated with measures of hematotoxicity, demonstrat-
ing its impact at air levels below the US occupational standard of 1
part per million, and among genetically susceptible subpopulations
(Lan et al., 2004). A cross-​sectional study that showed formaldehyde-​
associated hematotoxicity among exposed workers was cited as a key
justification for the IARC’s classification of formaldehyde as a human
leukemogen (IARC, 2012f; Zhang et al., 2010).
Cross-​sectional studies of biomarkers can shed light on potential
mechanisms, identify early events in the natural history, improve expo-
sure assessment, and, in the case of molecular biomarkers, identify
individuals susceptible to disease (Mayeux, 2004; Schulte, 1993).
However, a cross-​sectional study may be affected by reverse causation
or disease bias, that is, the biomarker may be the effect of the disease
rather than a cause (Checkoway et al., 2007).
Exposure Assessment
Although studies relating occupation and cancer are informative in
suggesting leads to occupational hazards, eventually investigations
must focus on specific exposures to provide solid information for haz-
ard and risk assessment. Quantitative occupational exposure assess-
ment is important in evaluating potential carcinogens and critical in
risk assessment. The data sources and approaches to develop such
quantitative assessments differ in industry-​based and population-​based
epidemiologic studies (Friesen et al., 2015).
Industry-​ based studies (generally cohort studies) are typically
focused on one or a few agents in one or a few types of occupational
settings. It is important to remember, however, that although the focus
of the research may be on “one or a few” exposures, there are very few
workplaces where is there is such a small number of exposures. The
subjects’ job histories are usually obtained from preexisting company
or union records. With the notable exception of radiation workers, per-
sonal exposure measurements for a large proportion of the subjects
in retrospective cohort studies are not usually available. There may
be some measurements for a few past workers in some settings and
area measurements at various work locations, but generally exposure
measurements for the time period critical for cancer initiation are lim-
ited. To overcome this limitation, researchers collect information from
a variety of sources to reconstruct historical exposures by task, job,
department, and time period, and then use that information to esti-
mate exposures experienced by individuals in the study (Friesen et al.,
2015). Data sources for such estimates include any existing personal
and area industrial hygiene sampling data (noting if the samples were
taken for routine monitoring or in response to a known or suspected
high-​exposure excursion), descriptions of the industrial process and
changes over time, production levels, exposure control devices and
efforts, and interviews with longtime workers with knowledge of his-
torical conditions. Experts then use these data to develop qualitative or
quantitative estimates of exposure by job, department, and time. The
exposure data may incorporate level and probability of the exposure,
as well as the expert’s confidence in the assessment. Reliability and
validity assessments are sometimes performed to provide an indication
of the reliability and accuracy of the exposure assessment, such as in
studies of diesel exposure (Stewart et al., 2010) and of ethylene oxide
(Hornung et al., 1994).
Population-​ based studies (either case-​ control or cohort studies)
typically include a wide variety of occupations and industries, with a
distribution representative of the general population. With the excep-
tion of a few common jobs, the number of subjects holding any spe-
cific job can be small. In population-​based case-​control studies using
interviews, self-​reported occupational histories have good reliability
for job, industry, and dates of employment, but poorer reliability for
reporting specific exposures (Friesen et al., 2015). Checklists of expo-
sures may help improve reporting of the job history itself, as well as
exposures of interest, but the data are prone to false positives and false
negatives. Reporting is somewhat better for exposures that are easily
sensed and recognizable, or if the person was involved with the deci-
sion-​making about the exposure, such as a farmer who buys, applies,
and tracks pesticide use. For many exposures, however, self-​reported
exposure histories can have serious limitations and may be affected by
case recall bias in case-​control studies. Even more problematic than
self-​reports are proxy reports. Spouses and children provide less accu-
rate job and exposure histories than the subjects themselves (Brown
et al., 1991). Coworkers have provided job and exposure information
for deceased subjects in some studies (e.g., Chernobyl cleanup work-
ers [Romanenko et  al.,  2008]). Generic JEMs (vs. industry-​specific
JEMs described earlier) can be used to assign exposure status based
on the occupational histories, although one must consider possible dif-
ferences across geographic areas before applying a JEM developed in
one country to a study conducted in another (Friesen et al., 2015; Hoar
et al., 1980).
In some studies, detailed sets of questions are triggered if the sub-
jects have held jobs for which additional data are needed to assess
the potential for exposures of interest. These “occupational modules”
gather information on materials and equipment used, sensory descrip-
tions (e.g., smell), dermal exposure, work practices, engineering con-
trols, and personal protective equipment used to improve the accuracy
of the assessment of exposure potential and amount at the individual
subject level (Siemiatycki et al., 1997; Stewart et al., 1998)
Expert reviews and exposure assignments are time-​ consuming,
expensive, not transparent, and may not always be reproducible, so
more systematic approaches are being developed (Fritschi et al., 2009;
Russ et al., 2014, 2016). Current efforts that aim to overcome these
limitations include the development of algorithm-​and measurement-​
based decision rules, applying machine learning methods to classifica-
tion tree models, computerized decision rules (e.g., OccIDEAS: http://​
www.occideas.org/​#!whousing/​c1ykh) (Fritschi et  al., 2009), and
computer-​assisted occupational coding software (e.g., SOCcer: http://​
soccer.nci.nih.gov) (Russ et al., 2014, 2016).
In many settings, it may be important to consider multiple expo-
sures simultaneously to assess interaction among exposures, to evalu-
ate possible confounding, and to clarify the credibility of associations.
De Roos et al. (2003) performed an integrative assessment of multiple
pesticides as risk factor for non-​Hodgkin’s lymphoma. Consideration
of mixtures is important to evaluate if there are enhanced effects from
a mixture, which is greater than that expected from single exposures;
this has been reported in a few studies for pesticides (De Roos et al.,
2003; Hohenadel et  al., 2011; Lerro et  al., 2015). In contrast, there
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Occupational Cancer 283
might be diminished effects from combinations of exposures, such as
the observation that the risk of adenocarcinoma of the lung associated
with diesel exposure was ameliorated in presence of endotoxin expo-
sure (Tual et al., 2015).
Attention must also be given to consideration of gender differences
that may affect exposure assessment (Friesen et al., 2012; Locke et al.,
2014). Men and women with the same job title do not always have the
same duties and exposures. There are also gender differences in self-​
reports of exposures, work practices, personal hygiene, and the effec-
tiveness of protective equipment and engineering controls that affect
the accuracy of exposure assessment (Zahm and Blair, 2003).
It would be ideal if it were possible to use a biomarker of exposure,
which would characterize the total internal dose rather than external
exposure. However, biomarkers of exposure are often short-​lived in
the body. To fully characterize exposure over the years would require
multiple biologic collections, or there would need to be (1) limited
intra-​individual variation of the biomarker over time, (2) an accurate
laboratory assay, and (3) long enough persistence in the body so that
the measure could reflect an exposure that occurred during the time
period when carcinogenesis was initiated. Furthermore, for case-​con-
trol studies, the biomarker would need to be not affected by disease
status or treatment (Baris et  al., 2000; Steenland and Moe, 2016).
Nonetheless, biomarkers can often help in the assessing the relation-
ship between historical exposures and dose.
Genetic Susceptibility
Because occupational studies are likely to have better assessment of
work-​related exposures than studies of many other types of exposures,
they offer excellent opportunity to explore potential interactions with
genetic susceptibility. For example, using the candidate gene approach,
it was established that the slow N-​acetylation phenotype, caused by var-
iation in the NAT2 gene, confers increased risk for bladder cancer among
workers exposed to aromatic amines (Gu and Wu, 2011). Technological
advances have enabled researchers to look at extremely large numbers
of genetic variants in an agnostic fashion in genome-​wide association
studies (GWAS), accelerating the search for gene-​environment inter-
actions. A small genome-​wide study of gene–​environment interaction
for asbestos exposure in lung cancer susceptibility has been conducted
with some promising results, particularly when a pathway approach was
used, but more research with a larger number of subjects is needed (Wei
et al., 2012). Some recent examples of possible gene-​exposure interac-
tions include a large GWAS study of bladder cancer that found evidence
of interaction for rs798766 (TMEM129-​TACC3-​FGFR3) with expo-
sure to straight metalworking fluids, with the interaction more apparent
among patients with tumors positive for FGFR3 expression (Figueroa
et  al., 2015). Gene–​environment interactions between prostate cancer
susceptibility loci identified via GWAS and occupational exposure to
pesticides have been identified among applicators in the Agricultural
Health Study (Koutros et  al., 2010, 2013). In addition to genomics,
the occupational setting can be a fertile ground for the application of
epigenomics, transcriptomics, proteomics, and metabolomics and other
“-​omics” technologies (Vlaanderen et al., 2010).
In summary, occupational cancer epidemiology is a powerful tool for
(1) protecting workers’ health through identifying and reducing expo-
sure to carcinogens; (2) protecting the public by identifying and reduc-
ing exposure to occupational carcinogens that otherwise would enter
the non-​workplace environment or consumer products; and (3) eluci-
dating mechanisms of carcinogenesis.
QUANTITATIVE RISK ASSESSMENT
Evaluation of the carcinogenicity of occupational exposures consists
of not only identification of carcinogens (qualitative risk assessment),
such as that done by the IARC Monograph Program, but also of quan-
titative risk assessment, which is the characterization of the proba-
bility of human cancer resulting from specific levels of exposures to
environmental hazards. Quantitative risk assessment is typically con-
ducted by government regulatory agencies. Quantitative risk assess-
ment may be based on either animal data or human data. The former
has an advantage in that exposures in observational human studies
are not assigned as in animal experiments, and thus there can be con-
siderable uncertainty in exposure estimates. However, animal studies
require extrapolation from animals to humans and hence involve much
more uncertainty. For this reason, human (epidemiological) data are
generally preferred, but are not always available. When human data are
available, occupational quantitative risk assessment, aimed at setting
permissible exposure levels, is based on exposure–​response data from
one or more occupational studies. These results provide information on
the increased rate of disease per unit of exposure (exposure–​response
data) for an exposed population that must typically be converted to the
excess risk of disease over a lifetime for specific exposures to iden-
tify a permissible exposure level. The US Occupational Safety and
Health Administration (OSHA) usually seeks to limit excess risk to 1
in 1000 deaths (or serious disease) for exposed populations. For exam-
ple, if the background lifetime risk for lung cancer in the non-​exposed
general population is 5% (0.05), then OSHA will seek the level of
exposure that will not increase lifetime risk for an exposed population
beyond 5.1%. Other countries have adopted similar approaches for
carcinogens that are genotoxic (Nielsen and Ovrebø, 2008).
There are two major issues of concern for quantitative risk assess-
ment based on epidemiological exposure–​response models. The first
is the shape of the exposure–​response curve. When data are sparse,
and sometimes even when they are not, it may be difficult to choose
among competing models used for setting permissible limits, and dif-
ferent models can have very different consequences. Typical questions
involving model selection might be whether the exposure–​response
relationship shows a linear increase in disease rate per unit of expo-
sure, whether there is a threshold below which there is no risk followed
by an increase, or conversely, whether there is a cut-​point above which
disease risk begins to flatten out or even decrease. In general, one
expects that greater exposure to a carcinogen would lead to a greater
occurrence of cancer. However, risk for some established carcinogens
plateaus at higher doses; examples include ethylene oxide, dioxin,
beryllium, diesel fumes, and nickel (Stayner et  al., 2003; Steenland
et al., 2011). Plateaus in disease rate at higher exposure levels in occu-
pational studies may occur due to (1) bias introduced by the healthy
worker survivor effect; (2) depletion of the number of susceptible peo-
ple in the population at high exposure levels; (3) a natural limit on the
relative risk for diseases with a high background rate; (4) inaccurate
measurements or misclassification of exposure; (5) influence of other
risk factors that vary by the level of the main exposure (confounding);
and (6) saturation of key enzyme systems or other processes involved
with the development of disease (Stayner et al., 2003). As an example
of a biological process that affects the shape of the dose–​response
curve, high doses of radiation result in cell death, while lower doses
damage cells and result in malignant transformation, so risk for thy-
roid cancer, but not other sites, plateaus and may even decrease with
increasing dose (Berrington de González et al., 2013).
A second question typical of quantitative risk assessment is the
nature of the exposure–​response relationship in the low-​dose region,
where there may be few data. This question often arises when occupa-
tional epidemiological studies (high exposure) are used for risk assess-
ment for general environmental exposures (lower exposure), such as
diesel fumes, dioxin, or asbestos. Traditionally, when data are sparse in
the low-​dose region, a linear extrapolation of risk down to zero expo-
sure is used by regulatory agencies, starting from a point of departure
that is a function of the lowest level of risk for which observed data
are considered reliable. This procedure may also provide the best fit
to data in which the exposure–​response relationship plateaus at higher
exposures (Steenland et al., 2011).
By way of example of quantitative risk assessment, consider a
recent occupational cancer risk assessment for lung cancer and die-
sel fumes (Vermeulen et  al., 2014). These authors took three occu-
pational studies of workers exposed to diesel fumes (two truck driver
studies, one miner study), which were the only epidemiologic studies
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284 PART III:  THE CAUSES OF CANCER
with quantitative exposure–​response data using the same exposure
metric (cumulative exposure to elemental carbon to characterize die-
sel exhaust), therefore permitting a joint analysis. They combined the
three studies to derive a common exposure–​response curve, which
indicated that for each 1µg/​m3-​year of elemental carbon exposure, the
log RR (relative risk) for lung cancer would increase by 0.00098; this
translates to an RR of about 2 for 700 µg/​m3-​years, which in turn to
an average exposure of about 35 µg/​m3 elemental carbon for someone
exposed for 20 years (the miners had an average exposure of about
this level). Next, the authors translated this finding into an estimate
of excess lifetime risk for death from lung cancer (above background
lifetime risk for an individual not occupationally exposed to diesel
fumes, which is about 5%), at different exposure levels over a hypo-
thetical 45-​year working lifetime. US OSHA uses the 45-​year work-
ing lifetime as a default assumption for setting permissible levels for
workers. Exposure for 45 years at 1 µg/​m3 (45 ug/​m3-​years) would be
expected to lead to an excess lifetime risk of 1.7/​1000 (i.e., increasing
a background risk of 0.0500 to 0.0517). Given that OSHA seeks to
keep excess lifetime risks below 1/​1000, this would argue for a per-
missible exposure level for workers of slightly less than 1 µg/​m3. Risk
assessors must then weigh the optimal standard from a health stand-
point versus economic feasibility. Currently, with the exception of
miners, exposed workers have diesel exhaust exposures in the range of
3–​13 µg/​m3, while members of the public in urban areas are exposed
to about 0.8 µg/​m3 (Vermeulen et al., 2014).
ATTRIBUTABLE FRACTION
To estimate the impact of occupational cancer, we can calculate the
attributable fraction (AF) of cases or deaths for a specific cancer
(or all cancers) due to occupation; this is sometimes also called the
attributable risk. The AF is calculated by AF = [(RR – ​1)p]/​[(RR – ​1) •  smoke, radon, tetrachloroethylene, and arsenic, as well as occupa-
p + 1], where RR is the relative risk of disease for the exposed ver-
sus non-​exposed, and p is the proportion of the population exposed.
The proportion of the population exposed includes those exposed cur-
rently and those exposed in the past. An overall RR for exposed versus
non-​exposed and an overall proportion of the population exposed are
commonly used. However, sometimes the population exposed is bro-
ken down into different levels and/​or duration of exposure, and RRs
specific by level/​duration of exposure are used to calculate separate
AFs by exposure level or duration. There is considerable judgment
involved in these calculations; for example, if one wants to calculate
the AF for all cancers due to occupation, one must choose which can-
cer/​occupations associations are to be included. RRs for some spe-
cific cancers and occupations/​exposures may be based on one large
and very well-​conducted study, but more often use a meta-​analysis
of existing studies to determine an average RR across studies. Often,
authors restrict themselves to occupational carcinogens considered
definite or probable according to IARC (Group 1 or 2A). A common
difficulty is that estimates of the proportion of the population exposed
are not routinely available.
AFs can be calculated for both incident cancers and for fatal can-
cers. Further calculations can be done to estimate disability-​adjusted
life years lost (DALYs). DALYs attempt to quantify years lost due to
premature death, or years lived with lower quality of life following a
disease. They are a weighted estimate of the number of years lived with
disability, where the weighting is based on the severity of the disability.
There have been a number of estimates of the AF for occupational
cancer in the United States and other countries. One of the first and per-
haps the best known was published by Doll and Peto in 1981, in which
they estimated that 4% (1.2% for females, 7% for males) of US cancer
deaths were due to occupational cancer, primarily from lung cancer and
with the principal occupational exposure being asbestos (Doll and Peto,
1981). Doll and Peto noted that this estimate could be off by a factor of
two in either direction. It is important to put the estimate of AF of 4%
for occupational exposures in perspective with other cancer risk factors.
Doll and Peto (1981) estimated that tobacco had an AF of 30% and diet
of 35%, but all others were generally in the range estimated for occu-
pational exposures, for example, infections (10%), reproductive/​sexual
behavior (7%), geophysical factors (3%), alcohol (3%), and medicines
(1%). In addition, the risk from occupational exposures is borne largely
by blue-​collar workers who represented only about 25% of the US
population in 2000 (those in the construction, extraction, maintenance,
transportation, and material moving industries; see https://​www.cen-
sus.gov/​prod/​2003pubs/​c2kbr-​25.pdf); thus the AF among blue-​collar
workers must be considerably larger than 4%.
Doll and Peto’s original estimate has stood up relatively well to the
test of time (Blot and Tarone, 2015). Since then, there have been a num-
ber of other estimates in the United States and other countries, as more
information accumulated on the relative risks of cancer from specific
agents, and as the prevalence of occupational exposure has changed.
Steenland et al. (2003) estimated that 2.3%–​4.8% of US cancer deaths
were attributable to occupational factors (0.8%–​1.0% among females,
3.3%–​7.3% among males), which accounted for 13,000 to 26,000 can-
cer deaths annually. The highest AFs were for lung cancer, estimated
to be between 6% and 17% for men, and to be about 2% for women.
To give a more recent example of an AF for a specific agent and a spe-
cific cancer, we can use the example of diesel fumes and lung cancer
discussed earlier (Vermeulen et al., 2014). These authors estimated that
at current exposure levels to diesel fumes, the occupational exposure is
responsible for about 1% of lung cancer deaths in the United States and
England, and another 5% of lung cancer is due to environmental expo-
sures to diesel fumes.
AFs from other countries and worldwide are not dissimilar. For
example, Rushton et al. (2012) estimated that 5.3% (8.2% men, 2.3%
women) of cancer deaths in England in 2005 were due to occupational
exposures. The principal cancer sites considered were mesothelioma,
sinonasal, lung, nasopharynx, breast, non-​ melanoma skin cancer,
bladder, esophagus, soft tissue sarcoma, and stomach. The principal
carcinogens were asbestos, mineral oils, solar radiation, silica, diesel
engine exhaust, coal tars and pitches, dioxins, environmental tobacco
tional circumstances such as shift work and occupation as a painter
or welder.
Recent estimates on a global scale were made by the Global Burden
of Disease (GBD) 2013 group (GBD 2013 Risk Factors Collaborators,
2015), which estimated that IARC Group  1 (definite) occupational
carcinogens accounted for about 3.7% of worldwide cancer deaths in
2013 (304,000 deaths). More detailed information available from the
GBD website (https://​vizhub.healthdata.org/​gbd-​compare/​), estimates
that the principal cancers caused by occupational exposures were
lung cancer (269,000 deaths), mesothelioma (25,000 deaths), laryn-
geal cancer (4600 deaths), and leukemia (3200 deaths). Similarly, the
GBD 2103 group estimated that there were 5.8 million occupational
cancer DALYs out of a total of 197 million all-​cause cancer DALYs,
so cancer DALYs attributable to occupation were 2.9% (GBD 2013;
Risk Factors Collaborators, 2015). The principal occupational cancers
contributing to DALYS were lung cancer (5.0  million), mesotheli-
oma (514,000), leukemia (108,000), and laryngeal cancer (102,000)
(https://​vizhub.healthdata.org/​gbd-​compare/​).
The case of mesothelioma is particularly interesting, because it is
(1)  only caused by asbestos, largely an occupational exposure, and
(2) a highly fatal cancer that has a very long latency (e.g., typically
40  years instead of approximately 20  years for most solid tumors).
Thus while the burden of many occupational cancers is gradually
decreasing in developed countries, where exposures have been low-
ered and heavy industry has decreased (which is not the case in less
developed countries), the burden from mesothelioma in the developed
countries may have not yet peaked. Figure 16–1 shows the increas-
ing mortality rate of mesothelioma in England over time among older
men. The number of male mesothelioma deaths per year in England
is expected to peak at around 2500/​year in the year 2020 (Health and
Safety Executive, 2014).
It should be remembered that these estimates of the burden of can-
cer associated with occupational exposures do not account for second-
ary exposures. In some circumstances, occupational exposures have
been observed to increase the risk of cancer among the spouses and
children of workers. Asbestos fibers carried home on workers’ cloth-
ing, skin, and hair pose a risk for family members (Ferrante et al.,
 285
Occupational Cancer 285
1000
100
Rate per 1,000,000 person-years
10
1 the risks at lower levels of exposure [Hayes et  al., 1997; Schnatter
Age group
85+
75–84
65–74
55–64
45–54
35–44
0.1
1970 1980 1990 2000 2010
Year of death
Figure 16–1.  Age-​adjusted mortality rate for mesothelioma among males
in the United Kingdom, 1969–​2013.
2007; IARC, 1987, 2012c). In fact, secondary exposure to asbestos is
thought to be the major risk factor for mesothelioma among women.
Family members on farms where pesticides are applied may be
exposed via contact with contaminated clothing of the applicator as
well as environmental exposure to airborne pesticides drifting over
residential areas, residential dust, and ingestion (Deziel et al., 2015).
Spouses and children of farmers had a doubling of the urinary levels
of a metabolite of the pesticide carbaryl following application by the
farmer on the family farm, documenting secondary exposure (Shealy
et al., 1997). In the Agricultural Health Study, pesticide levels in the
homes of farmers have exceeded those in non-​farm homes (Curwin
et al., 2005). Children of the Agricultural Health Study participants
have excess lymphoma (Flower et al., 2004). Other studies of paren-
tal exposure to pesticides have suggested that the children’s second-
ary exposures play a role in the risk of leukemia and brain cancer,
and less consistently with Wilms tumor, Ewing sarcoma, soft-​tissue
sarcoma, and Hodgkin’s lymphoma (Bailey et  al., 2014; Daniels
et al., 1997; Rodvall et al., 2003; Zahm and Ward, 1998).
CONTROVERSY
Occupational studies often generate considerable controversy.
Cancer is a devastating disease with special emotional overtones in
all situations, and especially where individuals have little control
over exposures that may cause the disease. Studies linking work-
place exposures to cancer may lead government regulators to control
exposure. Because regulation has economic consequences, studies
of cancer and occupational exposures receive intense scrutiny. They
are often reviewed and dissected beyond what may occur for other
cancer risk factors. Because of these pressures, intense debates and
disagreements regarding the quality of individual studies and the
weight of evidence are standard for each occupational exposure–​can-
cer relationship when associations are new and the amount of scien-
tific information is less robust than it will eventually be. Eventually,
however, sufficient scientific information may accumulate to allow
general agreement among scientists, stakeholders, and the public
regarding an issue. All widely accepted occupational carcinogens
(e.g., arsenic, asbestos, benzene, and silica) went through this per-
iod—​sometimes a lengthy period—​of debate and controversy. Even
after general acceptance that a substance is a carcinogenic hazard to
humans by the public and scientific community, there may be disa-
greement regarding the exposure–​response relationship and other risk
assessment issues. Examples of established occupational carcinogens
where disagreements continue include arsenic (where risk from expo-
sure at low levels is debated [Tsuji et al., 2014]), for chrysotile asbes-
tos (although classified as a human carcinogen by the IARC [2012c],
there is continuing debate about whether the cancer risk associated
with chrysotile asbestos is actually due to concomitant amphibole
asbestos exposure [Bernstein et al., 2013; Kanarek, 2011; van der Bij
et  al., 2013; Yarborough,  2006]), and benzene (where there is disa-
greement on the range of lymphohematopoietic cancers affected and
et al., 2012]). The debate regarding the adequacy of the data to con-
clude that a substance is a carcinogenic hazard is still ongoing for sub-
stances of more recent concern, for example, diesel exhaust (Gamble
et al., 2012; Sun et al., 2014), formaldehyde (Checkoway et al., 2012;
Gentry et al., 2013; McLaughlin and Tarone, 2014), trichloroethylene
(Alexander et al., 2007), and shift work (Brudnowska and Peplonska,
2011; Erren et al., 2010).
The example of diesel exhaust, now an established lung carcino-
gen, is instructive regarding the controversy and special interests often
associated with studies of occupational cancer. The National Cancer
Institute (NCI) and the National Institute for Occupational Safety and
Health (NIOSH) initiated a study of diesel-​exposed miners in 1992,
which was not published until 2012. The study faced numerous legal
challenges from the mining industry, through its lobbying group The
Methane Awareness Research Group (MARG), and was subject to
Congressional oversight throughout protocol development, data col-
lection, analysis, peer review, and journal publication. These pres-
sures delayed the study for years (Monforton, 2006; Morris, 2012;
Kean, 2012).
FUTURE DIRECTIONS
There are many occupational exposures that require further evalu-
ation. An obvious starting point for selection of a few high-​priority
candidates could be the substances in the probable (2A) and possible
(2B) categories of IARC classification that affect large populations.
For these, there is already some information suggesting an associa-
tion, and this information can provide direction for new investiga-
tions. There are an even larger number of occupational exposures
that have been linked to cancer in animal bioassays for which epi-
demiologic data are largely nonexistent. Even for those exposures
that are already classified as human carcinogens, additional studies
could provide important information. The recent IARC re-​evalua-
tions in Volumes 100 A through F of factors in Group 1 (sufficient
evidence for human carcinogenicity) show that even studies of
known carcinogens can be beneficial in that they reveal links to spe-
cific cancers not previously documented, as well as new mechanis-
tic and toxicological understanding, and data on exposure–​response
relationships. It appears, however, that, despite numerous leads and
the clear need for study of occupational exposures, research efforts
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286 PART III:  THE CAUSES OF CANCER
on occupational cancer have been diminishing in recent years (Raj
et al., 2014).
Future studies should take advantage of the new technologies that
allow characterization of mechanistic pathways, gene–​exposure inter-
actions, and epigenetic influences. Also, new techniques in exposure
assessment are available that reduce exposure misclassification and
result in more accurate estimates of exposure–​response relationships.
Effective use of these new opportunities will require less reliance on
the historical cohort design, which has been the design of choice in
occupational investigations in the past, and more use of prospective
designs (Blair et al., 2015a) that allow the incorporation of biologic
and mechanistic components. The changing dynamics and geographi-
cal location of various industries also indicate that future investiga-
tions should expand beyond studies that are composed of white men
in high-​income countries, which have predominated in the past (Raj
et al., 2014).
Although it is difficult to precisely predict specific exposures or
workplace conditions that are most important for study in the future,
following are a few that deserve consideration, based on some evi-
dence of hazard, number of people exposed, and possible magnitude
of population burden.
Sedentary Behavior
Lack of physical activity contributes to a number of diseases, includ-
ing cancer (US Department of Health and Human Services, 1996).
Amount of time spent in sedentary behaviors appears to be associ-
ated with an additional disease burden beyond that from low levels of
physical activity (Matthews et  al., 2012). In the past, most physical
activity was associated with work, but currently, many occupations
make a negligible contribution to overall activity, and this leads to
health threats (Straker et al., 2009). The high level of physical activity
in earlier times is dramatically demonstrated in an Old Order Amish
community whose lifestyle is similar to that common 150 years ago
(Bassett et al., 2004). Their physical activity may play a role in their
low overall cancer rate (Westman et al., 2010). In general, over time
there has been a drastic decrease in the proportion of jobs that require a
moderate intensity of physical activity, with a corresponding increase
in jobs with largely sitting and sedentary behavior (Church et  al.,
2011). Consequently, many individuals must rely almost entirely on
leisure time activities to achieve appropriate levels of physical activ-
ity, especially in developed countries. However, there are certainly
many occupations in developed countries that still require consider-
able physical activity.
Shift Work
Shift work has been classified as probably carcinogenic in humans (2A)
based on limited evidence in humans, sufficient evidence in experimen-
tal animals, and mechanistic actions that may be relevant in humans
(IARC, 2010a). In humans the strongest association was with breast
cancer, but links with other sites (prostate, endometrium, and colon)
were observed in some studies. Night work suppresses melatonin,
which inhibits tumors, although other mechanisms have also been sug-
gested (Fritschi et al., 2011). The overall evidence regarding shift work
and ill health is still in flux. A  recent study provided some evidence
for a relationship with lung cancer (Gu et al., 2015). This suggests that
additional studies are needed for breast cancer, which is most strongly
associated with shift work at the present time, but perhaps studies are
also needed to consider links with other cancers. Studies should also
evaluate different forms of shift work, characterize exposure more
accurately, evaluate timing issues regarding exposure to light at night,
explore possible mechanistic actions, and assess possible interaction
with other lifestyle and occupational factors. It should be noted that
this is a common exposure. For example, Purdue et  al. (2015) have
estimated that if shift work causes breast cancer, an estimated 6% of
US incident breast cancers in 2010 would have been attributable to
shift work.
Pesticides
Pesticides provide many important benefits in food production and
protection, public health, and aesthetics, but some may present risk
of cancer and other diseases (Blair et  al., 2015b). Experimental
investigations have been conducted for most pesticides, but epide-
miologic data are much more limited. The IARC, for example, has
only evaluated a few specific pesticides, but has recently described
plans for a series of monographs on pesticides currently in use, and
has conducted two. The initial IARC effort concerned commonly
used organophosphate insecticides and a very common herbicide
(glyphosate, commercial name Round-​Up). The monograph clas-
sified tetrachlorvinphos and parathion as possibly carcinogenic to
humans (2B) and malathion, diazinon, and glyphosate as probably
carcinogenic to humans (2A) (Guyton et  al., 2015). In a second
evaluation, the IARC classified DDT as a probable carcinogen (2A),
lindane (an organophosphate largely banned) as a definite carcinogen
(1), and 2-​4-​5-​T (a widely used herbicide) as a possible carcinogen
(2B) (Loomis et al., 2015). DDT use remains common in Africa and
India for malaria control, although it was banned as an insecticide in
most countries in the late 1970s and early 1980s. Many pesticides
currently in use, however, have not been adequately evaluated in epi-
demiologic studies. In addition to inadequate studies on many pes-
ticides currently in use, new pesticides are periodically developed
and introduced to overcome pest resistance that develops over time.
Consequently, there is a growing need to initiate new epidemiologic
studies to evaluate the cancer hazard that may emanate from estab-
lished and new pesticides.
Diesel Exhaust
Diesel exhaust has recently been classified by the IARC as a human
carcinogen (IARC, 2014a). Epidemiologic studies that made major
contributions to this decision (Attfield et  al., 2012; Garshick et  al.,
2008; Silverman et al., 2012; Steenland et al., 1990) evaluated expo-
sures largely from an older engine technology. These older engines
will eventually be replaced by newer, cleaner-​ burning engines
designed to reduce exhaust exposures. There is a need for new epide-
miologic investigations to evaluate the potential hazard from exhausts
from these new engines.
Nanoparticles
Naturally occurring nanoparticles are found in engine exhausts and
burning carbon materials, but most of the future concern is in relation
to engineered nanoparticles. Human exposure to engineered nanopar-
ticles can occur during creation in the laboratory, large-​scale manu-
facture, use, and environmental contamination (Kumar and Dhawan,
2013; Rim et al., 2013). NIOSH recently conducted an industry-​wide
study and exposure assessment (Dahm et al., 2015; Schubauer-​Berigan
et al., 2011) and found that to date there are only about 1000 workers
in the United States judged as exposed. However, many nanoparticles
are composed of known or suspect carcinogenic agents, and the num-
ber of exposed individuals is expected to grow rapidly, particularly in
the chemical industry, photochemical electricity generation, and imag-
ing and molecular diagnosis (Stark et al., 2015). The IARC evaluated
nanoparticles in 2014; most were judged not classifiable in humans
(Group 3), but one type was found to have sufficient animal evidence
of carcinogenicity, and was classified Group 2B (possible carcinogen)
(Grosse et al., 2014).
ACKNOWLEDGMENT
The authors would like to thank David Check for graphics contributions.
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 291
17 Air Pollution
JONATHAN M. SAMET AND AARON J. COHEN
OVERVIEW
A wide variety of man-​made and naturally occurring air pollutants
are known to cause cancer. Diverse exposures such as tobacco smoke,
radionuclides (radon), chemicals (benzene, mustard gas, and volatile
organic compounds), fibers (asbestos), and metals and metalloids
(chromium, nickel, and arsenic) have long been classified as carcino-
genic to humans. Historically, the evidence base for these classifica-
tions predominantly concerned high levels of exposure in occupational
settings. Over the last 30–​40 years, scientific attention has focused on
quantifying the adverse health effects of indoor and outdoor air pollut-
ants at exposure levels several orders of magnitude lower than those
studied initially. These include secondhand smoke, household expo-
sure to radon, residential and environmental exposure to asbestos, soot
from diesel powered engines, ambient exposures to small particles
(PM2.5), and indoor air pollution from the combustion of biomass and
coal. This chapter provides an overview of recent epidemiologic stud-
ies of air pollutants and cancer. It is necessarily selective, because the
evidence on air pollution and lung cancer in particular is now exten-
sive. Issues fundamentally important to policy development concern
dose–​response relationships and risk assessment. Of great concern is
that exposures in economically developing countries rival and often
dramatically exceed those found in high-​income Western countries.
INTRODUCTION
In the early decades of the twentieth century, lung cancer was a rare
disease. By mid-​century, however, it was evident that an epidemic of
lung cancer was occurring among males in the United States and a
number of European countries, and a parallel epidemic followed at
mid-​century among women. By then, there were already several estab-
lished and suspect causes of lung cancer. The evidence was stron-
gest for radon, linked to lung cancer in underground miners based
on epidemiological and clinical observations in mines in Eastern
Europe and the measurement of high levels of radon in these mines.
Epidemiological research was implemented to search for causal fac-
tors, targeting specific groups of workers at high risk as well as the
general population. By the 1920s and 1930s, clinicians were already
beginning to make the link between smoking and lung cancer, and the
ubiquitous and serious air pollution in cities was also considered as a
potential cause, a hypothesis supported by the presence of an urban–​
rural gradient in risk (Hoffman, 1929, 1931; Macklin and Macklin,
1940; Overholt and Rumel, 1940; Stocks and Campbell, 1955). These
two non-​exclusive hypotheses were given equal weight by Doll and
Hill (Doll and Hill, 1952)  as a rationale for their case-​control study
of lung cancer in London. After smoking was quickly identified as
a powerful cause of lung cancer, concern persisted that air pollution
may cause lung and other cancers, and research was ongoing on this
hypothesis. Additionally, by the 1950s, other respiratory carcinogens
had been identified, including radon and asbestos.
The hypothesis that air pollution causes lung cancer had a strong
basis in the known release of carcinogens into outdoor air from
industrial sources, power plants, and motor vehicles, and in the rec-
ognition that indoor air is contaminated by respiratory carcinogens.
Historically, epidemiological studies have shown for decades that
air pollution increases lung cancer risk. By 2013, the totality of the
evidence on outdoor air pollution and cancer had become sufficiently
cohesive to support a conclusion by the International Agency for
Research on Cancer (IARC) that outdoor air pollution is a Group  1
carcinogen (IARC, 2015).
During recent decades, a number of airborne carcinogens, viewed
as potential threats to public health, have been particularly contro-
versial. The energy crisis of the early 1970s led to increased man-
ufacture of diesel-​powered vehicles; recognition that diesel-​ soot
particles were mutagenic raised concern that the increasing numbers
of diesel-​powered vehicles would increase lung cancer risk for the
population. Three indoor carcinogens received widespread attention
from the scientific community and the public during the 1980s and
1990s: tobacco smoke inhaled by non-​smokers, radon, and asbestos
fibers. Policies and programs for reducing the risks to the popula-
tion of each of these carcinogens became extremely controversial.
Critics questioned whether the risks were exaggerated and whether
the high costs of control, particularly for radon and asbestos, were
justified. The scientific evidence on secondhand smoke was repeat-
edly challenged by the tobacco industry as it sought to maintain con-
troversy, even as review panels concluded that secondhand smoke
caused lung cancer (IARC, 1986; National Research Council and
Committee on Passive Smoking, 1986). Now, definitive and incon-
trovertible conclusions on the carcinogenicity of secondhand smoke
have been made by both the IARC (2004) and the Surgeon General
(2006). In the United States, there has also been extensive litigation
around indoor asbestos in the past. For these and other inhaled car-
cinogens, substantial research has been motivated by concern for the
public’s health, and by the need to develop the scientific foundation
of evidence for control strategies to address carcinogens for which
exposure is widespread.
This chapter provides an overview of the evidence that outdoor
and indoor air pollution are causally related to lung and other types of
cancer. The topic of secondhand smoke and lung cancer is addressed
in Chapter 11 of this volume as well. The evidence on air pollution
and lung cancer is now extensive and this review is necessarily selec-
tive, emphasizing the most recent findings, primarily from the epi-
demiologic literature. A 1990 monograph provides a more complete
review of the earlier literature on outdoor air pollution (Tomatis,
1990). The IARC has published a review monograph that compre-
hensively covers combustion products, including indoor and outdoor
air pollution, and cancer, as well as completing a series of volumes
on the carcinogenicity of these agents (IARC, 2010a, 2010b, 2013b,
2013c, 2015). This chapter focuses on outdoor, primarily urban, air
pollution and indoor air contaminants in relation to lung cancer in
high-​income countries. Mounting evidence indicates that people in
developing countries have exposures to indoor and outdoor environ-
ments that rival and often dramatically exceed those found in high-​
income Western countries (Gordon et al., 2014). Indoor air pollution
from coal combustion and cooking fumes are thought to account for
the high lung cancer risk among women in China and Hong Kong,
despite the low prevalence of smoking (Bruce et al., 2015). Rising
pollution of outdoor air in the mega-​cities of the developing world
also poses a risk for lung cancer. These topics are addressed else-
where (Brauer et al., 2012, 2016; Katsouyanni, 2013; Krzyzanowski
et al., 2014).
291
29

292 PART III:  THE CAUSES OF CANCER

EXPOSURES TO INHALED CARCINOGENS Table 17–​1. Summary Concentrations of Air Toxics “Pollutants

of Interest” in the United States for 2010

Factors That Affect Exposure Compound Median 25th Percentile 75th Percentile
Exposures to inhaled carcinogens take place in a variety of settings, PAHsa
including the home, the workplace, other public and commercial Acenaphthene 2.04 0.983 4.30
locations, and outdoors. The concept of total personal exposure pro- Benzo(a)pyrene 0.02 0 0.1
vides a useful framework for conceptualizing exposures to inhaled Fluorene 2.91 1.75 5.39
carcinogens and evaluating the contributions of outdoor and indoor Naphthalene 66.4 36.6 117
air pollution (National Research Council et al., 2012). Total personal
exposure represents the integrated exposure to an agent accumulated Metalsb
in multiple microenvironments (i.e., environments having a relatively Arsenic (PM10) 0.415 0.240 0.700
homogeneous concentration of the agent of interest during a speci- Beryllium (PM10) 0.002 0.0003 0.004
fied time period). For an inhaled carcinogen such as benzo[a]‌pyrene, Cadmium (PM10) 0.084 0.050 0.176
relevant microenvironments over the day might include outdoor air Lead (PM10) 2.32 1.45 3.74
contaminated by vehicle exhaust and industrial emissions, workplace Manganese (PM10) 4.03 2.15 7.97
exposures, and air contaminated by tobacco smoke in a bar. For each Nickel (PM10) 0.845 0.594 1.22
microenvironment, the exposure received depends on the concentra- Hexavalent chromium 0.018 0 0.032
tion of the carcinogen and the time spent in the microenvironment. Carbonylsc
Total personal exposure is the sum of the products of concentration Acetaldehyde 0.893 0.597 1.29
with time spent in each microenvironment. Formaldehyde 1.66 1.09 2.47
Also relevant is the total volume of inhaled air, which for adults VOCsd
is about 10,000 liters per day. Because of the large volume inhaled, Acrylonitrile 0 0 0
meaningful doses of carcinogens may reach the lung at relatively low Benzene 0.245 0.173 0.373
concentrations. The actual lung dose of the carcinogen will further 1,3-​Butadiene 0.026 0.012 0.048
depend on the exposed person’s ventilation rate and pattern, physical Carbon tetrachloride 0.037 0.013 0.272
characteristics of the agent, and other factors that affect the location Chloroform 0.020 0.014 0.031
and amount of deposition in the lung (National Research Council and p-​Dichlorobenzene 0.007 0 0.019
Panel on Dosimetric Assumptions Affecting the Application of Radon 1,2-​Dichloroethane 0 0 0
Risk Estimates, 1991). Inhaled carcinogens may be absorbed into the Ethylbenzene 0.053 0.03 0.1
systemic circulation. Doses to other organs (e.g., the urinary bladder) Tetrachloroethylene 0.016 0.008 0.03
depend on uptake, metabolism, distribution, and excretion. Trichlororethylene 0 0 0
The relevant microenvironments vary depending on the carcinogen Vinyl chloride 0 0 0
of concern. Because most time is typically spent at home, exposures to
contaminants in household air dominate for certain pollutants such as
PAHs: polycyclic aromatic hydrocarbons; PM10: particulate matter with particles of
radon. Based on time-​activity patterns and policies regarding smoking, aerodynamic diameter, 10μm; SD: standard deviation; VOCs: volatile organic compounds.
the workplace can be a significant source of exposure to secondhand a
PAHs: unit is ng/​m3.
smoke as well as industrial carcinogens. In high-​income countries, b
Metals: unit is ng/​m3.
adults generally spend little time outdoors, but pollutants in ambient
c
Carbonyls: unit is ppbv.
d
VOCs: unit is ppbv.
air can diffuse into homes. The microenvironments in which exposures Source: IARC, 2015
occur influence the choice of control strategies. Some environments
are shared and public; initiatives to control exposure in these settings
require action at the societal level, often involving regulations. Other Incinerator emissions are also mutagenic; their activity reflects PAH
environments are private, and control lies with individuals. Whereas content and nitroarenes (DeMarini et al., 1998). The IARC has sum-
regulations are often essential to control toxic exposures in public set- marized the findings of hundreds of studies of the mutagenicity of par-
tings, education is usually the mainstay of initiatives to reduce expo- ticles collected in outdoor air (IARC, 2015). Investigators have used
sures to carcinogens in the home. biomarkers of exposure to ambient air pollutants to better characterize
patterns of exposure. These studies have been primarily focused on
polycyclic aromatic hydrocarbons and markers of oxidative stress. The
OUTDOOR AIR POLLUTION results have been mixed. In a 1992 study in Poland (Perera et al., 1992),
Perrera and colleagues measured PAH-​DNA adducts in lymphocytes
as markers of molecular and genetic damage. Residents of a highly
Exposures to Carcinogens in Outdoor Air
industrialized and polluted area had higher mean levels of PAH-​DNA
Ambient air, particularly in densely populated urban environments, adducts than residents of a comparison area. Autrup and colleagues
contains a variety of known human carcinogens, including organic (Autrup et  al., 1999)  compared measurements of bulky carcinogen-​
compounds such as benzo[a]‌ pyrene and benzene, inorganic com- DNA adducts and 2-​amino-​apidic semialdehyde, a marker of oxidative
pounds such as arsenic and chromium, and radionuclides (Table 17–​1) stress, in non-​smoking Danish bus drivers and postal workers. The lev-
(IARC, 2015). These substances are present as components of com- els of adducts, but not the biomarker of oxidative stress, were higher in
plex mixtures, which may include carbon-​based particles to which the the bus drivers in central Copenhagen. In a study in Germany, markers
organic compounds are adsorbed, oxidants such as ozone, and aerosols of exposure to benzo[a]‌pyrene tended to be higher in city dwellers,
of sulfuric acid. The combustion of fossil fuels for power generation or compared with suburban dwellers. In the AULIS project in Greece,
transportation is the main source of organic and inorganic compounds, the mean levels of bulky DNA adducts were higher in residents of
oxidants, and acids; combustion byproducts contribute heavily to par- the the rural town of Halkida than in Athens (Georgiadis et al., 2001;
ticulate air pollution in most urban settings. Radionuclides also result Kyrtopoulos et  al., 2001), although the levels were also higher in
from fuel combustion, as well as from mining operations. those exposed to secondhand smoke. The findings in relation to resi-
The plausibility that outdoor air pollutants cause cancer is sup- dence location were unanticipated, given that prior studies tended to
ported by studies that have addressed its genotoxicity using in vitro show higher levels of markers of genotoxicity in urban workers and
assay systems and biomarkers. Urban air samples are mutagenic in residents (Kyrtopoulos et  al., 2001). By contrast, in a study of stu-
the Salmonella assay, and much of the activity is attributable to poly- dents in Copenhagen, measured personal exposure to small particles
cyclic aromatic hydrocarbons (PAHs) (DeMarini, 2013; IARC, 2015). was associated with 7-​hydro-​8-​oxo-​2′-​deoxyguanosine, a marker of
 293
Air Pollution 293
DNA damage in lymphocytes; other associations between exposure
and biomarker levels were not found (IARC, 2015). The differences in
findings may reflect the differing levels of exposure and the markers
considered.
Unfortunately, there are few databases that record long-​term
measurements of carcinogens and other products from fossil fuel
combustion that could be used in epidemiologic studies. Available
data indicate that there have been improvements in some indi-
ces of air quality in the United States and some other developed
countries in recent decades (US Environmental Protection Agency
[EPA], 2016).
Particulate matter with an aerodynamic diameter < 2.5 μm, PM2.5, has
been the airborne pollutant of greatest current interest with respect to
lung cancer because particles of size 2.5 μm or less can be inhaled and
deposited in the lung. These generally originate from combustion and
may transport carcinogens, such as polycylic aromatic hydrocarbons,
on their surfaces. Comprehensive monitoring of PM2.5 has only been in
place since about 2000; previously, the US Environmental Protection
Agency (EPA) monitored particles with diameters up to PM10; before
1988, it monitored only total suspended particulates (TSP), some of
which are too large to be inhaled into the lung. Progressive declines
in these indicators of combustion product pollution have been docu-
mented, following emissions reductions for these pollutants and their
precursors (US EPA, 2016).
The data discussed in the preceding refer to ambient air pollu-
tion over relatively large geographic areas. However, the exposure of
human populations to carcinogens in ambient air may result from local
sources, such as small businesses (e.g., automotive body or chrome
plating shops), municipal facilities (e.g., waste incinerators), or areas
with high vehicular traffic (Health Effects Institute, 2010). Studies in
Harlem show that diesel particle exposures to pedestrians can be sub-
stantial (Kinney et al., 2000) and that high school students are exposed
to a variety of toxic air pollutants throughout the day (Kinney et al.,
2002). Levy and colleagues collected spot air samples along sidewalks
in a section of Boston with heavy diesel bus traffic, and detected “hot
spots” for exposure to benzo-​(a)-​pyrene, a marker for combustion
emissions (IARC, 2013b; Levy et al., 2000).
Combustion Products
As noted earlier, the combustion of fossil fuels for transportation and
power generation generates many known or suspected carcinogens.
The following section discusses some of the more significant pollut-
ants in terms of exposure prevalence and/​or lung carcinogenicity. The
IARC’s Outdoor Air Pollution (Volume 109) provides more detailed
information on these pollutants (IARC, 2015).
Polycyclic Organic Matter
Polycyclic organic matter (POM), comprises a large and varied class
of chemical compounds that include polycyclic aromatic hydrocar-
bons (PAH) and nitro-​PAHs. The IARC classifies both categories as
carcinogenic and mutagenic (IARC, 2010b, 2013a). These POM have
common chemical features (one or more benzene rings and a boiling
point > 100°C), and can be found in both the solid and gas phases
contaminants of ambient air, depending on their exact chemical struc-
ture. Those with > 5 benzene rings tend to be associated with the par-
ticle phase. In addition to the compounds released directly into the
environment by combustion, others (such as the byproducts of diesel
combustion) are created secondarily by chemical and photochemical
reactions in the environment (Greenberg, 1987; Natusch, 1978; Winer
and Busby Jr, 1995; Zielinska et al., 2010).
Although the combustion of fossil fuels is a ubiquitous source of
POM in the urban air, it is not the only source of human exposure to
POM, and for some individuals it may not be the main source. Other
exposure comes from inhaling tobacco or wood smoke, and from diet
(e.g., from the consumption of grilled meat).
Benzo-​(a)-​pyrene is a constituent of POM that has been extensively
studied and is known to be carcinogenic. It is frequently used as a sur-
rogate or marker for combustion sources in epidemiologic studies and
risk assessment (see later in this chapter). Armstrong and colleagues
have reviewed the literature on cancer risk in relation to occupational
and environmental exposure to PAHs (Armstrong et al., 2004). They
concluded that PAHs are associated with increased lung cancer risk in
occupational and urban environments. Workers exposed to mixtures of
polycyclic compounds in coke-​ovens and coal gasification plants (Doll
et al., 1972; Redmond, 1983) have increased lung cancer risk (IARC,
2012b). The levels of POM encountered in urban air are substantially
less than in these settings.
Particles
The IARC’s Outdoor Air Pollution (Volume 109) classified particulate
matter in outdoor air pollution as a Group 1 carcinogen (IARC, 2015).
Like POM, particulate air pollution is not a single entity, but rather
a chemically and physically diverse group of pollutants. Particles
derive from sea spray and crystal dust, as well as from combustion of
diesel fuel. Carbonaceous particles produced by burning fossil fuels
are in the respirable range (generally < 1.0 μm in aerodynamic diam-
eter) and can transport carcinogens, such as PAHs, adsorbed to their
surfaces. Carcinogenicity appears to be modified by the rate of expo-
sure. Experiments in animals demonstrate that even relatively pure
carbon particles can induce lung cancer in rats when administered
at high concentrations, suggesting that particles per se might, under
some conditions, be carcinogenic (Mauderly, 1997). The relevance
of these findings for humans is controversial, since the tumors in
rats were observed at doses that far exceeded the exposures to die-
sel exhaust and overwhelmed lung clearance mechanisms (Winer and
Busby Jr, 1995).
Gaseous pollutants, such as sulphur dioxide (SO2) and oxides of
nitrogen (NOx), are produced by the combustion of fossil fuels and
then are converted into fine particles in the atmosphere. Epidemiologic
studies have not found consistent evidence of lung cancer risk from
occupational exposure to SO2. The IARC has classified strong sulphuric
acid aerosol as a known human carcinogen based on increased lung
and laryngeal cancer in heavily exposed occupational groups (IARC,
2012b).
Diesel
Diesel exhaust is a ubiquitous component of air pollution worldwide.
The IARC recently summarized current estimates of the proportionate
contribution of diesel exhaust to ambient PM2.5. These ranged from
approximately 2% in remote rural locations to more than 30% in cities
(IARC, 2013b). The IARC has classified diesel exhaust as a human
carcinogen, based on occupational studies and supporting animal and
mechanistic data (IARC, 2013b).
Other
The combustion of fossil fuels contributes known or suspected indi-
vidual carcinogenic chemicals to urban ambient air. In addition to such
known human lung carcinogens as arsenic, chromium, and nickel, sev-
eral others are of note, and are discussed briefly here.
Radionuclides.  Alpha-​emitting radionuclides can also be mea-
sured in outdoor air. These include isotopes of lead, radium, thorium,
and uranium (Natusch, 1978) that are naturally present in fossil fuels
and are released by combustion. These contribute a relatively small
proportion of the radiation dose received by the general population
(National Council on Radiation Protection and Measurements, 2009).
1,3-​butadiene.  1,3-​butadiene is a volatile organic compound used
since the 1930s to produce synthetic rubber. Industrial emissions contrib-
ute to its presence in some urban areas. However, the major source in the
United States is automotive exhaust. Emissions are substantially greater
for vehicles with more than two axles (Sapkota and Buckley, 2003).
Levels of 1,3-​butadiene in ambient air generally range from 1 to 10 ppb,
about 1000-​fold less than occupational exposure levels (IARC, 1992).
1,3-​butadiene has been classified by the IARC as a human car-
cinogen (Group 1) based largely on animal experiments, which found
increased tumor occurrence at multiple sites, including the lung (IARC,
2012b). Epidemiologic studies of occupationally exposed populations
294
294 PART III:  THE CAUSES OF CANCER
(rubber workers and butadiene monomer production workers) have
consistently observed increases in hematopoietic cancers, but not can-
cers of the respiratory system (IARC, 2012b).
Aldehydes.  Various aldehydes are classified as hazardous air pol-
lutants by the US EPA. Formaldehyde and acetaldehyde are present in
urban ambient air largely because of the combustion of gasoline and
diesel fuel (Health Effects Institute, 2010). Exposures to formaldehyde
and acetaldehyde in outdoor air tend to be highly correlated. Outdoor
concentrations of formaldehyde generally range from 1 to 20 μg/​m3.
Levels up to 100 μg/​m3 have been observed in heavy traffic or episodes
of air pollution (IARC, 2012b). Combustion of alternative fuels, such
as methanol, and oxygenated fuels containing the additive MBTE also
yields aldehydes (Health Effects Institute, 1993). Formaldehyde is
present in indoor as well as outdoor air.
Formaldehyde has been classified as a human carcinogen by the
IARC and the National Toxicology Program (IARC, 2006, 2012b;
National Toxicology Program, 2014), based on evidence from animal
experiments and occupationally exposed workers with an excess of
nasal and nasopharyngeal cancer and leukemia.
Point Sources
Industrial point sources also contribute to air pollution. Electrical
power plants fueled by fossil fuels (e.g., coal, oil, and natural gas) emit
known and suspected carcinogens (Natusch, 1978). These include met-
als and metalloids (chromium, nickel, and arsenic), radionuclides such
as radon and uranium, and POM such as benzo(a)pyrene. Non-​ferrous
metal smelters emit inorganic arsenic and other metals, and sulphur
dioxide (Pershagen et  al., 1977). Municipal solid waste incinerators
emit heavy metals (e.g., lead and cadmium), PAHs, organic compounds
(such as dioxins), and acidic gases (World Health Organization, 1988).
Unfortunately, these sources of air pollution are often located in or
near poor, working-​class communities. Reports describing cancer rates
around point sources have addressed chemical disasters (e.g., dioxin in
Seveso, Italy) (Bertazzi et al., 1993), radiation from the nuclear reactor
accident at Three Mile Island, Pennsylvania (Hatch et al., 1990, 1991),
and other sources (Pershagen, 1990). Such studies have been useful
for examining specific issues but are not essential for addressing the
broader issue of air pollution and cancer. Methods have been devel-
oped for studying point sources (Elliott, 2006).
Fibers
Asbestos fibers contaminate ambient air in rural and urban environ-
ments, and apparently have been present in the ambient environment
for at least 10,000 years. The literature on levels of asbestos in outdoor
air was reviewed as part of a comprehensive report on the health effects
of asbestos in public buildings (Health Effects Institute et al., 1991).
The median levels of asbestos fibers in rural environments, where
there are no known natural sources of asbestos, were on the order of
0.01–​0.001 ng/​m3; few individual measurements exceeded 1  ng/​m3.
In urban environments, where there is both a greater prevalence of
asbestos-​containing materials and a higher frequency of release of
fibers from building materials and vehicular brake linings, the median
levels ranged from 0.02 to 10 ng/​m3 and a much larger proportion of
individual measurements exceeded 1 ng/​m3 (Health Effects Institute
et al., 1991).
Epidemiologic studies of occupational groups, such as asbestos
miners and asbestos textile production workers, who were exposed
to asbestos at concentrations several orders of magnitude greater
than those cited in the preceding, have consistently observed
increased rates of lung cancer. Based on a large body of experi-
mental and epidemiologic evidence, asbestos is considered to be a
known human carcinogen (IARC, 2012a). Lung cancer occurrence
was not increased in relation to exposure at levels observed in the
ambient urban environment in a study of chrysotile-​asbestos min-
ing regions (Camus et al., 1998). The risks of different fiber types
remain contentious.
EPIDEMIOLOGIC EVIDENCE ON OUTDOOR
AIR POLLUTION AND CANCER
Research Approaches
Epidemiologists have used three approaches to examine the role of
indoor and outdoor air pollution, in the etiology of lung and other can-
cers: cohort, case-​control, and ecologic designs. Historically, some of
the earliest studies of outdoor air pollution were based on ecologi-
cal approaches, comparing lung cancer mortality rates in urban and
rural areas (Stocks and Campbell, 1955). Ecological studies have also
been used in exploratory assessments of the association of indoor
radon with lung cancer. However, the recent and most critical evi-
dence comes largely from cohort and case-​control studies, which use
more refined approaches for exposure assessment than earlier studies
(IARC, 2015).
Cohort studies of outdoor air pollution have usually defined expo-
sure based on residence location. Thus, the information on age, gen-
der, potential confounders such as cigarette smoking, and exposure
to air pollution were classified at the individual level, whereas the
information on the covariates was ecological. Recent studies have
refined exposure estimates based on statistical models of the location
of residence (Krewski et  al., 2009; Raaschou-​Nielsen et  al., 2013).
The case-​control approach provides investigators with an efficient way
to estimate the relative risk of lung cancer in relation to air pollution
exposure without requiring access to an existing cohort or the collec-
tion of information on an entire population. In case-​control studies,
cases of lung cancer that occur in the population are identified and
classified according to their exposure to outdoor or indoor air pollu-
tion; a sample of the study population—​the controls—​is selected and
similarly classified according to their exposures. While most recent
data come from cohort studies, nested case-​control studies are useful
for assessing biomarkers.
In contrast to the cohort and case-​control designs, ecologic, or
aggregate-​level, studies do not collect information on individual sub-
jects, but instead compare the incidence or mortality rates of lung or
other cancers in relation to the levels of air pollution. This approach
uses routinely collected data on both lung cancer rates and regional
measurements of air pollution. In these studies, surrogate measures
of exposure have been used based on geologic features, housing char-
acteristics, or measurements of indoor concentrations. Relative risks
can be estimated from ecologic data, but the interpretation of these
estimates is more complicated than for estimates derived from cohort
and case-​control studies. In most cases, data are not available to take
into account inter-​individual and between-​region differences in other
lung cancer risk factors. Ecological studies of air pollution are no lon-
ger informative.
All three designs potentially suffer from a common problem when
applied to the study of air pollution and lung cancer: the difficulty of
characterizing accurately the subjects’ exposure to air pollution and
mixtures of diverse carcinogens inhaled in indoor and outdoor envi-
ronments. As described earlier, an individual’s exposure to carcino-
gens in outdoor and indoor environments may be complex and may
occur in multiple microenvironments; therefore it may be difficult to
estimate exposure for the purpose of epidemiologic analysis. Some
of the exposure assessment approaches used are listed in Table 17–​2
(Di et al., 2016; van Donkelaar et al., 2015); these range from cat-
egorical indicators, such as self-​report and residence location, to
contemporary geographic information systems and statistical models
based on monitoring and satellite data, and land use characteristics.
The early lung cancer studies often classified exposure to outdoor
air pollution based on urban or rural residence, a crude indicator of
current or lifetime exposure. In some subsequent studies, approaches
based on residence location were refined by more fully capturing
the residential history and incorporating duration of residence into
exposure indexes.
Exposure estimates have been refined by using available monitoring
data in combination with air pollution models that incorporate land-​
use information (e.g., roadways and major point sources and, most
 295
Air Pollution 295
Table 17–​2. Methods of Assessing Exposure
Source of Information Type of Information
Source strength Emission rate (mass per time), traffic
density
Geographical information Distance of place of residence from the
source
Dispersion models Spatiotemporal concentration distributions
from modeling of emission rates,
meteorology, air chemistry, geography
Outdoor–​indoor penetration Modeling from outdoor concentration,
building, and ventilation characteristics
Stationary monitoring Concentration over time and by place
Questionnaires and interviews Source strength, distance from the source,
time activity
Personal monitoring Continuous or cumulated concentrations
over time
Human samples Concentrations of biomarkers of exposure
in biospecimens
Toxicological models Concentration and dose of pollutants
in target organs modeling from
concentration, breathing rate, metabolism
Monitoring data, land use regression,
Spatial models satellite data
Source: van Donkelaar et al., 2015; Di et al., 2016.
recently, satellite data) to assign concentrations to the residences where
study participants live. For example, the European Study of Cohorts
for Air Pollution Effects (ESCAPE) pooled data from 17 cohorts
across Europe. Measurements were made in each study site, and then
a land-​use regression model was developed to estimate concentrations
of particulate matter and nitrogen oxides at the home addresses of par-
ticipants (Raaschou-​Nielsen et al., 2013). These approaches have been
continually refined and are now complemented by the use of satellite
data to estimate concentrations of airborne particulate matter and other
pollutants (Di et al., 2016; van Donkelaar et al., 2015).
There has also been extensive attention given to the development of
approaches to estimating exposures to indoor carcinogens, particularly
secondhand smoke and radon, and, to a lesser extent, asbestos. While
the association of secondhand smoke with lung cancer is not specifi-
cally covered in this chapter, the conceptual approaches to assessing
exposure to secondhand smoke are covered because of their relevance
to the topic of air pollution and cancer. For each of these agents, the
validity of exposure assessment approaches and the degree of misclas-
sification and resulting bias in risk estimates have figured prominently
in the interpretation of the epidemiological findings.
The micro-​environmental model has become the model for expo-
sure assessment. For radon, individual-​and population-​level expo-
sures are largely driven by exposures at home, as mentioned earlier.
These reflect both the time spent at home and the home concentra-
tions. Radon concentrations can be measured in homes, using passive
and relatively inexpensive but accurate measuring devices that record
the average concentration across intervals ranging from days to a
year. A technique to measure longer-​term exposures has been devel-
oped that uses levels of surface radioactivity in glass (Steck et  al.,
2002). Issues related to misclassification based on these approaches
are considered in the section of this chapter on indoor radon.
For secondhand smoke, exposure measurement has involved quali-
tative assessments based on questionnaires and quantitative assess-
ments based on biomarkers or air measurements (Apelberg et al., 2013;
Avila-​Tang et al., 2013a, 2013b). Study participants can describe the
smoking status of their spouse, the number of smokers at home, and
the extent of exposure at work or in other settings in the recent past.
Cotinine and other biomarkers of tobacco smoke provide objective
evidence of exposure within the past 3–​7 days. Self-​reported informa-
tion on exposures in childhood and at various periods throughout life
cannot be validated directly, but can provide qualitative information
about past exposures. The issue of misclassification was central to the
efforts of the tobacco industry to discredit the extensive evidence that
secondhand smoke causes lung cancer (Proctor, 2012).
All exposure estimates in studies of air pollutants are subject to some
misclassification. Usually this misclassification is non-​differential, in
that its effects are similar in subjects with and without lung cancer.
This form of misclassification attenuates the association between an
air pollutant and cancer (Jurek et  al., 2005; Szpiro et  al., 2011)  and
can obscure a monotonic relationship with exposure (Birkett, 1992;
Dosemeci et al., 1990; Jurek et al., 2005). Studies may differ in the
degree of misclassification, however. This can create the misimpres-
sion that their results are in conflict (Lubin et  al., 1995a, 1995b;
Rothman and Greenland, 1998). Differential misclassification can
spuriously elevate as well as attenuate estimates of association. This
form of bias is of less concern than confounding, however. Most stud-
ies of air pollution attempt to collect data on other lung cancer risk
factors, such as cigarette smoking or occupational exposures. Errors
in the measurement of potential confounders can introduce bias, even
if air pollution exposures are estimated with relatively little error; the
result may be either over-​or underestimation of the air pollution effect
(Greenland, 1980).
Epidemiologic Studies of Ambient Air Pollution
and Lung Cancer
The first studies on lung cancer and air pollution compared lung can-
cer death rates in urban and rural areas. These studies coincided with
the early studies of smoking and lung cancer; consequently, some (but
not all) attempted to control for smoking. Most studies found over-
all excesses of lung cancer mortality of about 30%–​40% in the urban
areas. The attribution of these excesses to differences in air quality was
strengthened by evidence of urban/​rural differences in ambient levels
of carcinogens, such as benzo-​(a)-​pyrene, and by the persistence of
the urban excess after adjustment for cigarette smoking status in some
studies.
Later studies have used increasingly sophisticated methods to esti-
mate exposure and control for potential confounders. Detailed descrip-
tions of these studies are provided in the IARC’s Outdoor Air Pollution
(Volume 109; IARC, 2015). Groundbreaking findings came from the
Harvard Six Cities Study and the American Cancer Society’s (ACS)
Cancer Prevention (CPS) II Study, with initial findings published in
1993 and 1995, respectively. Both found increased risk for lung cancer
in association with higher levels of exposure to PM2.5, a finding repli-
cated in many subsequent studies. A meta-​analysis of 18 studies, car-
ried out in support of the IARC’s Volume 109, found that lung cancer
risk increased by nearly 10% (meta-​relative risk 1.09; 95% CI: 1.04,
1.14) with each 10 μg/​m3 increase of PM2.5 (Figure  17–1) (Hamra
et al., 2014). There was no strong evidence for variation by geographic
region or smoking status.
In most of the cohort studies, the exposures were assigned based
on air pollution data at a single point in time or averaged over
extended periods. Consequently, most studies have not examined
the relationship between air pollution and lung cancer with respect
to the timing of exposure. Analyses of extended follow-​ups of both
the Six Cities and ACS cohorts suggest that more recent exposures
may have the strongest effects on all-​ cause mortality (Krewski
et al., 2000).
The current evidence suggests that lung cancer attributable to air
pollution may occur among both smokers and non-​smokers (Hamra
et al., 2014); therefore, residual confounding and effect modification
by air pollution must be considered, especially among the smokers.
Most studies report air pollution relative risks adjusted for cigarette
smoking, but the adjustment may not have controlled completely for
potential confounding. Most cohort studies have information on ciga-
rette smoking only at the beginning of follow-​up. The possibility that
changes in tobacco use were correlated with air pollution exposure
cannot be excluded, since patterns of smoking cessation have varied
geographically in the United States. On the other hand, the associa-
tion of lung cancer with air pollution was largely unaffected in the
Six Cities Study (Dockery et al., 1993), when longitudinal information
296

296 PART III:  THE CAUSES OF CANCER

Study by region RR (95% CI) Weight

North America
McDonell et al. 2000 1.39 (0.79, 2.46) 0.66
Krewski et al. 2009 1.09 (1.05, 1.13) 21.19
Hart et al. 2011 1.18 (0.95, 1.48) 3.77
Lipsett et al. 2011 0.95 (0.70,1.28) 2.22
Lepeule et al. 2012 1.37 (1.07, 1.75) 3.20
Hystad et al. 2013 1.29 (0.95, 1.76) 2.14
Jerrett et al. 2013a 1.12 (0.91, 1.37) —
Puett et al. 2014 1.06 (0.90, 1.24) 6.48
Subtotal (/ 2 = 0.0%, p = 0.490) 1.11 (1.05, 1.16) 39.67
Europe
Beelen et al. 2008 0.81 (0.63, 1.04) 3.11
Carey et al. 2013 1.11 (0.86, 1.43) 3.07
Cesaroni et al. 2013 1.05 (1.01, 1.10) 20.21
Raaschou-Nielsen et al. 2013 1.39 (0.91, 2.13) 1.17
Subtotal (/ 2 = 50.0%, p = 0.112) 1.03 (0.89, 1.20) 27.56
Other
Cao et al. 2011 1.03 (1.00, 1.07) 21.25
Katanoda et al. 2011 1.24 (1.12, 1.37) 11.52
Subtotal (/2 = 91.0%, p = 0.001) 1.13 (0.94, 1.34) 32.77

Overall (/2 = 53.0%, p = 0.010) 1.09 (1.04, 1.14) 100.00

0.5 1 2 3

Figure 17–​1.  Estimates of lung cancer relative risk associated with relative risks. Source: Hamra et al. (2014).

on cigarette smoking was used in a reanalysis. Several case-​control
studies have adjusted for smoking using time-​varying information and
still found increased risk for air pollution exposure (e.g., Nyberg et al.,
2000). With one exception (Turner et al., 2011), the studies that show
increased lung cancer risks among self-​reported never-​smokers have
been small and the effect estimates imprecise. However, Turner and col-
leagues (2011) estimated that long-​term residential exposure to PM2.5
increased lung cancer mortality by 15% to 27% per 10μg/​m3 increase
in exposure in 188,699 lifelong never-​smokers in the American Cancer
Society’s CPS II cohort (Turner et al., 2011). A subsequent analysis
of this cohort by Turner et  al. (2014) found that the effects of joint
exposure to PM2.5 and tobacco smoking were greater than additive,
corroborating the results of several earlier studies (IARC, 2013c).
Limitations of approaches to exposure estimation also contribute to
uncertainty in risk estimates. The ACS and Six Cities studies estimated
the exposure of each participant based solely on long-​term average con-
centrations in the metropolitan area of residence. While this approach
may accurately reflect exposure to pollutants that are distributed homog-
enously over large areas for several decades, it does not capture finer
spatial and temporal variation; more recent studies in Europe and North
America are now incorporating spatial statistical methods to estimate
individual long-​term exposure histories, linking residential histories,
measurements of traffic density on nearby streets, and long-​term records
of specific air pollutants. With this approach, the variations in exposures
can be estimated in relation to time and space, perhaps with less mis-
classification (Hoek et al., 2002; Nyberg et al., 2000; Reynolds et al.,
2001). Hoek and colleagues observed larger relative risk estimates for
cardiopulmonary mortality among subjects who lived near major roads
than were observed in studies that used larger-​scale urban and regional
measurements (Hoek et  al., 2002). The highest relative risk estimates
were with exposure 20 or more years before diagnosis (Nyberg et al.,
2000). By providing exposure estimates at the individual level, these
studies also reduce the possibility of aggregate-​level (ecologic) bias.
Risk Attribution
Estimates of the population attributable risk of lung cancer due to out-
door air pollution have been based on markedly different methods and
vary by an order of magnitude. The early estimates of burden were
low. Doll and Peto based their estimate on past and current estimates
of benzo-​(a)-​pyrene in urban air and extrapolation from occupational
studies of PAH-​exposed workers (Doll and Peto, 1981). They esti-
mated that less than 1% of future lung cancer in the United States
would be due to air pollution from the burning of fossil fuels. They did
note, however, that perhaps 10% of the lung cancers then occurring
in large cities might have been due to air pollution. In 1990, the US
EPA (US EPA, 1990) estimated that 0.2% of all cancer, and probably
less than 1% of lung cancer, could be attributed to air pollution. This
estimate was obtained by applying the unit risks for over 20 known or
suspected human carcinogens found in outdoor air to estimates of the
ambient concentrations and numbers of persons potentially exposed.
The Global Burden of Disease project provides the most com-
prehensive worldwide estimates of the global burden of lung can-
cer due to ambient and household air pollution (Cohen et  al., 2016;
Forouzanfar et al., 2015; Institute for Health Metrics and Evaluation,
2016). Exposure to ambient PM2.5 was estimated to have contributed
to 387,000 (UI: 350, 000–​420,000) lung cancer deaths (23.6% of the
total), and a resultant loss of 8.3 million (uncertainty interval [UI]: 7.5–​
9.1 million) disability-​adjusted life years (DALY) worldwide in 2013.
The estimated global lung cancer mortality rate attributable to ambient
PM2.5 increased from 4.64 to 5.41 per 100,000 from 1990 to 2013.
Fifty-​two percent (52%) of global lung cancer mortality due to PM2.5
in 2013 was estimated to have occurred in China.
When all causes of death were considered, ambient PM2.5 was the
seventh ranking global mortality risk factor in 2013. Exposure to
ambient PM2.5 contributed to an estimated 2.93  million (UI:  2.78–​
3.07 million) premature deaths and a loss of 69.7 million (UI: 65.5–​
75.5 million) DALY in 2013, or 5.3% of total global deaths and 2.9%
of global DALY. Sixty percent of this burden occurs in in low-​and
middle-​income countries in East and South Asia. The absolute number
of deaths estimated as attributable to ambient PM2.5 increased by 31%
from 1990 to 2013. Exposure to ozone was estimated to cause an addi-
tional 217,000 (UI: 161,000–​272,000) premature deaths and a loss of
5.1 million (UI: 3.6–​6.6 million) DALY in 2013. Worldwide, ambient
PM2.5 was the second leading cause of lung cancer mortality in 2013
after tobacco smoking.
Household air pollution (HAP) from burning of solid fuels was the
eighth ranking global mortality risk factor in 2013 (Institute for Health
 297
Air Pollution 297
Metrics and Evaluation, 2013). Exposure to HAP contributed to an
estimated 2.89 million (UI: 2.46–​3.30 million) premature deaths and
81.1 million (UI: 70.0–​92.8 million) DALY in 2013, largely in low-​
and middle-​income countries in East and South Asia. The absolute
number of deaths attributable to HAP increased by 1.3% from 1990
to 2013.
HAP was the fifth ranking cause of lung cancer in 2013, contributing
to 127,701 (UI: 57,000–​202,900) lung cancer deaths, and 2.9 million
(UI: 1.3–​4.6 million) DALY worldwide in 2013, with the preponder-
ance again in low-​and middle-​income countries in East and South
Asia (Institute for Health Metrics and Evaluation, 2013). Between
1990 and 2013 the estimated global lung cancer mortality rate (per
100 persons) attributable to HAP declined by 6.1%.
Diesel Exhaust and Cancer of the Lung and Bladder
The epidemiological evidence regarding the carcinogenicity of diesel
exhaust has been reviewed extensively and repeatedly, partly because
of the large numbers of people exposed and the implications for
regulation. Most of the evidence comes from studies of occupational
exposure rather than general populations, for whom exposure is dif-
ficult to estimate accurately (HEI Diesel Epidemiology Panel, 2015;
IARC, 2013b).
Epidemiologic evidence indicates that workers exposed to diesel
exhaust for prolonged periods in a variety of occupational settings are
at increased risk of lung cancer. Workers in jobs that entailed prolonged
exposure to diesel exhaust in the trucking and railroad industries and in
urban transport were shown to have approximately 20%–​50% higher
risk of lung cancer mortality in meta-​analyses of studies dating from
the 1950s through the mid-​1990s. This increased risk was independent
of tobacco smoking (Cohen and Higgins, 1995; Larkin et  al., 2000;
Lipsett and Campleman, 1999).
Occupational exposure to diesel exhaust is also linked to increased
risk of bladder cancer, based on less consistent evidence. The IARC’s
Monograph 105 (“Diesel and gasoline engine exhausts and some
nitroarenes”) noted that case-​control studies generally reported an
increased risk in occupationally exposed workers but cohort studies
did not (Cohen and Higgins, 1995; IARC, 2013b).
Until recently, few studies had linked lung cancer risk to quantitative
estimates of long-​term exposure to diesel exhaust; the resulting uncer-
tainty limited both causal attribution and quantitative risk assessment
(Health Effects Institute, 1999). New studies of underground miners and
trucking industry workers have linked long-​term exposure to respirable
elemental carbon (EC), a component of diesel particles, to lung cancer
in these settings. Underground miners exposed to extremely high levels
of diesel particles experienced 2-​to 3-​fold increases in lung cancer mor-
tality in analyses that controlled for tobacco smoking; trucking industry
workers experienced a 40% increase (Garshick et al., 2012; Silverman
et al., 2012). A recent reanalysis of these studies by the Health Effects
Institute corroborated the reported results and concluded that the new
studies provided a basis for quantitative risk assessment of lung cancer
due to diesel exhaust exposure (HEI Diesel Epidemiology Panel, 2015).
IARC’s Monograph 105 provides the most recent and comprehen-
sive summary of the numerous cohort and case-​control studies of die-
sel exhaust and cancer. This included the newer and more definitive
studies, and largely corroborated the conclusions of the earlier meta-​
analyses (IARC, 2013b).
Diesel exhaust is now considered by IARC to be “carcinogenic to
humans” (Group 1), based on epidemiologic and toxicologic evidence
(IARC, 2013b). With the finding that diesel exhaust is carcinogenic,
emphasis has shifted to quantitative risk assessment (HEI Diesel
Epidemiology Panel, 2015). To this end, Vermeulen et al. pooled the
results of three cohort studies (two of truckers and one of miners)
(Vermeulen et al., 2014). They estimated that lifetime environmental
exposure to 0.8 μg/​m3 EC would cause 21 excess lung cancer deaths
per 10,000 persons. They further estimated that “[b]‌ased on broad
assumptions regarding past occupational and environmental expo-
sures . . . approximately 6% of annual [US and UK] lung cancer deaths
may be due to DEE exposure (p. 175).” This estimate is broadly con-
sistent with earlier estimates by US regulatory agencies. Both the EPA
(2002) and the California EPA (1998) based their risk estimates on the
occupational epidemiology studies available at the time. Both agen-
cies have concluded that the evidence from occupational studies is
consistent with a causal relationship with lung cancer. The California
EPA calculated a unit risk value (1998), which ranged from 1 to 24
excess deaths in 10,000 people per 1 μg/​m3 diesel PM lifetime expo-
sure. The US EPA estimated a possible range of lung cancer risk from
environmental exposure to diesel exhaust (0.1 to 10 excess deaths
in 10,000 people per 1 μg/​m3 diesel PM lifetime exposure). The US
EPA, however, acknowledged recent improvements in diesel technol-
ogy, and uncertainty as to the relevance of these risk estimates to pres-
ent engines, a concern that was recently underscored by the result of a
major toxicologic study of the carcinogenicity of emissions from the
latest diesel engines. The ACES study of the Health Effects Institute
reported “dramatic improvements in emissions and the absence of any
significant health effects (especially cancer)” and concluded that “the
overall toxicity of exhaust from modern diesel engines is significantly
decreased compared to emissions from traditional-​technology diesel
engines (p. 5)” (HEI, 2015; US EPA, 2002).
Childhood Cancer and Exposure to Traffic-​Related
Air Pollution
Motor vehicle exhaust contains a number of known carcinogens,
including benzene, a known leukemogen (Chapter 38). In 1989 Savitz
and Feingold, using data from an earlier case-​control study of resi-
dential exposure to electric and magnetic fields (Savitz and Feingold,
1989), reported that vehicular traffic density at the residence of can-
cer cases was associated with an increased risk of leukemia and brain
cancer among children in Denver. As interest in the health effects of
air pollution on children has increased, and spatial statistical methods,
such as the geographic information system (GIS), have become more
widely available, this relationship has been studied by others with
inconsistent results (IARC, 2015). The IARC’s Outdoor Air Pollution
(Volume 109)  reviewed studies of all childhood cancers combined,
leukemia and lymphoma, and brain tumors. The evidence was con-
sidered to be subject to potential publication bias, but indicative of
possible weak association.
INDOOR AIR POLLUTION
Carcinogens in indoor air have large potential implications for risk
because people spend substantial amounts of time indoors. Indoor
air pollution may stem from incoming outdoor air or may originate
indoors from tobacco smoking, building materials, soil gas, household
products, and combustion from heating and cooking (Spengler, 1991).
In more developed countries, two of the most important indoor pollut-
ants that influence lung cancer risk in never-​smokers are passive smok-
ing (US Department of Health and Human Services, 1986, 2006) and
radon (National Research Council and Committee on Health Risks of
Exposure to Radon, 1999). Asbestos exposure may pose a risk to build-
ing occupants, but the resulting risk is estimated to be minimal, par-
ticularly if asbestos-​containing materials are appropriately managed
in place (Health Effects Institute et al., 1991). Other carcinogens are
present in indoor air, but have received less attention in high-​income
countries.
One major concern in economically developing countries is indoor
air pollution from the use of unprocessed solid fuels, notably coal,
for cooking and space heating (Martin et al., 2013). The high risk of
lung cancer among non-​smoking Chinese women has been mentioned
earlier.
Asbestos
Asbestos, a well-​established occupational carcinogen, includes several
forms of fibrous, naturally occurring silicate minerals that have been
widely used in products found in homes and public and commercial
buildings (Health Effects Institute et al., 1991). The epidemiologic evi-
dence on asbestos and lung cancer dates to the 1950s, although clinical
298
298 PART III:  THE CAUSES OF CANCER
case series had previously led to the hypothesis that asbestos causes
lung cancer (Lynch and Smith, 1939; Wedler, 1944). In a retrospec-
tive cohort study published in 1955, Doll observed that asbestos textile
workers at a factory in the United Kingdom had a 10-​fold elevation
in lung cancer risk and that the risk was most heavily concentrated
during the time frame before regulations were implemented to limit
asbestos dust in factories (Doll, 1955). A 7-​fold excess of lung cancer
was subsequently observed among insulation workers in the United
States (Selikoff et al., 1964, 1979). The peak incidence occurred 30–​
35 years after the initial exposure to asbestos (Selikoff et al., 1980).
Subsequently, numerous studies of specific worker groups and of the
general population have repeatedly documented the carcinogenicity of
asbestos (IARC, 2012a). The risk of lung cancer has been noted to
increase with increased exposure to asbestos and to be associated with
the principal commercial forms of asbestos. Asbestos and cigarette
smoking are both independent causes of lung cancer; in combination,
they act synergistically to increase risk in a manner compatible with a
multiplicative effect (Hammond et al., 1979; IARC, 2004).
With the recognition in the 1970s and 1980s that asbestos-​containing
materials were prevalent in indoor environments and a potential source
of airborne fibers, concern was raised as to risks to the general popula-
tion for both mesothelioma and lung cancer. In the United States, pro-
grams were initiated to either remove or manage asbestos-​containing
materials to limit releases of fibers. Because the concentrations were
generally very low, the risks could not be directly addressed using
epidemiological approaches. A  risk assessment was carried out by
the Health Effects Institute that used all available measurements of
indoor asbestos fiber concentrations and a concentration–​risk relation-
ship from studies of workers (Health Effects Institute et  al., 1991).
The concentration information considered by the Health Effects
Institute showed that exposures in indoor environments were gener-
ally quite low and were not elevated in comparison with levels in urban
outdoor air.
The US EPA estimates that an individual who continuously breathed
air containing asbestos at an average of 0.000004 fibers/​cm3 over his or
her entire lifetime would theoretically have no more than a 1 in 1 mil-
lion increased risk of developing cancer from this exposure. Similarly,
the EPA estimates that breathing air containing 0.00004 fibers/​cm3
would result in not greater than a 1 in 100,000 increased chance of
developing cancer, and air containing 0.0004 fibers/​cm3 would result
in not greater than a 1 in 10,000 increased chance of developing cancer
(US EPA, 1999). This risk was considered sufficiently low as to not
warrant removal of asbestos from buildings. The EPA now promotes
in-​place management of asbestos-​containing materials.
Radon
Radon is an inert gas produced naturally from radium in the decay
series of uranium. It decays into a series of relatively short-​lived
particle progeny; two of the short-​lived decay products emit alpha
particles that can, by virtue of their high energy and mass, damage
DNA in respiratory epithelial cells. Laboratory experiments involving
exposure of cells to single alpha particles show that even one “hit”
from an alpha particle causes permanent change in a cell. Even though
cancer is a multistage phenomenon, this finding implies that radon
exposure may result in increased risk at any level (National Research
Council and Committee on Health Risks of Exposure to Radon, 1999).
Research on radon is now quite consistent regarding carcinogenicity.
The various lines of evidence (dosimetric, in vitro, and epidemiologi-
cal) consistently support a linear no-​threshold risk relationship.
Epidemiologic studies of underground miners of uranium and
other ores have long established that exposure to radon and its decay
products causes lung cancer (Lubin et al., 1995a; National Research
Council and Committee on Health Risks of Exposure to Radon, 1999;
National Research Council and Committee on the Biological Effects
of Ionizing Radiation, 1988). In fact, radon exposure was probably
the first occupational respiratory carcinogen to be identified, based
on the extremely high rates of lung cancer documented in the under-
ground metal miners of Schneeberg and Joachimsthal and the high
levels of radon measured in the mines (National Research Council
and Committee on the Biological Effects of Ionizing Radiation,
1988; Proctor, 2012). While lesser risks have been observed for more
recent worker cohorts, the newer epidemiological studies show clear
evidence of a continued increase in cancer risk (Hunter et al., 2013;
Tirmarche et al., 2012). Cigarette smoking and radon decay products
synergistically influence lung cancer risk in a manner that is supra-​
additive but sub-​multiplicative (Lubin et al., 1995a; National Research
Council and Committee on Health Risks of Exposure to Radon, 1999).
Radon is of broad societal interest because it is a ubiquitous indoor
air pollutant, entering buildings in soil gas. On average, indoor expo-
sures to radon for the general population are much less than those
received by occupational groups such as uranium miners. For exam-
ple, even the lowest historical radon concentration in a uranium mine
is still roughly an order of magnitude higher than in the average home
(Lubin et  al., 1995a). However, measurements of indoor radon con-
centrations in homes show a log-​normal distribution with all homes
having some radon detectable at an average around 1 picocurie per
liter (37 becquerels per m3), but with a highly skewed tail of the dis-
tribution that corresponds to exposures in uranium mines. As a basis
for developing control strategies, risk assessments have estimated the
magnitude of the problem and the extent to which exposures must be
reduced to protect public health. Because of the prevalence of low and
average exposures in the population, these are of greatest concern.
After the problem of indoor radon was first widely recognized in the
early 1980s, case-​control studies were carried out to estimate the risks
directly. These studies complemented the information from cohort
studies of underground miners, which generally had much higher
levels of exposure. Most studies incorporated measurements of radon
concentrations in the homes of lung cancer cases and controls. The
interpretation of the findings was limited by exposure misclassifica-
tion, a particularly difficult problem in estimating lifetime exposure
(Lubin et al., 1995a). Measurement of implanted polonium-​210 in the
surface of glass (e.g., window glass or glass covering a picture) has
been proposed as an indicator of long-​term concentration and has been
applied in several epidemiological studies (Brownson and Alavanja,
2000; Field et  al., 2002; Steck et  al., 2002). Nonetheless, the risk
estimates from individual case-​control studies have been relatively
imprecise. A  meta-​analysis of the findings through the mid-​1990s
did show evidence for a significant and positive exposure–​response
relationship that was consistent with the extrapolated risks in the
miner studies (National Research Council and Committee on Health
Risks of Exposure to Radon, 1999). Subsequent pooled analyses of
the European and North American case-​control studies provide risk
estimates that are also consistent with the risk models based on the
underground miner studies (Darby et al., 2005; Krewski et al., 2005).
For the purpose of risk assessment and policy formulation, risk
models have been developed based on the findings in the underground
miners (US EPA, 2003). There are inherent uncertainties in extending
such models to the general population, particularly the extrapolation of
findings from highly exposed uranium miners to the much lower expo-
sures indoors. The studies of miners lacked information on women and
children and had little control over other differences between mines
and homes, such as exposure to diesel exhaust. Effect modification by
smoking added further uncertainty; the evidence from the miners indi-
cated synergy between smoking and radon, but the combined effect
was sub-​multiplicative (National Research Council and Committee on
Health Risks of Exposure to Radon, 1999).
From the policy perspective, the most critical uncertainty is whether
radon causes lung cancer at all exposures—​that is, is there a thresh-
old exposure below which radon does not cause cancer? Biological
evidence supports the assumption that a single hit to a cell by an
alpha particle causes permanent cellular change, an assumption lead-
ing to a non-​threshold dose–​response relationship (Hei et  al., 1994,
1997; National Research Council and Committee on Health Risks
of Exposure to Radon, 1999). Additionally, the case-​control study
findings to date provide evidence for increased risk down to levels
of exposure not substantially greater than that associated with typical
indoor concentrations. When combined in a meta-​analysis, studies of
the general population show a significant association between indoor
radon and lung cancer in the general population that is quantitatively
 29
Air Pollution 299
compatible with risk models derived from the underground miners.
This coherence lends support to using extrapolation of the miner data
with a linear, non-​threshold model to estimate the risk of indoor radon.
Consequently, the risk model developed by the National Research
Council’s Biological Effects of Ionizing Radiation (BEIR) VI
Committee (National Research Council and Committee on Health
Risks of Exposure to Radon, 1999) and subsequently applied by the
US EPA incorporates a linear model without a threshold. The assump-
tions made by the Environmental Protection Agency (US EPA, 1992b)
and the Biological Effects of Ionizing Radiation (BEIR) IV and VI
Committees of the National Research Council (National Research
Council and Committee on Health Risks of Exposure to Radon, 1999;
National Research Council and Committee on the Biological Effects
of Ionizing Radiation, 1988)  led to estimates that approximately
21,000 lung cancer deaths per year in the United States are attribut-
able to radon (with an uncertainty range of 8000 to 45,000), an esti-
mate that makes indoor radon the second-​leading cause of lung cancer
(US EPA, 2003). The story of research on radiation and lung cancer is
relatively complete and illustrates how epidemiological evidence can
inform policy decisions.
Secondhand Smoke
In 1981 reports were published from Japan (Hirayama, 1981)  and
from Greece (Trichopoulos et  al., 1981)  that indicated increased
lung cancer risk in non-​smoking women married to cigarette smok-
ers. This once controversial association has subsequently been
examined in numerous investigations in the United States and other
countries. A causal relationship between secondhand smoke (SHS)
and lung cancer is biologically plausibile, given the many carcino-
gens in sidestream smoke and the lack of a documented threshold
dose for respiratory carcinogens in active smokers (IARC, 2004; US
Department of Health and Human Services, 2006, 2010). Moreover,
genotoxic activity has been demonstrated for many components of
SHS (Claxton et  al., 1989; Hillerdal, 1996; IARC, 2004; Lofroth,
1989; Weiss, 1989). Experimental exposure of non-​ smokers to
SHS has validated the excretion of 4-​ (methylnitrosamino)-​
1-​(3-​
pyridyl)-​1 butanol (NNAL), a tobacco-​specific carcinogen, in urine
as a valid biomarker of exposure to tobacco smoke (Anderson et al.,
2001; Hecht et al., 1993). Non-​smokers exposed to SHS also have
increased concentrations of adducts of tobacco-​related carcinogens
(Crawford et al., 1994; Maclure et al., 1989).
Through the 1980s and 1990s, the tobacco industry sought to
maintain controversy and uncertainty about the carcinogenicity of
SHS (Proctor, 2012). In fact, the US courts found the tobacco indus-
try guilty of fraud and deception about the risks of SHS exposure
(Kessler, 2006).
There are long-​standing authoritative conclusions that SHS causes
lung cancer. By 1986, the evidence had mounted, and three consensus
reports published in the same year concluded that SHS was a cause
of lung cancer. The IARC (1986) concluded that “passive smoking
gives rise to some risk of cancer.” In its monograph on tobacco smok-
ing, the agency supported this conclusion on the basis of the char-
acteristics of sidestream and mainstream smoke, the absorption of
tobacco smoke materials during involuntary smoking, and the nature
of dose–​response relationships for carcinogenesis. In the same year,
the National Research Council (1986) and the US Surgeon General
(1986) also concluded that involuntary smoking increases the inci-
dence of lung cancer in non-​smokers. In reaching this conclusion, the
National Research Council (1986) cited the biological plausibility of
the association between exposure to SHS and lung cancer and the sup-
porting epidemiological evidence. Based on a pooled analysis of the
epidemiological data adjusted for bias, the report concluded that the
best estimate for the excess risk of lung cancer in non-​smokers mar-
ried to smokers was 25%. The 1986 report of the Surgeon General
(1986) characterized involuntary smoking as a cause of lung cancer
in non-​smokers. This conclusion was based on the extensive informa-
tion already available about the carcinogenicity of active smoking, the
qualitative chemical similarities between SHS and mainstream smoke,
and the epidemiological data on involuntary smoking.
In 1992 the US EPA (1992a) published its risk assessment of SHS
as a carcinogen. The agency’s evaluation drew on the toxicologic evi-
dence on SHS and the extensive literature on active smoking. A meta-​
analysis of the 31 studies published to that time was central in the
decision to classify SHS as a class A carcinogen—​namely, a known
human carcinogen. Overall, the analysis found a significantly increased
risk of lung cancer in never-​smoking women married to smoking men;
for the studies conducted in the United States, the estimated relative
risk was 1.19 (90% CI: 1.04, 1.35).
Subsequent conclusions reaffirmed those of the earlier reports.
A 2004 report by the IARC (2004) reiterated the conclusion with the
following statement: “evidence is sufficient to conclude that involun-
tary smoking is a cause of lung cancer in never-​smokers. The magni-
tudes of the observed risks are reasonably consistent with predictions
based on studies of active smoking in many populations.” The 2006
report of the US Surgeon General (p.  15), which focused on SHS,
concluded: “1. The evidence is sufficient to infer a causal relationship
between secondhand smoke exposure and lung cancer among lifetime
nonsmokers. This conclusion extends to all secondhand smoke expo-
sure, regardless of location and 2. The pooled evidence indicates a 20 to
30 percent increase in the risk of lung cancer from secondhand smoke
exposure associated with living with a smoker” (US Department of
Health and Human Services, 2006). The burden of lung cancer attrib-
utable to passive smoking has been estimated as 31,620 deaths glob-
ally (Global Burden of Disease Study 2013 Collaborators, 2015).
EXPOSURE IN LOW-​AND MIDDLE-​INCOME
COUNTRIES
Current knowledge about ambient air pollution and lung cancer is
based largely on the experience of populations of Western industri-
alized nations. The levels of exposures in low-​and middle-​income
countries (LMICs) in Asia, Africa, and the Middle-​East rival and often
exceed those commonly observed in high-​income countries.
Some LMICs face a double air pollution challenge: the first from
increasing levels of ambient air pollution due to urbanization and
industrialization, and the second from a continuing reliance on solid
fuels for domestic energy needs. The latter is most common among
the rural poor, who still lack access to clean energy (Balakrishnan
et al., 2014). Although the proportion of the global population that
uses solid fuels such as coal or biomass for household cooking or
heating has declined over the past three decades, the populations
have grown and the number of people who rely on solid fuels has
remained largely unchanged at 2.8 billion. These exposures occur
mostly in sub-​Saharan Africa and South and East Asia. Forty-​one
percent (41%) of global households and 60% percent of households
in sub-​Saharan Africa and South Asia were estimated to have burned
solid fuels in 2010 (Bonjour et  al., 2013). Indoor burning of solid
fuels has also been associated with increased rates of cancer of
the upper airways. Exposure to household air pollution is highest
in women due to their role in food preparation (Forouzanfar et al.,
2015). Exposures to levels of fine particles (PM2.5) and other health-​
damaging air pollutants, such as carbon monoxide, are many-​fold
higher in households where solid fuels are burned in unventilated liv-
ing areas. The emissions from the combustion of solid fuels include
known human carcinogens such as polycyclic aromatic hydrocar-
bons, formaldehyde, and benzene (IARC, 2010a). Household com-
bustion of solid fuels also contributes to ambient air pollution in
settings where solid fuels are widely used, and was estimated to be
responsible for 12% of global population-​weighted PM2.5, 37% and
26% in sub-​Saharan Africa and South Asia, respectively, in 2010
(Chafe et al., 2014).
Indoor burning of coal causes lung cancer in humans and is associ-
ated with a 2-​fold increase in lung cancer risk (Hosgood et al., 2011;
IARC, 2010a). The risk from indoor combustion of low-​grade “smoky”
coal approximates the risks from active smoking. Indoor burning of
biomass, such as wood and dung, is also associated with increased
lung cancer (Bruce et  al., 2015; Hosgood et  al., 2010). In addition,
cooking-​oil emissions from high-​temperature frying may also cause
30
300 PART III:  THE CAUSES OF CANCER
lung cancer (IARC, 2010a). In some parts of China, household coal
burning has resulted in markedly elevated lung cancer rates among
non-​smoking women, and the venting of emissions and introduction of
cleaner burning stoves have been demonstrated to reduce lung cancer
rates in exposed women (Hosgood et al., 2011; Lan et al., 2002). The
use of cleaner fuels, such as compressed natural gas, is associated with
reduced rates of lung cancer and other adverse health outcomes rela-
tive to the use of coal and biomass.
There has been little research on ambient air pollution and lung
cancer among urban residents of the burgeoning cities in LMICs,
although mounting levels of urban air pollution from local station-
ary and, increasingly, mobile sources are recognized as an important
environmental problem (World Health Organization [WHO], 2002).
In the cities of the poorest developing countries, WHO’s Global
Environmental Monitoring System observed average ambient con-
centrations of total suspended particles of 300 μg/​m3; the exposure
in places where coal is used for fuel, such as poor communities in
South Africa, may exceed 1 mg/​m3 (WHO, 1990). Estimated levels
of PM10 in cities in developing countries also exceed those com-
monly encountered in Europe and North America (Pandey et  al.,
2006). One might predict that the high levels of ambient air pol-
lution found in cities in the developing world would be associated
with greater excess lung cancer occurrence than has been observed
in Western industrialized settings. Although there are currently few
relevant investigations, a case-​control study in Shenyang, China,
observed a 200% increase in lung cancer risk after adjustment for
age, education, and smoking, among residents in “smoky” areas of
the city and a 50% increase among those in “somewhat or slightly
smoky” areas (Xu et al., 1989)
As a greater proportion of the world’s population moves from rural
communities to the rapidly expanding and highly polluted cities of
Asia and the Southern Hemisphere, there is a clear need for research
on outdoor air pollution in the developing world. Epidemiologic
studies in these settings will present even greater challenges than
those in the industrialized West. In addition to the generic problem
of estimating long-​term exposure to air pollution discussed earlier,
the ambient air pollution mixture in urban centers in the developing
countries is changing, due in part to the increase in vehicular traffic.
Careful planning will be required to characterize these changes over
time, including the choice and development of methods to measure
indicator pollutants for different sources. In addition, the current dra-
matic increases in cigarette smoking in the developing world (Peto
and Lopez, 2003), and the thoroughly predictable consequences,
will complicate the interpretation of studies of air pollution and lung
cancer.
FUTURE DIRECTIONS
There is now abundant evidence that specific air pollutants increase
lung cancer risk in smokers and non-​smokers. Carcinogens can be
measured in indoor and outdoor environments; toxicologic data indi-
cate the potential for human carcinogenicity. Epidemiologic research
shows evidence of effects of indoor and outdoor air pollution on lung
cancer risk, albeit weak for some agents. Various indoor air pollutants
are confirmed causes of cancer, as is outdoor air pollution generally.
Research is still needed on air pollution and lung cancer to guide
policies for protection of public health. Critical remaining questions
relate to the magnitude of the risk at the lower pollution levels now
present in many high-​income countries and to the specific pollutants
leading to increased lung cancer risk. Direct epidemiologic obser-
vation of exposed populations can provide the best information for
evaluating the magnitude of outdoor air pollution–​related excess lung
cancer. In general, large-​scale epidemiologic studies of air pollution
and lung cancer are needed if we are to obtain sufficiently informative
and precise data on risks. Large numbers of cases will be necessary to
measure the effects of air pollution among women and ethnic minori-
ties and to measure the joint effects of air pollution and other factors,
such as occupation and smoking. Evidence is particularly needed for
low-​and middle-​income countries.
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 305
18 Water Contaminants
KENNETH P. CANTOR, CRAIG M. STEINMAUS, MARY H. WARD,
AND LAURA E. BEANE FREEMAN
OVERVIEW
Humans have long recognized the hazards of microbial contamination
of drinking water. Only since the 1960s, however, have epidemiologic
studies systematically examined whether naturally occurring and/​or
man-​made pollutants in drinking water affect cancer risk. Ironically,
some of the measures taken to reduce microbial hazards have increased
exposure to other contaminants. This chapter will begin by discuss-
ing three waterborne exposures that affect large numbers of people
and have been studied most extensively: inorganic arsenic, disinfec-
tion byproducts, and nitrate. Of these, only arsenic and its compounds
are currently designated as carcinogenic to humans. We then discuss
the evidence concerning two emerging issues: the carcinogenicity of
toxins from cyanobacteria, an ancient and ubiquitous family of prokar-
yotic organisms formerly known as blue-​green algae, now affected by
climate change, and the methods of studying cancer in local communi-
ties where the water supply has been contaminated by industrial chem-
icals. Methodologic challenges complicate studies of these issues. The
long induction period following exposure, especially when the expo-
sure affects early stages of carcinogenesis, requires that researchers
reconstruct historical levels that existed many decades in the past. The
exposed populations must be sufficiently large, stable, and well defined
that epidemiologic studies can detect associations with specific cancer
sites. The presence of multiple exposures complicates efforts to eval-
uate individual exposures in relation to a ­priori hypotheses. Despite
these obstacles, there have been important advances in studying the
potential carcinogenicity of waterborne pollutants, as well as new
opportunities to integrate genetic and metabolomic approaches into
future studies.
INTRODUCTION
Water is essential to life. However, drinking water may be contami-
nated by biological, chemical, and other pollutants that lead to ill
health and death. Access to clean water has been a prerequisite for
successful human settlements since ancient times. The engineering
feats of the Romans more than 2000 years ago (Gagarin, 2010) and the
Incas prior to the Spanish Conquest (Wright et al., 1997) attest to the
central importance of uncontaminated water in human cultures.
People have long taken steps to reduce microbial contamination of
drinking water. Efforts to assess the relationship between waterborne
contaminants and cancer are relatively recent, however. Not until the
1960s did epidemiologic studies begin to evaluate systematically
whether naturally occurring and/​or man-​made chemicals and other
substances in drinking water affect cancer risk (International Agency
for Research on Cancer [IARC], 2012a).
Epidemiologic studies of water pollution and cancer confront
special challenges that are not generally problematic when studying
microbial contaminants in drinking water. These can be illustrated
by contrasting the seminal study of waterborne cholera in mid-​nine-
teenth-​century London by Dr. John Snow (1855) with an evaluation
of cancer risk in relation to chemical contamination of water. In the
case of cholera, the incubation period is measured in hours, or at most
a few days. The consequences of infection are rapid and unambiguous;
severe symptoms and even death may follow shortly after ingestion of
even a small inoculum of bacteria. The short incubation period virtu-
ally eliminates the opportunity for those exposed to cholera to move
or change their water supply before the onset of disease. Snow’s map
depicting the cross-​sectional clustering of cases along the distribution
pipes of the contaminated water system strongly implicated drink-
ing water as the vector for disease transmission, and argued against
‘miasma’ as a plausible alternative explanation.
In contrast to the study of infectious agents, epidemiologic studies
of cancer typically confront exposures for which the induction period
may last 20, 50, or more years, depending on the stage(s) of carcino-
genesis that are affected. Retrospective studies (case control or his-
torical cohort) and ecological analyses are usually more feasible than
prospective studies for estimating risk, although these studies require
that researchers reconstruct historical exposures that occurred many
decades in the past. Mobility creates logistical problems in identifying
and tracking the exposed population (Meliker et  al., 2007; Nuckols
et al., 2011), and in characterizing exposure at different periods of life.
Studies often rely on a single, contemporaneous questionnaire seek-
ing information about historical levels of water consumption that are
assumed to accurately represent lifetime patterns. Exposed populations
may not be sufficiently large and/​or well defined that an epidemiologic
study can detect associated levels of risk in site-​specific cancers.
Despite these obstacles, there has been substantial progress in study-
ing the potential carcinogenicity of waterborne pollutants and in devel-
oping opportunities to integrate genetic and metabolomic analyses into
this area of research (Antonelli et al., 2014; Cantor et al., 2010). The
present chapter will discuss developments in the field since the third
edition of this text (Cantor et al., 2006).
INORGANIC ARSENIC
Exposure
Human exposure to inorganic arsenic occurs primarily through water
ingestion, although exposure can also occur via air, food, and tobacco
smoking (IARC, 2012a). The most common source of high exposure is
from drinking water contaminated with arsenic from naturally occur-
ring geologic sources. Industrial exposure occurs through the inhala-
tion of arsenic-​containing particulates, especially during the mining
and smelting of copper, tin, and lead; some agricultural workers con-
tinue to be exposed to arsenical pesticides. Medications containing
arsenic were a staple of the pharmacopeia until the 1940s; patients
were treated for a wide range of ailments, particularly dermatologic
conditions (Cantor et al., 2006; Cuzick et al., 1992). With the excep-
tion of arsenic trioxide, used to treat promyelocytic leukemia (Coombs
et  al., 2015), medicinal arsenic is no longer a significant source of
exposure.
In natural waters, inorganic arsenic occurs primarily as pentavalent
arsenate [As(V)] or trivalent arsenite [As(III)] (Cantor et  al., 2006).
Arsenic can also occur in organic forms such as arsenobetaine or other
arsenosugars. These occur more commonly in food (e.g., seafood) and
are considerably less toxic than inorganic arsenic. Tens of millions of
people worldwide are exposed to naturally occurring inorganic arsenic
305
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306 PART III:  THE CAUSES OF CANCER
in drinking water, including an estimated 50  million in Bangladesh,
30 million in India (mostly in West Bengal), 15 million in China, and
millions more in Europe and South and Central America (Ravenscroft,
2007). Exposures in Bangladesh and West Bengal are primarily the
result of widespread introduction of tube wells, beginning in the 1970s,
to reduce exposure to microbial pathogens in surface water. By 1993,
widespread arsenic contamination of tube wells was confirmed, lead-
ing to enormous public health concerns (Smith et al., 2000). A 1998–​
1999 survey of 3534 tube wells throughout Bangladesh found that
25%–​27% of wells had arsenic concentrations > 50 µg/​l, five times
the current World Health Organization recommended maximum of
10 µg/​l, and 9% had concentrations > 200 µg/​l. It was estimated that
57 million people in Bangladesh were exposed to water with arsenic
concentrations > 10 µg/​l, and 35 million were exposed to concentra-
tions > 50 µg/​l (British Geological Survey, Government of the People’s
Republic of Bangladesh, 2001). Mitigation efforts have reduced the
proportion of wells with arsenic concentrations > 50 µg/​l from 25%
to 13% (Flanagan et al., 2012). Despite this, an estimated 22 million
people in Bangladesh still rely on the highly contaminated wells.
In most other areas with naturally contaminated water, arsenic
water concentrations are generally lower than those in Bangladesh.
According to the Environmental Protection Agency (EPA) in the
United States, an estimated 12% of all public water systems (5252
of 43,443) have arsenic concentrations between 5–​10 µg/​l (US EPA,
2000a). Several million people in the United States are thought to be
exposed to higher levels from drinking water drawn from unregulated
private wells. Arsenic concentrations > 50 µg/​l have been reported in
many US states, but levels > 200 µg/​l are rare (Chappells et al., 2014).
A case-​control study of skin, bladder, and kidney cancer conducted
in parts of Hungary, Romania, and Slovakia reported that 25% of the
population was exposed to an average concentration of arsenic in
drinking water of > 10 µg/​l, and 8% were exposed to > 50 µg/​l. Levels
above 200 µg/​l were reported in only a few wells (Hough et al., 2010).
Another source of arsenic exposure is food, which, on average,
accounts for about 8–​10 μg of ingested arsenic per day (Dabeka et al.,
1993; Tao and Bolger, 1999). Arsenic can be taken up by plants grown
in soil with elevated arsenic levels. Some arsenic in soil can result from
previous use of arsenic-​based pesticides, or irrigation with arsenic-​
contaminated water (Rahman and Hasegawa, 2011). Exposure to arse-
nic in rice has received considerable attention. Rice actively extracts
arsenic from soil, and detectable levels have been seen in many rice
products. In 2012, the US Food and Drug Administration (FDA) found
arsenic in almost all of the nearly 200 brands of rice, rice cakes, rice
baby foods, and rice cereals it tested (US FDA, 2012). A 2011 study of
229 pregnant women in the United States found that women who ate rice
had significantly higher urinary arsenic levels than those who did not.
Eating 0.56 cups of cooked rice per day was associated with an arsenic
intake equivalent to that from drinking one liter per day of water with
an arsenic concentration of 10 µg/​l (the current standard for drinking
water specified by the United States and WHO; Gilbert-​Diamond et al.,
2011). Rice also absorbs arsenic from cooking water as well as during
growth. Thus, intake from rice is likely higher in areas where arsenic-​
contaminated water is used for cooking (Rahman and Hasegawa, 2011).
Exposure Measurement in Epidemiologic Studies
Residential Exposure
Epidemiologic studies of arsenic and cancer often use residential his-
tories in combination with historical records of water concentration to
estimate exposure in regions with highly contaminated drinking water.
For example, Marshall et al. investigated cancer mortality following a
13-​year period of very high arsenic exposure in a desert area (Region
II) in northern Chile (Marshall et al., 2007). The period of high expo-
sure began in 1958 when two rivers with arsenic water concentrations
near 860 µg/​l were piped to the city for drinking, and ended in 1971
when an arsenic treatment plant was installed. The epidemiologists
measured cancer mortality rates for the years before, during, and after
this high exposure period, and compared these with death rates in a
socio-​demographically similar region in Chile (Region V). Figure 18–​1
shows the temporal trend of arsenic concentration in drinking water in
relation to the rate ratio (RR) estimates for lung and bladder cancer
mortality. The RR estimates for both cancer sites started to increase
about 10 years after the large initial increase in arsenic exposure and
continued to rise until the late 1980s. Subsequent analyses have shown
that cancer mortality rates in this area remained high up to 2000, the
last year assessed, approximately 40  years after the high exposures
began and approximately 30 years after the maximum exposure was
ended (Smith et al., 2012).
Biologic Metrics of Arsenic Exposure
Humans excrete arsenic primarily through the urine, and urinary levels
of inorganic arsenic and its metabolites are commonly used to estimate
recent internal absorption (IARC, 2012a; NRC, 1999). The biological
half-​life of arsenic in urine following ingestion is approximately 39–​
59 hours (Buchet et al., 1981); thus, urinary concentrations are most
valuable for assessing recent exposures or exposures among people
whose intake levels have not changed much over time. Arsenic can
also be measured in blood, hair, and nails (Orloff et  al., 2009). The
half-​life of arsenic in blood is fairly short, so blood levels are only
useful for detecting recent exposures. Arsenic levels in the hair and
nails have a longer half-​life, so these can be used to assess exposures
over several months or more. Hair and nails can be contaminated by
external exposures to arsenic, so specialized cleaning procedures are
employed when using hair and nails to assess internally absorbed arse-
nic (Orloff et al., 2009).
Statistical Modeling of Exposure
Historical exposure records are rarely available, especially in regions
where private wells are common. Several studies have used statisti-
cal modeling to estimate arsenic exposures from sources that lack
direct measurements. For example, in a bladder cancer case-​control
study in New England, investigators measured arsenic concentra-
tions in water samples from 2611 current and 448 past residences of
study subjects (Nuckols et al., 2011). In this region, almost half the
population obtains drinking water from private wells. The available
measurements covered residences that accounted for only 27% of
the total lifetime person-​years of participants in the study. In order
to estimate exposures during the remaining residential history of
the subjects, the researchers developed statistical regression mod-
els that combined empirical measurements from the sampled wells
with geological data for two major strata and geochemical data for
public water supplies drawn from different sources. Model results
were applied to estimate the arsenic level at each historic residence
where direct data were not available. In a validation survey done
as part of this investigation, measures of sensitivity, specificity, and
overall agreement varied. For example, using a dichotomous cutoff
of 5 µg/​l, overall agreement between measured and predicted level
of drinking water arsenic from bedrock wells (from one of the mod-
els) varied between 57% and 70%, depending on the buffer radius
that was used for the estimate. Sensitivity varied from 58% to 78%
and specificity from 52% to 73%. While these results are adequate
for some purposes, the level of exposure misclassification in these
estimates is high enough to compromise findings in epidemiologic
analyses, highlighting the difficulties that can occur using modeling
approaches to estimate past exposure. Other modeling or statistical
approaches have been used, including geological averages, kriging,
and using the arsenic concentration in nearest neighboring wells.
Reported correlation coefficients between the arsenic concentrations
predicted by these methods and concentrations in known wells in
validation surveys have ranged from fair to good (i.e., correlation
coefficients between 0.4 and 0.8) (Dauphine et  al., 2013; James
et al., 2014; Meliker et al., 2008).
Cancer Outcomes
Experimental Studies in Animals
Until recently, arsenic has been one of the few human carcinogens
without an animal model. More recent experiments using arsenical
 307

Water Contaminants 307

Lung Cancer Mortality Lung Cancer Mortality
Men aged 30 and over Women aged 30 and over
4 600 4 600

3 450 3 450

Arsenic µg/L
Arsenic µg/L

Rate Ratio
Rate Ratio

2 300 2 300

1 150 1 150

0 0 0 0
1950 1960 1970 1980 1990 2000 1950 1960 1970 1980 1990 2000
Years Years

Bladder Cancer Mortality Bladder Cancer Mortality

Men aged 30 and over Women aged 30 and over
12 600 12 600

10 10
450 450
8 8

Arsenic µg/L
Arsenic µg/L
Rate Ratio

Rate Ratio
6 300 6 300

4 4
150 150
2 2

0 0 0 0
1950 1960 1970 1980 1990 2000 1950 1960 1970 1980 1990 2000
Years Years

Figure 18–​1.  Lung and bladder cancer mortality rate ratios comparing Region II with Region V, Chile, for men and women aged 30 and above, separately,
as estimated by Poisson regression with smoothing. The circles are the mortality rate ratios plotted at the midpoint of each successive 3-​year period. The
shading represents the 95% confidence intervals of these rate ratios. Histograms (gray lines) of the population-​weighted average arsenic water concen-
trations for Region II, from 1950 to 1994 in 5-​year increments, are also presented (vertical axes at right). The dramatic rise and decline in arsenic water
concentrations were in the years 1958 and 1970, respectively. They were incorrectly drawn in the original published graphs shown here.

methylation metabolites and early-​life exposures have shown increases
in cancer in rodents (IARC, 2012a; Tokar et al., 2010a).
There are important interspecies differences in the metabolism
of arsenic between laboratory animal species and humans. These
may account for differences in the toxicity and dose–​response rela-
tionships in different species (Vahter, 1999b). For example, mice
are very effective at metabolizing arsenic. In rats, methylated inor-
ganic arsenic accumulates in red blood cells; storage inside red
blood cells may limit toxicity to other organs. This does not occur
in humans. Consequently, long-​term feeding studies of laboratory
animals may not reliably predict the carcinogenic effects in humans.
The designation of inorganic arsenic as a human carcinogen by the
IARC is based on data from humans rather than animals (IARC,
2012a), and refers primarily to cancers of the skin, bladder, and
lung. Associations have been observed with cancers of the kidney,
liver, and prostate, but these are not currently regarded as definitive
(IARC, 2012a).
Among the first human evidence linking arsenic to cancer in
humans were case reports describing skin and internal cancers fol-
lowing ingestion of medicinal arsenic, arsenic in drinking water, or
wine contaminated with arsenical pesticides. The earliest quantitative
epidemiologic studies of ingested arsenic and cancer were ecologi-
cal in design, conducted primarily in areas with chronic arsenicism
and highly contaminated drinking water, such as Taiwan, Argentina,
and Chile. The arsenic exposure in Taiwan began in the 1940s, long
before the tragic exposures in Bangladesh, but also resulted from a
shift from surface water to wells to avoid microbial contaminants in
surface water. Ecological studies in the 1960s through 1990s reported
elevated mortality from cancers of the skin, bladder, lung, liver, and
kidney (Cantor et al., 2006). More recently, cohort and case-​control
studies that collected individual data on arsenic drinking water lev-
els and potential confounders have confirmed these associations. For
example, in a prospective cohort study of 8086 residents of north-
western Taiwan, relative risks of urothelial cancer associated with
residential arsenic water concentrations of < 10, 10–​49.9, 50–​99.9,
100–​299.9, and ≥ 300 µg/​l at the time of study recruitment were 1.00
(reference), 1.85 (95% confidence interval [CI]: 0.45, 7.61), 2.19 (CI:
0.43, 11.1), 5.50 (CI: 1.39, 21.8), and 10.8 (CI: 2.90, 40.3), respec-
tively (Chen et al., 2010b). Relative risks for lung cancer were 1.00
(reference), 1.10 (CI: 0.74, 1.63), 0.99 (CI: 0.59, 1.68), 1.54 (CI:
0.97, 2.46), and 2.25 (CI: 1.43, 3.55) (Chen et al., 2010a). In northern
Chile, arsenic concentrations in drinking water have been measured
longitudinally in almost all sources for decades, allowing researchers
to estimate lifetime exposures (Ferreccio et al., 2000). A 2007–​2010
case-​control study in Chile reported odds ratios for lifetime average
arsenic water concentrations of < 26, 26–​79, 80–​197, and > 197 µg/​l
of 1.00 (reference), 0.92 (95% CI: 0.52, 1.61), 2.62 (CI: 1.53, 4.50),
and 6.00 (CI: 3.38, 10.64), respectively, for bladder cancer, and 1.00
(reference), 0.98 (CI: 0.62, 1.53), 1.70 (CI: 1.05, 2.75), and 3.18 (CI:
1.90, 5.30) for lung cancer (Steinmaus et al., 2013). Elevated odds
ratios were also reported for kidney cancers, helping to confirm pre-
vious ecologic mortality observations for kidney cancer (Chen et al.,
1988; Ferreccio et al., 2013a). Extensive summaries of other epide-
miologic studies on arsenic and cancer in humans and experimental
308

308 PART III:  THE CAUSES OF CANCER

animal studies are provided elsewhere (Agency for Toxic Substances
and Disease Registry [ATSDR], 2007; IARC, 2012a; NRC, 1999,
2014).
Interestingly, not all of the effects of arsenic on cancer are detrimen-
tal. As mentioned previously, arsenic trioxide is an effective treatment
for promyelocytic leukemia (Coombs et  al., 2015), once considered
among the most fatal forms of leukemia. Also provocative is that a
study from northern Chile found a 49% decrease in breast cancer mor-
tality among women over age 30 years during the 13-​year period of
high arsenic water concentrations (near 860 µg/​l) in the area (Smith
et al., 2014). In fact, during the latter part of the high-​exposure period
(1965–​1970), breast cancer mortality among exposed women under
age 60 years was 70% lower than that among unexposed women.
Regional differences in diagnosis, treatment, and confounding vari-
ables were found to be unlikely causes for the lower risk. Although this
finding has not yet been replicated elsewhere, its biologic plausibility
is supported by in vivo evidence of increased apoptosis of breast can-
cer cells at exposure levels similar to those in the Chile study area (Sun
et al., 2011; Xia et al., 2012).
Factors That May Affect Risk
Several factors have been reported to influence susceptibility to arsenic-​
related cancers. These include demographic traits (age, gender), meta-
bolic capability, genetic susceptibility, nutrition, and smoking.
Demographic Factors
Age at exposure appears to modify susceptibility to certain arsenic-​
related cancers. Exposure in utero or during childhood is more strongly
associated with lung and bladder cancer than the same level of expo-
sure in adulthood. In the Chile case-​control study (noted earlier), odds
ratios of 5.24 (95% CI:  3.05, 9.00) for lung cancer and 8.11 (95%
CI: 4.31, 15.25) for bladder cancer were seen among adults exposed to
high arsenic water concentrations in utero or as children. Odds ratios
were lower among those whose exposure began later (Steinmaus et al.,
2014). Ecologic studies in Chile also found evidence of increases in
kidney, laryngeal, and liver cancer mortality among adults who had
been highly exposed in early life (Smith et al., 2012). These findings
are supported by studies in mice showing that prenatal arsenic expo-
sure increases the occurrence of lung, liver, and other tumors later in
life, whereas the same level of arsenic exposures in adulthood does not
affect risk (Tokar et al., 2010a). The mechanisms by which in utero
or long-​term/​early-​life exposure affect risk are unknown, although
the in utero period is a time of major epigenetic reorganization, and
arsenic has been linked to epigenetic changes in laboratory animals
and humans (Kile et al., 2014). Epigenetic changes could affect gene
expression and regulation later in life. Other proposed mechanisms
relate to the effects of arsenic on the developing immune system or
other rapidly developing organs, to exposure before the develop-
ment of detoxification enzymes or to the higher dose relative to body
mass index (BMI) in fetuses and children compared to adults (Miller
et al., 2001).
Metabolism
In humans, ingested inorganic arsenic is metabolized through a com-
plex series of reduction and methylation steps (Figure 18–​2). Ingested
inorganic pentavalent arsenate [As(V)] is rapidly reduced to arsenic
trioxide [As(III)], which then accepts a methyl group from S-​adenosyl
methionine (SAM) to produce the methylated pentavalent species
monomethylarsonic acid, MMA(V). MMA(V) is then reduced to tri-
valent monomethylarsonous acid, MMA(III). An additional methyl
group can then be added to yield dimethylarsinic acid, DMA(V),
which can be reduced to small amounts of DMA(III) (NRC, 2014). As
mentioned, urine is the primary route of arsenic excretion in humans.
A potentially useful marker of an individual’s ability to metabolize
inorganic arsenic is the percentage that different metabolites contrib-
ute to the total amount in urine. Although there is substantial inter-​
individual variation, on average, As(III) and As(V) together account
for 10%–​30% of the total, MMA(III) and MMA(V) contribute 10%–​
20%, and DMA(III) and DMA(V) combined account for the remain-
ing 60%–​70% (Hopenhayn-​Rich et al., 1993; Vahter, 1999a).
The methylation of arsenic was previously thought to contribute pri-
marily to detoxification, since the pentavalent metabolites, MMA(V)
and DMA(V), are acutely less toxic in vitro and more rapidly excreted
than arsenic in its inorganic form (Vahter and Concha, 2001). However,
more recent in vitro studies have shown that MMA(III) may be more
toxic, at least acutely, than inorganic arsenic (Styblo et al., 2000). This
suggests that MMA(III) could be the principal toxicant and that people
who are less able to metabolize MMA(III) to DMA(V) may be more
susceptible to arsenic toxicity. MMA(III) is difficult to measure in
epidemiologic studies because it is rapidly oxidized to its pentavalent
form in urine (Kalman et al., 2014).
Epidemiologic studies have found that people with high urinary
proportions of total MMA or low proportions of total DMA have 2–​5
times higher risk of arsenic-​related cancers and other diseases than
individuals who do not (Smith and Steinmaus, 2009). For example, in
the highly exposed southwest coast of Taiwan, odds ratios for urothe-
lial carcinoma were calculated for different strata of lifetime exposure
to arsenic, further stratified according to high or low proportions of
urinary inorganic arsenic excreted as MMA (%MMA). Subjects in
the lower category of both cumulative exposure (< 20 mg/​l-​years) and
%MMA (< 11.40%) served as the reference group. The odds ratios for
urothelial cancer in subjects with cumulative exposure ≥ 20 mg/​l-​year
were 1.5 (95% CI: 0.4, 5.9) in those with %MMA < 11.40%, versus
3.7 (95% CI: 1.2, 11.6) in those with higher %MMA values (Huang
et al., 2008). Similar patterns have been seen in Chile for lung cancer,
where odds ratios for arsenic water concentrations >200 ug/​l were 3.16
(95% CI: 1.59, 6.32) in subjects with low %MMA values (< 12.5%)
but 6.81 (95% CI: 3.24, 14.31) in subjects with higher %MMA values
(Melak et al., 2014).
Genetic Susceptibility
Polymorphisms in genes that code for the enzymes involved in
arsenic methylation have been linked to poor arsenic metabo-
lism. The most consistent evidence for this involves the arsenic
(3+) methyltransferase (AS3MT) genes (Figure 18–​2), for which

As (V) As(III) MMA (V) MMA (III) DMA (V)

GSH GSSG SAM SAH SAM SAH
OH OH CH3
OH OH
I I I
I I
O = Asv – OH AsIII – CH3 O = AsV – CH3
OH – AsIII – OH O = AsV – CH3
I I I
O– AS3MT OH AS3MT OH

Figure 18–​2.  Arsenic metabolism: in humans, ingested inorganic arsenic is metabolized through a series of reduction and methylation steps. In the past,
this was thought to be primarily a detoxification process since DMA(V) is more readily excreted and is less toxic than inorganic arsenic (As(V) or As(III)).
However, more recent evidence suggests that the intermediary species, MMA(III), may be more toxic than As(V) or As(III).
Abbreviations: As(V) = arsenate; GSH = glutathione; GSSG = glutathione disulfide; As(III) = arsenite; SAM = S-​adenosyl methionine; SAH = S-​adenosyl homo-
cysteine; AS3MT = arsenic-​3-​methyltransferase; MMA(V) = monomethylarsonic acid; MMA(III) = monomethylarsonous acid; DMA(V) = dimethylarsinic acid.
 309
Water Contaminants 309
polymorphisms have been statistically significantly associated with
urinary methylation patterns (Antonelli et al., 2014). For example,
in an arsenic-​exposed region in Mexico, subjects with the C allele
of Met287Thr in the AS3MT gene had higher mean urinary %MMA
levels (15 vs. 10%, p < 0.05) and a higher odds of having arsenic-​
related premalignant skin lesions (odds ratio [OR]  =  4.28; 95%
CI:  1.0, 18.5) (Valenzuela et  al., 2009). Polymorphisms in other
genes have also been linked to arsenic metabolism, including sev-
eral glutathione-​s-​transferase genes.
Nutrition
The availability of certain micronutrients may also affect a person’s
ability to methylate arsenic. For example, low intakes of methionine,
protein, and choline have been shown to impair arsenic methylation
in experimental animals (Vahter and Marafante, 1987). Low body
mass or weight has been associated with increased risks of arsenic-​
related skin lesions in India and Bangladesh (Ahsan et al., 2006; Guha
Mazumder et  al., 1998). Folate affects one carbon metabolism, and
therefore may modify the transfer of methyl groups from S-​adenosyl
methionine that occur in arsenic methylation (Hall and Gamble, 2012;
Kile and Ronnenberg, 2008). In arsenic-​exposed areas of Bangladesh,
folate supplementation was associated with decreased blood arsenic
levels and an increased percentage of inorganic arsenic excreted as
DMA (Gamble et al., 2006; Peters et al., 2015). Folate deficiency has
been linked to arsenic-​caused skin lesions (Melkonian et  al., 2012);
most of these studies have been cross-​sectional, and clear prospec-
tive associations between folate intake and cancer have not been seen
to date.
Selenium increases the non-​enzymatic methylation of inorganic
arsenic, and has been associated with reduced arsenic toxicity and
increased arsenic excretion in animal and laboratory tests (Zwolak and
Zaporowska, 2012). Both selenium and arsenic affect DNA methyla-
tion in vivo and in vitro, suggesting that in cytosine DNA methyltrans-
ferase, selenium, and arsenic compete for methyl donation from SAM.
Higher levels of blood selenium have been associated with lower
percentages of MMA in blood or urine (Basu et  al., 2011; Pilsner
et  al., 2011), and with lower risks of premalignant arsenic-​related
skin lesions (Chen et al., 2007), but little information is available on
whether selenium modifies cancer risks related to arsenic.
Other Factors
Synergistic associations have been seen between arsenic exposure in
either air or water, and tobacco smoking (Chen et  al., 2004; Hertz-​
Picciotto et al., 1992). For example, in Chile, arsenic water concentra-
tions > 200 µg/​l were associated with lung cancer odds ratios of 8.0
(95% CI:  1.7, 52.3) among never-​smokers, but 32.0 (95% CI:  7.22,
198.0) in ever-​smokers (Ferreccio et al., 2000). Some evidence of syn-
ergy between arsenic in water and certain occupational exposures has
been reported in relation to premalignant or malignant skin lesions or
other cancers for pesticides, silica, asbestos, and wood dust (Ferreccio
et al., 2013b; Melkonian et al., 2011). Recently, evidence of synergy
between arsenic and excess BMI were reported in a cancer case-​
control study in Chile (Steinmaus et al., 2015).
Cancer Risks at Lower Exposures
The most convincing epidemiologic evidence of the carcinogenicity
of ingested arsenic comes from studies involving high exposure lev-
els, that is, drinking water arsenic concentrations > 100 µg/​l. Findings
at exposure levels below this are mixed (Gibb et  al., 2011)  (Table
18–​1). This issue is important because millions of people worldwide
are exposed to these lower levels, but the associated cancer risks are
unknown. Linear extrapolation from higher dose studies suggests that
the cancer risks at (lifetime) exposures near the US and World Health
Organization limits for arsenic in water (10 µg/​l) may be on the order
of one extra cancer case for every 300 people (NRC, 2001). Some have
suggested that the dose–​response relationship between ingested arse-
nic and cancer is not linear and that relatively low arsenic exposure lev-
els may be associated with little or no excess risk (Cohen et al., 2013).
Much of the controversy about the effects of arsenic at low expo-
sure levels reflects the difficulty of measuring long-​term exposures.
Because of the long latency of arsenic-​associated cancer, retrospec-
tive studies must collect or estimate exposure data from the distant
past (which are not commonly available), and prospective studies must
follow subjects over a period of decades (which can be prohibitively
expensive). Assessing past or long-​term exposure patterns can be dif-
ficult if subjects change water sources throughout their lives, or use
different water sources with different arsenic concentrations through-
out the day (i.e., at home, work, and school). Single measurements of
arsenic in urine or hair will likely only represent a small portion of
lifetime exposure for many people. In addition, among people with
relatively low drinking water arsenic concentrations (e.g., < 10 µg/​
l), food-​borne arsenic can become a more important exposure source
(Meliker et al., 2006). Because food consumption patterns and arsenic
concentrations in foods may change over time, assessing past or long-​
term exposure to arsenic from food can also be challenging. Inaccurate
or missing data can increase misclassification of exposure, can lead to
errors in estimating study subjects’ true arsenic exposure, and there-
fore can limit the ability of a study to identify true associations (Cantor
and Lubin, 2007).
Other issues relate to statistical power and the limits at which rela-
tively small increases in risk can be detected in epidemiologic stud-
ies. In other words, if arsenic concentrations that are currently allowed
in drinking water were truly associated with increased cancer risks,
these increases would expected to be fairly small (e.g., relative risks of
< 1.15 at the current US and World Health Organization limits of
10 µg/​l) (Gibb et al., 2011). Such small increases in risk, while impor-
tant from a public health standpoint, are difficult to detect in epide-
miologic studies without very large sample sizes, detailed exposure
assessment, and rigorous control of confounding. Even small increases
in risk can be important if the exposure and endpoints are common.
Lung and bladder cancer are among the most common cancer types
worldwide. Given the potential importance of studies of low exposure,
such studies must be carefully designed and executed to provide mean-
ingful estimates of risk (Cantor and Lubin, 2007).
Mechanism(s) of Carcinogenicity
Currently, the primary mechanisms by which arsenic exerts its car-
cinogenic effects in humans are unknown. Numerous pathways
have been proposed. Evidence suggests that arsenic does not inter-
act directly with DNA (Nesnow et al., 2002), but may be genotoxic
through other mechanisms. One possibility is that the metabolism of
arsenic generates reactive oxygen species and/​or decreases antioxidant
defenses, leading to DNA damage and chromosomal changes (Kitchin
and Conolly, 2010). Chromosomal alterations from arsenic exposure
are evidenced by the induction of micronuclei in human lymphocytes
and in exfoliated bladder cells (Cantor et al., 2006). Arsenic may also
alter enzymes involved in DNA repair (Andrew et al., 2009; Hsu et al.,
2008) or DNA methylation. Both hypo-​and hypermethylation of DNA
have been associated with arsenic exposure in exposed populations
(Bailey and Fry, 2014; Ren et al., 2011). The role of these changes in
human cancer remains unclear. Cytotoxicity following sulfhydral pro-
tein binding of reactive metabolite species and subsequent regenerative
cell proliferation or hyperplasia might also lead to the development of
cancer (Cohen et al., 2013). Modulations in the immune system have
been linked to cancer risks (Finn, 2012), and arsenic has been associ-
ated with a variety of inflammatory and infectious diseases, as well
as to biomarkers of altered immune response that may be related to
immune suppression and altered immune surveillance of cancerous
cells (Dangleben et al., 2013). Increasing evidence regarding the role
of stem cells in cancer development, as well as the links between early-​
life arsenic exposure and adult disease, has led to theories regarding
the role of stem cells in arsenic carcinogenicity (Tokar et al., 2011).
In a rat kidney stem cell or partially differentiated progenitor cell
line, low-​level chronic arsenic exposure induced phenotypic changes
of cancer, including increases in colony formation (indicative of the
loss of contact inhibition), increased proliferation, increases in matrix
310

Table 18–​1. Cancer Studies in Populations with Arsenic Water Concentrations < 100 µg/​L

Study Area/​Outcome Results Description

Bates et al., Utah Cumulative arsenic ≥ 53 mg 1. Case-​control study

1995 Bladder cancer OR = 1.41 (90% CI: 0.7, 2.9) 2. No past arsenic water concentration measurements
3. No data on private wells
4. OR > 1.0 but not statistically significant in all subjects.
Corresponding OR in smokers = 3.32 (90% CI: 1.1, 10.3)
Lewis et al., Utah Cumulative arsenic > 5000 μg/​L-​yr 1. Retrospective cohort mortality study
1999 Multiple cancers Lung cancer: SMR = 0.44 (p < 0.05) 2. Rare population: rural Mormon population 1900+.
in males and 0.22 (p > 0.05) 3. Lifestyle factors (smoking, diet, other) not assessed
in females 4. Unusual results: low SMR for lung cancer potentially an
indication of major confounding
Karagas et al., New Hampshire Toenail arsenic > 97th percentile 1. Case-​control study
2001 Skin cancer OR = 2.07 (0.92, 4.66) 2. Toenails measure only a few months of exposure: past exposure
unknown
3. OR > 1.0 but not statistically significant
4. No clear dose–​response relationship
Steinmaus California/​Nevada Arsenic intake > 80 μg/​day 1. Case-​control study
et al., 2003 Bladder cancer OR = 1.78 (0.89, 3.56) for exposures > 2. Low power to assess past exposures
40 years before cancer diagnosis 3. < 9% of subjects lived in highly exposed areas > 40 years before
diagnosis
4. OR > 1.0 but not statistically significant
Karagas et al., New Hampshire Toenail arsenic > 97th percentile 1. Case-​control study
2004 Bladder cancer OR = 2.17 (0.92, 5.11) among smokers 2. Toenails measure only a few months of exposure: past exposure
unknown
3. OR > 1.0 but not statistically significant
4. OR not increased in never smokers
5. No clear dose–​response relationship
Lamm et al., United States County median arsenic concentration 1. Ecologic mortality study
2004 Bladder cancer ≥ 3 μg/​L 2. County median used despite wide variability within counties
SMR = 0.94 (0.90, 0.98) 3. Only a fraction of all wells within exposed counties were
measured
4. No data on past exposure
5. No data on smoking, diet, or other potential confounders
Heck et al., New Hampshire and Toenail arsenic ≥ 0.1137 μg/​g 1. Case-​control study
2009 Vermont OR = 0.89 (0.46, 1.75) All types 2. ORs much lower without multiple adjustments; the confounder
Lung cancer OR = 2.75 (1.00, 7.57) Squamous/​ causing this is unknown
small cell 3. Toenails measure only a few months of exposure: past exposures
unknown
4. No clear dose–​response relationship
Gilbert-​ New Hampshire Urine arsenic ≥ 5.31 μg/​L 1. Cross-​sectional: urine samples measured at the time of cancer
Diamond Skin cancer OR = 1.43 (0.91, 2.27) diagnosis
et al., 2013 2. Urine measures only a few weeks of exposure
3. No direct data on past exposure
4. OR > 1.0 but not statistically significant
5. OR not elevated in long-​term residents
Meliker et al., Michigan Exposed counties 1. Ecologic mortality study
2007 Multiple cancers Lung cancer: SMR = 1.02 (99% 2. Ecologic exposure data based on county
CI: 0.98, 1.06) in males and 1.02 3. Wide variability in exposure within counties
(99% CI: 0.96, 1.07) in females 4. Past exposure not assessed
Bladder cancer: SMR = 0.94 (99% 5. No data on smoking, diet, or other potential confounders
CI: 0.82, 1.08) in males and 0.98
(99% CI: 0.80, 1.19) in females
Meliker et al., Michigan Time weighted lifetime average water 1. Case-​control study
2010 Bladder cancer arsenic concentration > 10 μg/​L 2. Exposure in past private wells based on statistical modeling
OR = 1.10 (0.65, 1.86)
Garcia-​ Arizona, Oklahoma, and 80th vs. 20th percentile urinary arsenic 1. Prospective cohort mortality study
Esquinas North/​South Dakota HR = 3.30 (1.28, 8.48) Prostate cancer 2. Unusual findings: highest hazard ratios are for outcomes not
et al., 2013 Multiple cancers HR = 2.46 (1.09, 5.58) Pancreas cancer commonly linked to arsenic (prostate and pancreas cancer)
(Strong HR = 1.56 (1.02, 2.39) Lung cancer 3. Urine measures only a few weeks of exposure
Heart Bladder cancer: insufficient number
Study) of cases
Dauphine California/​Nevada Arsenic water concentration ≥ 85 μg/​L 1. Case-​control study
et al., 2013 Lung cancer OR = 1.39 (0.55, 3.53) for exposures > 2. Low power to assess past exposures
40 years before cancer diagnosis 3. < 15% of subjects lived in highly exposed areas > 40 years
before diagnosis
4. OR > 1.0 but not statistically significant
Baastrup Denmark Cumulative exposure 5 mg 1. Retrospective cohort study
et al., 2008 Multiple cancers IRR = 1.00 (0.98, 1.03) Lung cancer 2. Very low exposures: median exposures of 0.7–​2.1 ug/​L and 95th
IRR = 1.01 (0.98, 1.04) Bladder cancer percentiles of 2.0–​2.5 ug/​L
IRR = 0.94 (0.81, 1.09) Kidney cancer 3. Exposures from food not assessed
IRR = 0.99 (0.97, 1.01) Skin cancer
 31

Water Contaminants 311

Table 18–​1.  Continued

Study Area/​Outcome Results Description

Chen et al., Northeastern Taiwan For arsenic water concentration < 100 1. Cohort study
2010a Lung cancer µg/​L: 2. Arsenic water concentrations measured at the residence at the
RR = 1.10 (0.74, 1.63) for 10–​49.9 µg/L​ time of study recruitment
RR = 0.99 (0.59, 1.68) for 50–​99.9
ug/​L
Chen et al., Northeastern Taiwan For arsenic water concentration < 100 1. Cohort study
2010b Urothelial cancer µg/​L: 2. Arsenic water concentrations measured at the residence at the
RR = 1.85 (0.45, 7.61) for 10–​49.9 µg/L​ time of study recruitment
RR = 2.19 (0.43, 11.1) for 50–​99.9
ug/​L
Chen et al., Northeastern and For arsenic water concentration 10–​99 1. Cohort study
2004 southwest Taiwan µg/​L: 2. Includes some subjects in Chen et al., 2010
Lung cancer RR = 1.09 (0.63, 1.91) 3. Less than lifetime exposure in many subjects
Han et al., Idaho, US County average arsenic concentrations 1. Ecologic study
2009 Multiple cancers No statistically significant 2. Used county average arsenic well concentrations
correlations with lung, bladder, or 3. Mostly low exposures
kidney cancer incidence in adjusted 4. Did not account for latency
analyses
Buchet and Belgium Arsenic water concentrations 20–​50 1. Ecologic mortality study
Lison, 1998 Multiple cancers µg/​L 2. Limited exposure data
Males 3. Exposures from water and air, subjects living near zinc smelters
SMR = 1.05 (0.94, 1.18) Lung cancer
SMR = 0.92 (0.63, 1.35)
Bladder cancer
SMR = 1.13 (0.67, 1.91) Kidney cancer
Females
SMR = 1.24 (0.83, 1.87) Lung cancer
SMR = 1.20 (0.63, 2.31)
Bladder cancer
SMR = 0.91 (0.45, 1.81) Kidney cancer
Ferreccio Chile Arsenic water concentrations < 89 µg/​L 1. Case-​control study
et al., 2000 Lung cancer OR = 0.3 (0.1, 1.2) for 10–​29 µg/​L 2. Exposure based on average concentrations for the years
OR = 1.8 (0.5, 6.9) for 30–​59 µg/​L 1958–​1970
OR = 4.1 (1.8, 9.6) for 60–​89 µg/​L
Kurttio et al., Finland Arsenic water concentrations ≥ 0.5 µg/​L 1. Retrospective cohort study
1999 Bladder and kidney RR = 1.51 (0.67, 3.38) Bladder cancer 2. Very low exposures
cancer RR = 1.07 (0.46, 2.52) Kidney cancer 3. Elevated risk ratios seen in smokers: RR = 10.3 (1.16, 92.6) for
For exposures > 10 years before cancer bladder cancer
diagnosis
Steinmaus Chile As conc (µg/​L) OR   (90% CI) 1. Case-​control study
et al., 2014 Lung cancer   6.5 1.00 (ref) 2. Median arsenic water concentrations
23.0 1.43 (0.82, 2.52) 3. Some data obtained in interviews with next-​of-​kin
58.5 2.01 (1.14, 3.52)

As: arsenic; CI: confidence interval; HR: hazard ratio; IRR: incidence rate ratio; OR: odds ratio; RR: relative risk; SMR: standardized mortality ratio.
95% confidence intervals in parentheses unless otherwise noted.

metalloproteinases, and dysregulated signaling pathways (Tokar et al.,
2013). Other studies have shown that arsenic may affect stem cells in
other cell types, including skin and prostate (Sun et al., 2012; Tokar
et al., 2010b). Although a number of different mechanisms have been
proposed, the mechanism or combination of mechanisms most likely
responsible for the human health effects of arsenic is unknown.
Opportunities for Prevention
The most effective and practical way to reduce cancer risks from arse-
nic is to reduce exposure. Several countries have promulgated regula-
tory limits for arsenic concentrations in drinking water. In the United
States, these apply only to public water sources, not household wells.
Large municipal water suppliers have reduced arsenic concentrations
through various methods, including the development of new water
sources (e.g., tapping new aquifers, desalinization of ocean water),
mixing water from wells with higher arsenic concentrations with water
with lower arsenic concentrations, and coagulation with iron salts and
filtration (Albuquerque Bernalillo County Water Utility Authority,
2010; Sancha et al., 2000; Su et al., 2011; US EPA, 2012). Other treat-
ments include reverse osmosis, activated alumina, microfiltration, and
ion exchange (US EPA, 2000b). Smaller reverse osmosis filters are
commonly used to reduce arsenic concentrations in private domestic
wells, where most of the other approaches are prohibitively expensive
(Slotnick et al., 2006). The effectiveness of these filters may vary con-
siderably due to inconsistent maintenance and other factors (George
et al., 2006; Thomson et al., 2000; Walker et al., 2008).
A variety of approaches have been used to reduce arsenic exposures
in Bangladesh. A mass survey of over 5 million wells measured arse-
nic concentrations and used colored paint to indicate the level of con-
tamination. Wells with arsenic concentrations < 50 µg/​l were painted
green; wells over this level (approximately 1.4 million) were painted
red (Johnston and Sarker, 2007). Contamination in this area primarily
affected tube wells that accessed shallower aquifers (i.e., < 150 m).
Mitigation efforts have closed highly contaminated wells, expanded
the use of surface water, and created deep tube wells, shallow dug
wells, and sand pond filters. Educational programs were implemented
in highly exposed areas in Araihazar, Bangladesh. Participation in
312
312 PART III:  THE CAUSES OF CANCER
a school-​ based educational and intervention program resulted in
a five-​fold increase in switching to a lower arsenic well, and sig-
nificant declines in urinary arsenic levels among participants (Khan
et al., 2015).
Chelation therapy with British anti-​lewisite (BAL; dimercaprol) or
its analogs unithiol (DMPS) and succimer (DMSA) is used to treat very
high-​dose acute poisonings (e.g., occupational accidents, homicide, or
suicide attempts). Chelation has not been shown to be appropriate for
prevention or treatment of arsenic exposures from food or drinking
water (Kosnett, 2013). Biomonitoring and early detection have been
proposed in areas where arsenic exposures have already been reduced
(Adonis et al., 2014). To date, the effectiveness of such programs has
not been established.
DISINFECTION BYPRODUCTS
Exposure
The disinfection of drinking water is one of the triumphs of pub-
lic health, responsible for significant reductions in mortality and
morbidity due to infectious disease (Cutler and Miller, 2005). An
unintended consequence of this approach, however, has been the
formation of disinfection byproducts (DBPs) that may affect can-
cer risk. DBPs are formed by the reaction of chlorine or other dis-
infectants with organic matter; they include a complex mixture of
compounds that depends on both the treatment regimen and charac-
teristics of the source water. The formation of specific compounds
is influenced by the level and type of organic matter present, the
existence of bromide and/​or iodide, and the pH and temperature of
the water (Richardson et al., 2007). Trihalomethanes (THMs) com-
prise one category of DBP. They were discovered in 1974 (Rook,
1974)  and are composed of chloroform (typically the dominant
THM), dibromochloromethane, bromodichloromethane, and bromo-
form. More than 700 DBPs have now been identified. Major classes
that are regulated in the United States include the THMs, haloacetic
acids (HAAs), and oxyhalides (bromate and chlorite). There are also
multiple unregulated classes, such as the halonitromethanes, iodo-​
acids and other halo-​ acids, chlorinated hydroxy furanones (e.g.,
MX), haloamides and haloacetonitriles, nitrosamines, and aldehydes
(Richardson et  al., 2007). Many of these compounds have been
shown to be mutagenic and/​or genotoxic. As indicated earlier, only
three classes of compounds are regulated in the United States; it is
assumed that reduced levels of these compounds will reduce overall
exposure to DBPs (US EPA, 2003). The regulatory maximum con-
taminant level (MCL) in the United States is 80 ppb total for total
THM, 60 ppb for the HAAs, 10 μg/​l for bromate, and 1000 μg/​l for
chlorite (US EPA, 2006). Concern about bladder cancer was a key
consideration when the rules and cost–​benefit analysis were updated
in 2006 (US EPA, 2005).
In 1991, the IARC determined that there was inadequate evidence
to classify the use of chlorinated drinking water as carcinogenic to
humans (IARC, 1991). Since then, IARC has evaluated individual
DBPs, none of which is listed as a Class I carcinogen (IARC, 2004,
2013, 2014). Chloral and chloral hydrate were designated probable
human carcinogens (Group 2A), whereas dichloroacetic acid, trichlo-
roacetic acid, dibromoacetic acid, bromochloroacetic acid, and MX
were listed as possible human carcinogens (Group 2B) (IARC, 2004,
2013, 2014).
People can be exposed to DBPs through ingestion, dermal absorp-
tion, and inhalation. While ingestion has received the most attention
in epidemiologic studies, recent work has evaluated exposure through
inhalation or dermal absorption of low molecular weight, volatile,
non-​polar constituents (Richardson et  al., 2007). Studies have dem-
onstrated increased THM levels in blood following exposure, with
higher THM blood levels associated with showering than with inges-
tion (Backer et al., 2000). Additionally, studies of swimmers in chlo-
rinated pools show increased THM concentrations in exhaled air
(Aggazzotti et  al., 1993; Caro and Gallego, 2007; Kogevinas et  al.,
2010; Lourencetti et  al., 2012), blood (Aggazzotti et  al., 1990), and
urine (Caro and Gallego, 2007, 2008).
Types of Cancer
Soon after THMs were identified, ecologic studies conducted in the
United States, Norway, and Finland showed elevated cancer rates
associated with chlorination byproducts or surrogate measures (Cantor
et al., 2006). The exposures in these studies were broadly defined, with
some studies comparing the use of chlorinated to unchlorinated water,
and others comparing surface water (which tends to have higher lev-
els of DBPs) to groundwater. Levels of THM and mutagenicity were
estimated. The most commonly identified cancer sites with elevated
rates were bladder, colon, and rectum. Subsequently, a number of
death-​certificate-​based case-​control studies were conducted, focusing
on these and other sites. Information on cause of death and current
residence was obtained from death certificates (Cantor et  al., 2006).
Although these studies had methodologic limitations, including a
lack of historical exposure information and information on potential
confounders, they generally supported an association between chlori-
nated byproducts and risk of cancers of the bladder, colon, and rectum
(Cantor et al., 2006).
Following the ecological studies of cancer mortality, a series of
case-​ control studies of incident cancers collected more informa-
tion on longer-​term exposures, and variables that might confound or
interact with DBPs. The site with the strongest evidence of a causal
relationship was bladder, although risks associated with DBP were
generally modest, with ORs around 1.5 associated with estimated
total THM levels of 50 μg/​L (Costet et al., 2011). Three cohort and
eight case-​control studies evaluated this association, in addition to
several reviews and meta-​analyses (Costet et  al., 2011; Villanueva
et al., 2003). The cohort studies and all but two of the case-​control
studies were reviewed in the previous edition of this text and will not
be discussed here (Cantor et  al., 2006). Many of the earlier studies
focused on surrogates of exposure to DBPs, such as use of a chlori-
nated water source for drinking water, or duration of use of surface
versus groundwater. A meta-​analysis published in 2003 reported an
odds ratio of 1.2 (95% CI: 1.1, 1.4) associated with ever consuming
chlorinated water, and 1.4 (95% CI: 1.2, 1.7) for long-​term exposure
(Villanueva et al., 2003). Although results were generally consistent
among studies, variation existed particularly with respect to apparent
sex differences. Some studies showed stronger effects among men.
However, none of the individual studies had adequate power to detect
associations among women.
Since the previous edition of this text, two case-​control studies of
bladder cancer have been conducted, one from six regions in Spain
(Villanueva et al., 2007) and another in three northern New England
states in the United States (Beane Freeman et al., 2017). Both expanded
upon previous exposure assessment efforts by considering routes of
exposure other than ingestion, such as showering, bathing, and use
of swimming pools (Costet et  al., 2011; Villanueva et  al., 2004). In
Spain, THM levels were estimated by using historical information
from individual municipalities (Villanueva et al., 2006). Compared to
participants in the lowest quartile of long-​term average THM concen-
tration in water (< 8 µg/​l), those in the highest quartile (> 49 μg/​l) had
a two-​fold increase of bladder cancer risk (OR = 2.10; 95% CI: 1.09,
4.02). In a metric that incorporated both the THM concentration and
the amount of water ingested, there was a non-​significant increase in
bladder cancer risk among those with the highest intake of THM (> 35
μg/​d) compared to those with no exposure (OR = 1.35; CI: 0.92, 1.99)
(Villanueva et  al., 2007). Information about the duration of shower-
ing and bathing was combined with the average THM concentration
to evaluate inhalation and dermal exposure. Those with the highest
exposure levels had significantly elevated risk (OR = 1.83; CI: 1.17,
2.87). Bladder cancer risk was also elevated among those who reported
ever use of swimming pools, another potentially large source of DBP
exposure (OR = 1.57; CI: 1.18, 2.09), although risk did not increase
with increasing total lifetime hours of use. The results for ingestion
and concentration were stronger among men than women, whereas the
 31
Water Contaminants 313
associations with showering/​bathing and swimming pool exposures
were similar in both sexes.
In the population-​based case control study in New England (Beane
Freeman et al., 2017), historical information from public utilities and
residential histories were used to estimate total THM exposures, as
well as levels of chlorinated and brominated compounds. At the 95th
percentile of average daily intake (> 103.9 µg/​day), bladder cancer
risk was significantly associated with total THM (OR = 1.53; 95% CI:
1.01, 2.32) and brominated THMs (OR = 1.98; 95% CI: 1.19, 3.29).
For cumulative intake (mg) of chlorinated and brominated THMs from
age 10 through diagnosis or interview, bladder cancer risk was elevated
among those with > 95th percentile of total THM (OR = 1.45; 95% CI:
0.95, 2.2), and chlorinated and brominated THMs (OR = 1.77; CI:
1.05, 2.99 and OR = 1.78; CI: 1.05, 3.00, respectively). There was
no evidence of bladder cancer risk with swimming pool use (OR =
0.94; CI: 0.55, 1.59 for > 12,174 lifetime hours compared to those who
never used swimming pools).
Although both studies showed increased risk of bladder cancer
associated with increased THM levels, the risk estimates in the New
England study were lower than in Spain. It should be noted that the
estimated exposure to THMs was also much lower in New England
(Beane Freeman et  al., 2017; Salas et  al., 2013). Differences in the
association with swimming pool use may be due to chance or to dif-
ferences in swimming pool disinfection that are not well understood.
The DBPs in swimming pools are affected by the same characteristics
as drinking water. The specific DBPs formed in swimming pools vary
by the disinfection processes used (Lee et  al., 2010), the number of
swimmers in the pool, and the presence of urine, other body fluids, and
personal care products (Chowdhury et al., 2014). These issues should
be studied further.
Much less epidemiologic research has been conducted on the
association between DBP exposure and cancers other than bladder.
Colon and rectum cancer are the sites with the most evidence for
an association. A case-​control study in Spain and Italy reported no
association between total THMs and colorectal cancer, although
there was a suggestive increase in risk among men with the highest
quartile of brominated THM exposure (OR = 1.43; 95% CI: 0.83,
2.46, p trend = 0.04) (Villanueva et al., 2017). There was no associa-
tion with showering and bathing in water with higher levels of total
THMs, chloroform, or brominated compounds, nor were risks ele-
vated in women. There was a suggestion of an interaction between
brominated THMs and four genetic polymorphisms in the CYP2E1
gene. An interaction between this gene and total THMs was observed
in the Spanish study of bladder cancer. Results from this study were
similar for both colon and rectal cancers. Other studies, however,
have suggested that the risks may differ for colon and rectum can-
cer. For example, a case-​control study of colon and rectum cancer
in Ontario, Canada, reported increased risk of colon cancer in men,
with increasing cumulative exposure to THMs, duration of exposure
to chlorinated surface water, and duration of exposure to THM lev-
els > 50 µg/​l. No associations were observed with rectum cancer or
in women (King et al., 2000). A case-​control study in Iowa reported
increased risk of rectal cancer (Hildesheim et al., 1998). Recently,
two studies have suggested an increased risk of rectal cancer at higher
levels of bromoform exposure. A case control study of rectal cancer
in New York showed a statistically significantly increased risk at the
highest levels of bromoform exposure (1.69–​15.43 µg/​day), but not
with other THMs (Bove et al., 2007). An ecologic study in Australia
evaluated colon and rectal cancers in relation to total THMs and
individual species of THMs (Rahman et  al., 2014). The authors
reported a statistically significantly increased incidence rate ratio
for colon cancer with an increasing interquartile range of bromo-
form (IQR = 2 µg/​l) in men, but not women. No other individual spe-
cies were associated with risk, nor was total THM level. There were
no significant associations with rectal cancer. Although the study
was ecological, a strength was that it evaluated all THMs, separately
and in combination. A recent analysis of kidney cancer in a cohort
of postmenopausal women in Iowa found no association between
kidney cancer and long-​term average total THM (HRQ4vsQ1 = 0.70;
95% CI: 0.41=, 1.20), HAA5 (HRQ4vsQ1 = 0.65; 95% CI; 0.39, 1.08;
Table 18–​3), nor with individual THMs or HAAs in models adjusted
for water nitrate level (Jones et  al., 2016). More recently, a small
study conducted within the National Health and Nutrition Survey
demonstrated an association between blood levels of brominated,
but not chlorinated, THMs and cancer mortality overall (Min and
Min, 2016). Other sites that have been evaluated include brain,
esophagus, pancreas, and childhood leukemia (Cantor et al., 2006).
Each of these sites has at least one epidemiologic study that shows
some evidence of association with increasing exposure to DBPs.
As indicated, for both colon and bladder cancer there is some sug-
gestion that risk may differ by sex, with many studies showing associa-
tions with THMs only in men (Costet et al., 2011; King et al., 2000).
However, it should be noted that most studies are underpowered to
detect associations in women. The two largest studies of bladder can-
cer, with the most women, did not demonstrate sex differences (Beane
Freeman et al., 2017; Cantor et al., 1987).
Mechanisms of Carcinogenesis
Given the number of compounds identified as DBPs, it is not surpris-
ing that several mechanisms for carcinogenicity have been proposed.
Some DBPs are genotoxic or mutagenic, either alone or as part of a
mixture; chloroform is considered to be mutagenic only at very high
levels of exposure (Richardson et al., 2007). Water samples from five
European countries demonstrated cytotoxicity in mammalian cells that
increased with the number of DBP compounds identified in each sam-
ple (Jeong et al., 2012). Although there were differences in genotoxic-
ity among the samples, it did not appear that the genomic DNA damage
in these samples correlated with the chemical analyses. Therefore, it
may be that the observed associations were due to unidentified DBPs,
or perhaps to combinations of DBPs. There has been interest in the
effect of genetic susceptibility in modifying risk. In an analysis from
the Spanish bladder cancer study, Cantor and colleagues (Cantor et al.,
2010) demonstrated significant interaction between genetic variation
in key metabolizing pathways and DBP levels on bladder cancer risk.
Exposed individuals with high-​risk variants of GSTT1, GSTZ1, and
CYP2E1 were at increased risk compared with those without the high-​
risk forms. Other studies have not reported attempts to replicate these
findings.
It has been suggested that epigenetic mechanisms may also be
important, particularly with regard to long-​term, lower-​level expo-
sures. In controls from the bladder cancer case-​control study from
Spain, the levels of DNA methylation at some transposons (LINE-​1 5-​
methylcytosine levels) in granulocytes were associated with increased
lifetime exposure to THM (Salas et al., 2014). There was also some
evidence that levels of methylation modified the association between
THM levels and bladder cancer risk (p-​interaction = 0.03). In another
epigenome-​wide study, genes that have been associated with cancer
at several sites, including colorectal and bladder, were found to have
methylation levels that differed by THM level (Salas et al., 2015).
NITRATE
Exposure
Since the mid-​1920s, human activities have doubled the natural rate
at which nitrogen is deposited onto land. Most important has been the
production and application of nitrogen fertilizers, the combustion of
fossil fuels, and replacement of natural vegetation with nitrogen-​fixing
crops such as soybeans (Davidson EA, 2012; Vitousek et al., 1997). In
1909 the Haber-​Bosch process was developed to produce ammonia by
reacting nitrogen gas with hydrogen. This allowed a dramatic increase
in the production of synthetic fertilizers and expansion of global
agriculture. Fertilizer production has increased exponentially since
1960; half of all synthetic fertilizers have been produced since 1985
(Howarth, 2008). As a result, nitrogen inputs to the land have steadily
increased. Approximately half of all applied nitrogen drains from agri-
cultural fields to contaminate surface and groundwater (Davidson EA,
314
314 PART III:  THE CAUSES OF CANCER
2012). Nitrate levels in groundwater under agricultural land can be
several to 100 times higher than levels under natural vegetation (Nolan
BT, 2000). Approximately 15% of the US population relies on pri-
vately owned household wells for drinking water (Hutson, 2004). As
mentioned, these are not regulated by the EPA. The US Geological
Survey assessed available private well measurements in US aquifers
sampled in 1991–​2004 and found that 8% exceeded the 10 mg/​l maxi-
mum contaminant level (MCL) for nitrate-​nitrogen (NO3-​N) (Focazio
et al., 2006). Other private well surveys show that a significant propor-
tion of wells, particularly those less than 30 meters in depth in agricul-
tural areas, exceed the MCL for nitrate (Centers for Disease Control
and Prevention, 1998; Johnson and Kross, 1990). Almost all public
water supplies have nitrate levels below the MCL. However, in the past
few decades, nitrate levels have risen to levels approaching the MCL in
some public supplies located in agricultural areas (Ward et al., 2010).
Mechanisms of Carcinogenesis
The MCL for nitrate in drinking water was established at 10 mg/​l NO3-​
N to protect against infant methemoglobinemia, not cancer or other
health outcomes (US EPA, 2016). Nevertheless, nitrate is a precur-
sor compound of N-​nitroso compounds (NOC), many of which are
potent animal carcinogens. NOC cause cancer in every animal spe-
cies tested and at multiple organ sites (IARC, 2010; Lijinsky, 1986).
Approximately 5% of nitrate ingested in drinking water or in the diet
is reduced to nitrite by bacteria. This occurs mostly because of the
oral microbiome, but continues in the stomach, small intestine, colon,
and bladder when nitrate-​reducing bacteria are present (IARC, 2010).
Nitrite can then react with amines and amides to form nitrosamines
and nitrosamides, the two main types of NOC.
Nitrate is found in many foods, with the highest levels occurring in
certain green leafy and root vegetables (NRC, 1981). Average daily
intakes are estimated to be in the range of 30–​130 mg/​day as nitrate
(IARC, 2010). Endogenous NOC formation is blocked by ascorbic
acid, alpha-​tocopherol, and other polyphenols. Because these inhibi-
tors are present at high levels in most vegetables, dietary nitrate intake
from vegetables may not result in substantial NOC formation (Mirvish,
1995). Drinking water contributes the majority of nitrate intake when
levels are near the MCL (Chilvers et al., 1984; IARC, 2010). Sources
of exposure to preformed NOC include processed meats and fish, beer,
certain occupations, cosmetics, and some drugs. It is estimated that
45%–​75% of human exposure to NOC comes from in vivo formation,
however (Tricker, 1997). An IARC Working Group reviewed the epi-
demiologic studies of ingested nitrate and nitrite through mid-​2006.
The evidence for dietary nitrite ingestion and cancer is considered
limited (IARC, 2010), based on epidemiologic studies of stomach
and esophageal cancer. However, another recent IARC review con-
cluded that processed meats, which usually contain added nitrite and/​
or nitrate, cause cancer in humans, based mostly on the evidence for
colorectal cancer (Bouvard et al., 2015).
Endogenous NOC formation due to ingestion of water with elevated
nitrate has been demonstrated in human volunteers (Mirvish et  al.,
1992; Møller et al., 1989; Vermeer et al., 1998), generally under con-
ditions of low antioxidant intake (e.g., low vitamin C). NOC also have
been measured in human feces after ingestion of nitrate via drinking
water (Rowland et al., 1991). In each of these four studies, increased
nitrosation was observed at nitrate concentrations that exceeded the
MCL. Some of the NOCs that were formed were known carcinogens.
In the hundreds of animal studies conducted since the 1970s, NOCs
cause tumors of the upper and lower gastrointestinal tract, urinary
tract, lung, thyroid, breast, and ovary. Transplacental exposure induces
brain tumors in offspring (Rice, 1989). Long-​term exposure to lower
NOC concentrations has a stronger carcinogenic effect than short-​term
higher exposures (Lijinsky, 1986).
The IARC Working Group classified ingested nitrate or nitrite as
probably carcinogenic to humans (2A), when ingested under condi-
tions that result in endogenous nitrosation (IARC, 2010). This desig-
nation was based on human mechanistic studies, sufficient evidence in
animals for the carcinogenicity of nitrite in combination with amines
or amides, and limited epidemiologic evidence for dietary nitrite. The
epidemiologic evidence for drinking water nitrate was considered
inadequate. In human studies, it is important to assess effect modi-
fication by exposure to modifiers of endogenous nitrosation. To date,
there are few studies of any cancer site that have assessed long-​term
exposure from drinking water and potential interactions with dietary
factors that affect NOC formation.
Epidemiologic Studies
Most early epidemiologic studies were ecologic studies of mortality
from stomach cancer that used exposure estimates based on measure-
ments of nitrate in drinking water concurrent with death from cancer.
Results were mixed, with some studies showing positive associations,
many showing no association, and a few showing inverse associations.
The results of ecologic studies through 1995 were reviewed in Cantor
(1997). Since that review, an ecologic study of cancer incidence in
Slovakia (Gulis et al., 2002) evaluated 20-​year average nitrate levels in
public water supplies (highest quartile: 6–​10 mg/​l NO3-​N) and found
a positive correlation with stomach cancer incidence among women
but not men. Other ecologic studies of cancer incidence were largely
null: endpoints in these studies included the brain (Barrett et al., 1998;
van Leeuwen et al., 1999), bladder and colon (Gulis et al., 2002; van
Leeuwen et al., 1999), esophagus and stomach (Barrett et al., 1998),
kidney (Gulis et al., 2002), ovary (van Leeuwen et al., 1999), and non-​
Hodgkin lymphoma (NHL) (Cocco et al., 2003; Law et al., 1999; van
Leeuwen et  al., 1999). Among the limitations of ecologic studies is
their inability to assess individual-​level exposure or dietary factors
that might interact with nitrate metabolism and affect the endogenous
formation of NOC. They also do not identify potentially susceptible
subgroups or other interactions.
Since the previous version of this chapter was published, 8 case
control and 2 cohort studies have evaluated historical nitrate levels in
public water supplies in relation to several cancers. The levels were
largely below 10 mg/​l NO3-​N. Most of these studies evaluated poten-
tial confounders and factors affecting nitrosation. Details of 9 case-​
control and 2 cohort studies published through 2005 were presented in
the previous version of this chapter (Cantor et al., 2006). Table 18–​2
shows the study designs and results of more recent studies, includ-
ing the results of periodic follow-​ups of a cohort study of postmeno-
pausal women in Iowa (Inoue-​Choi et  al., 2012, 2015; Jones et  al.,
2016, 2017; Ward et al., 2010). In the first analysis of drinking water
nitrate in the Iowa cohort with follow-​up through 1998, Weyer and
colleagues reported that ovarian and bladder cancer were significantly
associated with the long-​term average residential nitrate levels at the
time of enrollment (Weyer et  al., 2001). They also observed signifi-
cant inverse associations for uterine and rectal cancer, but no associa-
tions with cancers of the breast, colon, rectum, pancreas, kidney, lung,
melanoma, NHL, or leukemia. Analyses of public water supply nitrate
concentrations and cancers of the thyroid, breast, ovary, bladder, and
kidney were published after additional follow-​up of the cohort. The
exposure assessment was improved by (a) the computation of aver-
age nitrate levels and years of exposure at or above 5 mg/​l NO3-​N,
based on time in residence (vs. using one public water supply average
nitrate estimate used by Weyer and colleagues); and (b) by estimation
of THM levels and dietary nitrite intake. Thyroid cancer was evaluated
for the first time after follow-​up of the cohort through 2004. A total of
40 cases was identified (Ward et al., 2010). Among women with > 10
years of public water supply whose levels exceeded 5 mg/​l NO3-​N for
5 years or more, thyroid cancer risk was 2.6 times higher than that of
women whose supplies never exceeded 5 mg/​l. Higher dietary nitrate
intake was also associated with increased thyroid cancer risk. With fol-
low-​up through 2010, the risk of ovarian cancer remained significantly
increased among women in the highest quartile of average nitrate in
public supplies (Inoue-​Choi et al., 2015). Ovarian cancer risk among
private well users was also elevated compared to the lowest nitrate
quartile for public supplies. Associations were stronger when vitamin
C intake was below median levels with a significant interaction for
users of private wells. Higher intake of processed meat sources of
dietary nitrite was also associated with increased risk. Overall, breast
  315
Table 18–​2. Case-​Control and Cohort Studies of Drinking Water Nitrate Levels and Cancer (2004–​2017)

First Author
(Year) Study Design, Years
Country Regional Description Exposure Description Cancer Sites Included Summary of Findingsa,b Comments

Mueller (2004) Population-​based case-​control Dipstick measurements of nitrate
6 countries Incidence, 1976–​1994 and nitrite in the pregnancy water
Los Angeles County, San supply among women who had not
Francisco Bay Area, Seattle–​ moved (185 cases, 341 controls);
Puget Sound region of the population excluding bottled water
United States; Paris, France; users (131 cases, 241 controls)
Milan, Italy; Valencia, Spain;
Winnipeg, Canada
Ward (2006) Population-​based case-​control Nitrate levels in public water
United States Incidence, 1998–​2000 supplies among those with nitrate
Iowa estimates for > 70% of person-​
years > 1960 (181 cases, 142
controls); nitrate measurements
for private well users at time of
interviews (1998–​2000; 54 cases,
44 controls).
Zeegers (2006) Cohort 1986 nitrate level in 364 pumping
Netherlands Incidence, 1986–​1995 stations, exposure data available
204 municipal registries across the for 871 cases, 4359 members of
Netherlands the subcohort
Ward (2007) Population-​based case control Nitrate levels in public water
United States Incidence, 1986–​1989 supplies among those with nitrate
Iowa estimates for > 70% of person-​
years > 1960 (201 cases, 1244
controls)
McElroy (2008) Population-​based case-​control, Limited to women in rural areas with
United States women no public water system (475 cases,
Incidence, 1990–​1992 and 1447 controls); nitrate levels at
1999–​2001 residence (presumed to be private
Wisconsin wells) estimated by kriging using
data from a 1994 representative
sample of 289 private wells
Ward (2008) Population-​based case control Controls from prior study of
United States Incidence, 1988–​1993 lymphohematopoetic cases and
Nebraska controls interviewed in 1992–​
1994; proxy interviews for 80%,
76%, 61% of stomach, esophagus,
controls, respectively.
Nitrate levels (1965–​1985) in public
water supplies for > 70% of
person-​years (79 distal stomach,
84 esophagus, 321 controls);
private wells sampled at interview
(15 stomach, 22 esophagus, 44
controls)
Childhood (< 15 years) > 11 mg/​L NO3-​N vs. ND OR = 1.0 Strongest associations for
malignant brain (CI: 0.4, 2.2); exclude bottled water astroglial tumors with dipstick
tumors users OR = 1.5 (CI: 0.6, 3.8) nitrate and nitrite measurements
> 1.5 mg/​L NO2-​N vs. ND OR = 2.1 at pregnancy residence
(CI: 0.6, 7.4); exclude bottled water
users OR = 5.2 (CI: 1.2, 23.3)
Well as water source for entire
pregnancy including periconceptual
period (vs. public supply) associated
with increased risk in Canada and
Seattle but not other centers
Non-​Hodgkin Private wells: > 5.0 mg/​L NO3-​N vs. No effect modification by vitamin
lymphoma ND OR = 0.8 (CI: 0.2, 2.5) C, smoking
Public supply average: > 2.9 mg/​
L NO3-​N vs. < 0.63 OR = 1.2
(CI: 0.6, 2.2)
Years > 5mg/​L NO3-​N: 10+ vs. 0
OR = 1.4 (CI: 0.7, 2.9)
Bladder Nitrate intake from water (highest No effect modification by vitamin
quintile > 1.7 mg/​day NO3-​N C, E, smoking
[median in quintile = 2.4 mg/​day]
vs. lowest RR = 1.11 (CI: 0.87,
1.41; p-​trend = 0.14)
Kidney (renal cell Public supply average: > 2.8 mg/​ Joint effects of water nitrate
carcinoma) L NO3-​N vs. < 0.62 OR = 0.89 and vitamin C showed
(CI: 0.57, 1.39); Years > 5mg/​ similar pattern to red meat
L NO3-​N 11+ vs. 0 OR = 1.03 (p-​interaction = 0.13)
(CI: 0.66, 1.60)
Joint effect for 11+ years > 5 mg/​
L NO3-​N and red meat (> 1.2
servings/​day) OR = 1.91 (CI: 1.04,
3.51); p-​interaction = 0.01
Colorectum Private wells > 10.0 mg/​L NO3-​N vs. Interactions with dietary intakes
< 0.5: Colorectal cancer OR = 1.52 not evaluated; no interaction
(CI: 0.95, 2.44); proximal colon with smoking
cancer: OR = 2.91 (CI: 1.52, 5.56);
no association for distal colon
cancer or rectal cancer
Stomach and esophagus Average nitrate quartiles (> 4.32 vs. > 2.7mg/​L NO3-​N & > 30g/​
(adenocarcinomas < 2.45 mg/​L NO3-​N): stomach day processed meat vs.
only) OR = 1.2 (CI: 0.5, 2.7); esophagus low intakes both: stomach
OR = 1.3 (CI: 0.6, 3.1); OR = 2.0 (CI: 0.8, 4.8);
Years > 10 mg/​L NO3-​N (9+ vs. p-​interaction = 0.21; no
0): stomach OR = 1.1 (CI: 0.5, 2.3); interaction for esophagus; no
esophagus OR = 1.2 (CI: 0.6, 2.7) interaction with vitamin C, red
Private well users (> 4.5mg/​L NO3-​ meat for either cancer
N vs. < 0.5) stomach OR = 5.1
(CI: 0.5, 52; 4 cases, 13 controls);
esophagus OR = 0.5 (CI: 0.1, 2.9; 8
cases; 13 controls)
(continued)

Table 18–​2  Continued
First Author
(Year) Study Design, Years
Country Regional Description
Ward (2010) Cohort of women ages 55–​69
United States Incidence, 1986–​2004
Iowa
Inoue-​Choi (2012) Cohort of women ages 55–​69
United States Incidence, 1986–​2008
Iowa
Inoue-​Choi (2015) Cohort of women ages 55–​69
United States Incidence, 1986–​2010
Iowa
Espejo-​Herrera (2015) Hospital-​based case-​control
Spain Incidence, 1998–​2001
Asturias, Alicante, Barcelona,
Valles-​Bages, Tenerife
provinces
Jones (2016) Cohort of women ages 55–​69
United States Incidence, 1986–​2010
Iowa
Exposure Description
Nitrate levels in public water
supplies (1955–​1988) and private
well use among women > 10 years
at residence (21,977 women; 40
thyroid cases); no measurements
for private wells
Nitrate levels in public water
supplies (1955–​1988) and private
well use among women > 10 years
at residence (20,147 women; 1751
breast cases); no measurements for
private wells
Nitrate levels in public water
supplies (1955–​1988) and private
well use among women > 10 years
at residence with nitrate and
trihalomethane estimates (17,216
women; 190 ovarian cases); no
measurements for private wells
Adjusted for total trihalomethanes
(TTHM) (1955–​1988), measured
TTHM levels in 1980s, prior years
estimated by expert)
Nitrate levels in public supplies
(1979–​2010) and bottled water
(measurements of brands with
highest consumption based on a
Spanish survey); analyses limited
to those with > 70% of residential
history with nitrate estimate (531
cases, 556 controls)
Nitrate levels in public water
supplies (1955–​1988) and private
well use among women > 10 years
at residence with nitrate and
trihalomethane estimates (20,945
women; 170 bladder cases); no
measurements for private wells
Adjusted for total trihalomethanes
(TTHM) (1955–​1988), measured
TTHM levels in 1980s, prior years
estimated by expert)
316
Cancer Sites Included Summary of Findingsa,b Comments
Thyroid Average nitrate quartiles (> 2.46 vs Dietary nitrate intake quartiles
< 0.36 mg/​L NO3-​N) HR = 2.18 positively associated with risk
(CI: 0.83, 5.76; p-​trend = 0.02) (p-​trend = 0.046)
Years > 5 mg/​L (> 5 years vs.
0) HR = 2.59 (CI: 1.09, 6.19;
p-​trend = 0.04);
private well (vs. < 0.36 mg/​L NO3-​N)
HR = 1.13 (CI: 0.83, 3.66)
Breast Average nitrate quintiles (> 3.8 vs. Interaction with vitamin C and
< 0.32 mg/​L NO3-​N) HR = 1.14 smoking not evaluated
(CI: 0.95, 1.36; p-​trend = 0.11);
private well (vs. < 0.32 mg/​L
NO3-​N) HR = 1.14 (CI: 0.97, 1.34)
Subgroup with folate > 400 µg/​
d: (> 3.8 vs. < 0.32 mg/​L NO3-​
N) HR = 1.40 (CI: 1.05, 1.87;
p-​trend = 0.04); private well (vs.
< 0.32 mg/​L NO3-​N) HR = 1.38
(CI: 1.05, 1.82)
No association among those with low
folate < 400 µg/​d
Ovary Highest vs. lowest quartile average (> Associations with average water
2.98 mg/​L vs. < 0.47 mg/​L NO3-​ nitrate and private well use
N) HR = 2.03 (CI: 1.22, 3.38; p-​ were stronger among women
trend = 0.003), adjusted for TTHM; with < median vitamin C intake
years > 5 mg/​L (> 4 years vs. (average nitrate p-​trend = 0.005;
0) HR = 1.52 (CI: 1.00, 2.31; p-​ p-​interaction = 0.33; private
trend = 0.05), adjusted for TTHM well p-​interaction = 0.01)
Private well users (vs. < 0.47 mg/​L No interaction with red meat
NO3-​N) HR = 1.53 (CI: 0.93, 2.54) intake
Bladder Average level (age 18-​interview) No interaction with vitamin C,
> 2.26 vs. 1.13 mg/​L NO3-​N E, red meat, processed meat,
OR = 1.04 (CI: 0.60, 1.81) average THM level
Years > 2.15 mg/​L NO3-​N (75th
percentile): > 20 vs. 0 years
OR = 1.41 (CI: 0.89, 2.24)
Bladder Highest vs. lowest quartile average Significant interaction with
(> 2.98 vs. < 0.47 mg/​L NO3-​N) smoking: Current smokers
HR = 1.47 (CI: 0.91, 2.38; p-​ with > 2.98 mg/​L NO3-​N vs.
trend = 0.11), adjusted for average non-​smokers < 0.47 mg/​L
TTHM levels NO3-​N HR = 3.67 (CI: 1.43,
Years > 5 mg/​L (> 4 years vs. 9.38); p-​interaction = 0.03;
0) HR = 1.61 (CI: 1.05, 2.47; p-​ no significant interaction with
trend = 0.03), adjusted for average vitamin C, TTHM levels
TTHM levels
Private well users (vs. < 0.47 mg/​L
NO3-​N) HR = 1.53 (CI: 0.93, 2.54)

Espejo-​Herrera (2016) Pooled case-​control studies Nitrate levels in public supplies
Spain, Italy Incidence, 2008–​2013 (2004–​2010) for 349 water
Spain (9 provinces) and supply zones, bottled water
population-​based controls; Italy (measurements of brands with
(two provinces) and hospital-​ highest consumption based on
based controls surveys in Spain and Italy),
and private wells and springs
(measurements in 2013 in 21
municipalities of León, Spain,
the area with highest non-​public
water use).
Analyses include those with nitrate
estimates for > 70% of period
30 years before interview (1869
cases, 3530 controls)
Espejo-​Herrera (2016) Hospital-​based case-​control Nitrate levels in public supplies
Spain Incidence, 2008–​2013 (2004–​2010), bottled water
Spain (8 provinces) (measurements of brands with
highest consumption based on a
Spanish survey), and private wells
and springs (measurements in
2013 in 21 municipalities of León,
Spain, the area with highest non-​
public water use).
Analyses include women with > 70%
of period from age 18 to 2 years
before interview (1245 cases, 1520
controls)
Jones (2017) Cohort of women ages 55–​69 Nitrate levels in public water
United States Incidence, 1986–​2010 supplies (1955–​1988) and private
Iowa well use among women > 10 years
at residence with nitrate and
trihalomethane estimates (20,945
women; 163 kidney cases); no
measurements for private wells
Adjusted for total trihalomethanes
(TTHM) (1955–​1988), measured
levels in 1980s, prior year levels
estimated by expert)
ND: not detected
a
Nitrate or nitrite levels presented in the publications as mg/​L of the ion were converted to mg/​L as NO3-​N or NO2-​N
b
Odds ratios (OR) for case-​control studies, incidence rate ratios (RR), and hazard ratios (HR) for cohort studies, and 95% confidence intervals (CI).
 317
Colorectal cancer Water nitrate intake based on average Stronger associations for men and
nitrate levels (estimated 30 to among those with high red meat
2 years prior to interview) and intake; no significant interaction
water intake (L/​day) with red meat, vitamin C, E,
> 2.3 vs. < 1.1 mg /​day NO3-​N fiber
OR = 1.49 (CI: 1.24, 1.78), adjusted
for diet/​other colorectal cancer risk
factors; colon OR = 1.52 (1.24,
1.86), rectum OR = 1.62 (1.23,
2.14)
Breast Water nitrate intake based on average Water nitrate intake estimated
nitrate levels (age 18 to 2 years from age 18 to 30 and from
prior to interview) and water 15 to 2 years before interview
intake (L/​day). Post-​menopausal showed similar results.
women: > 2.0 vs. 0.5 mg/​day Stronger associations among
NO3-​N OR = 1.32 (0.93, 1.86); postmenopausal women with
Premenopausal women: > 1.4 vs. high red or processed meat
0.4 mg/​day NO3-​N OR = 1.14 intake; no significant interaction
(0.67, 1.94) with red meat, vitamin C, E,
smoking
Kidney 95th percentile vs. lowest quartile of No significant interaction with
average nitrate level (> 5.00 vs. smoking, vitamins C or E
< 0.47 mg/​L NO3-​N) HR = 2.23
(CI: 1.19, 4.17; p-​trend = 0.35),
adjusted for TTHM
Years >5 mg/​L (> 4 years vs.
0) HR = 1.54 (CI; 0.97, 2.44; p-​
trend = 0.09), adjusted for THM
Private well users (vs. < 0.47 mg/​L
NO3-​N) HR = 0.96 (CI: 0.59, 1.58)
318
318 PART III:  THE CAUSES OF CANCER
cancer risk was not associated with water nitrate levels with follow-​up
through 2008 (Inoue-​Choi et  al., 2012). Among women with folate
intake ≥ 400 μg/​day, risk was significantly increased for those in the
highest average nitrate quintile (HR = 1.40; 95% CI: 1.05, 1.87) and
among private well users (HR = 1.38; 95% CI: 1.05, 1.82), compared
to those with the lowest average nitrate quintile. There was no asso-
ciation with nitrate exposure among women with lower folate intake.
Analyses of effect modification by other dietary factors were not pre-
sented. With follow-​up through 2010, there were 130 bladder cancer
cases among women who had used publicly supplied water > 10 years.
Risk remained elevated among women with the highest average nitrate
levels and was significantly increased among women whose drinking
water concentration exceeded 5 mg/​l NO3-​N for at least 4 years (Jones
et al., 2016). Risk estimates were not changed by adjustment for THM
levels. Smoking, but not vitamin C intake, modified the association
with nitrate in water; increased risk was apparent only in current smok-
ers. Dietary nitrite intake was not associated with risk. With follow-​
up through 2010, there were 125 kidney cancer cases among women
in the public water supply analysis; risk was significantly increased
among those in the 95th percentile of average nitrate (> 5.0 mg/​L
NO3-​N) compared with the lowest quartile (HR = 2.2; 95% CI: 1.2,
4.2). There was no positive trend with the average nitrate level and no
increased risk for women using private wells, compared to those with
low average nitrate in their public water supply (Jones et al., 2016).
Higher risk was evident in the 95th percentile of dietary nitrite intake
from processed meats but with no significant trend.
In contrast to the positive findings for bladder cancer among the
cohort of Iowa women, a cohort study of men and women aged 55–​69
in the Netherlands with lower nitrate levels in public supplies found
no association between water nitrate ingestion (median in top quin-
tile = 2.4 mg/​day NO3-​N) and bladder cancer risk (Zeegers et al., 2006).
Dietary intake of vitamins C and E and history of cigarette smoking
did not modify this observation. A hospital-​based case-​control study
of bladder cancer in multiple areas of Spain (Espejo-​Herrera et  al.,
2015) assessed lifetime water sources and usual intake of tap water.
Nitrate levels in public water supplies were low, with almost all aver-
age levels below 2 mg/​l NO3-​N. Risk of bladder cancer was not associ-
ated with the nitrate level in drinking water or with estimated nitrate
ingestion, and there was no evidence of interaction with factors affect-
ing endogenous nitrosation.
Several case-​control studies conducted in the Midwestern United
States obtained lifetime histories of drinking water sources and esti-
mated exposure for users of public water supplies. In contrast to
findings of an increased risk of NHL associated with higher average
nitrate levels in Nebraska public water supplies in an earlier study
(Ward et al., 1996), there was no association with similar concentra-
tions in public water sources in a case-​control study of NHL in Iowa
(Ward et  al., 2006). A  study of renal cell carcinoma in Iowa (Ward
et  al., 2007)  found no association with the level of nitrate in public
water supplies, including the number of years that the supply exceeded
5 or 10 mg/​l NO3-​N. Higher nitrate levels in public water supplies
increased risk among subgroups that reported above the median intake
of red meat intake or below the median intake of vitamin C, however.
These interactions were statistically significant. A small case-​control
study of adenocarcinoma of the stomach and esophagus among men
and women in Nebraska (Ward et  al., 1997)  estimated nitrate levels
among long-​term users of public water supplies and found no asso-
ciation between average nitrate levels and risk. A case-​control study
among rural women in Wisconsin estimated nitrate levels in private
wells using spatial interpolation of nitrate concentrations from a 1994
water quality survey and found a significant increased risk of proximal
colon cancer among women estimated to have nitrate levels > 10 mg/​l
NO3-​N compared to levels < 0.5 mg/​l. Risks of distal colon cancer and
rectal cancer were not associated with the nitrate level (McElroy et al.,
2008). Water nitrate ingestion from public supplies, bottled water,
and private wells and springs over the adult lifetime was estimated in
analyses that pooled case-​control studies of colorectal cancer in Spain
and Italy (Espejo-​Herrera et  al., 2016a). Risk of colorectal cancer
was significantly increased among those with > 2.3 mg/​day NO3-​N
(vs. < 1.1 mg/​day); risks were stronger among men, but there were
no significant interactions with red meat, vitamins C and E, and fiber
intakes. Postmenopausal and premenopausal breast cancers were not
associated with water nitrate ingestion in a hospital-​based case-​control
study in Spain (Espejo-​Herrera et al., 2016b).
Animal studies demonstrate that in utero exposure to nitrosamides
can cause brain tumors in the exposed offspring. Water intake during
pregnancy was estimated in a multicenter case-​control study of child-
hood brain tumors in five countries based on the maternal residen-
tial water source (Mueller et al., 2004). Nitrate/​nitrite levels in water
supplies were measured using a dipstick method for a subset of the
women; however, most of these measurements occurred many years
after the pregnancy. Drinking water from private wells versus public
water supplies was not consistently associated with risk of childhood
brain tumors. However, higher nitrite levels (> 1.5 mg/​l nitrite-​N) in
the drinking water were associated with significantly increased risk of
childhood brain tumors, especially astroglial tumors.
Biomarkers of Genetic Damage
Two cross-​sectional studies of the genotoxic effects of nitrate in drink-
ing water included individuals drinking well water with nitrate con-
centrations ranging from 11 to 65 mg/​l as NO3-​N. The first study found
no increase in the frequency of peripheral lymphocyte sister chromatid
exchanges with increasing levels of nitrate (Kleinjans et  al., 1991).
A  subsequent study employed the hypoxanthine-​guanine phosphori-
bosyltransferase (HPRT) variant frequency test in peripheral lympho-
cytes (van Maanen et  al., 1996). An increased prevalence of HPRT
variants in subjects drinking medium and high levels of nitrate was
observed. An inverse correlation between the labeling index in lym-
phocytes and nitrate exposure was suggestive of an exposure-​related
immunosuppressive effect. Future studies examining the genotoxic
potential of nitrate in drinking water can make valuable contributions
to understanding the adverse effects of nitrate exposure and warrant
further exploration.
CYANOBACTERIAL TOXINS
Cyanobacteria (formerly known as blue-​green algae) are an ancient and
ubiquitous family of prokaryotic organisms, with fossil remains dat-
ing back ~3.5 billion years. Photosynthesis by these bacteria is likely
responsible for earth’s oxygen-​enriched atmosphere, and subsequent
evolution of higher organisms (Olson, 2006; Paerl et al., 2011; Schopf,
2000). Cyanobacteria from more than 40 genera produce a wide vari-
ety of toxins (cyanotoxins). Among these are hepato-​, nephro-​, neuro-​,
and dermatotoxins belonging to several chemical classes (Chorus and
Bartram, 1999). Adverse human health effects range from minor skin
irritation to death from severe liver damage and possibly amyotrophic
lateral sclerosis (Cox and Sacks, 2002).
Evidence for carcinogenicity is strongest for microcystins (MCs),
nodularin, and cylindrospermopsin (Zegura et al., 2011). Microcystins,
usually the most common toxins found in fresh water, are cyclic
peptides containing seven amino acids, with two variable positions.
There are at least 80 analogs. Microcystin-​LR, the most thoroughly
studied, contains lysine (L) and arginine (R) in the variable positions
(Butler, 2009).
Epidemiologic evidence implicating cyanotoxins (particularly
microcystin-​LR) as human carcinogens comes largely from southeast-
ern coastal China. Here, elevated rates of hepatocellular carcinoma
(HCC) have long been recognized. The main causes are known to be
endemic infection with hepatitis B (and more recently C) viruses, in
combination with consumption of grain contaminated by aflatoxin.
An additional cofactor, however, may be consumption of surface
water contaminated by cyanotoxins. Many studies in this region have
reported much higher risk of HCC among populations that regularly
used surface waters (largely pond, ditch, or river water) as their pri-
mary water source, compared to those who consumed water from
shallow or deep wells (Shen et al., 1985; Su, 1979; Yu, 1989; Zhang,
1993). For example, in the period 1972–​1981 in Qidong County, Shen
 319
Water Contaminants 319
et al. (1985) observed annual incidence rates of HCC of 141.4, 72.3,
43.5, 22.3, and 11.7 per 100,000 for water consumers of house ditch,
field ditch, river, shallow wells, and deep wells, respectively. Among
99 HCC cases and 99 matched controls in Guangxi Autonomous
Region, Zhang et al. (1993) found an odds ratio of 3.7 (95% CI: 1.3,
11.0) for consuming pond/​ditch water, compared with well water. In
a review, Yu (1989) reported several studies of incidence and mortal-
ity from HCC conducted in Qidong, Nanhue, and Haimen counties in
1973–​1983. These showed a consistent pattern of higher incidence and
mortality rates among those who drank water from ponds and ditches
than among those who only used wells. For example, the standardized
incidence ratios (SIR) in Qidong were 2.6 and 1.4 per 100,000 for
pond and ditch water users, and 0.34 for shallow well water consum-
ers. Variability in hepatitis virus infection or aflatoxin (Yu, 1989) in the
affected populations did not explain the risk differences. In a public
health intervention (1973–​1978), the population was encouraged to
shift drinking water source from surface to wells, resulting in substan-
tially decreased HCC risks (Su, 1979).
Prior to 1990, researchers suspected that chemical contaminants in
surface waters in the endemic region probably accounted for the asso-
ciation between liver cancer and drinking surface water in the endemic
areas. Pesticides and other agricultural chemicals were considered
strong candidates. Empirical evidence for their involvement was lack-
ing, however.
Extracts from cyanobacteria have long been known to be highly
toxic to humans (Schwimmer and Schwimmer, 1955). In particular,
gastroenteritis, hepatotoxicity, and occasionally death from these
toxins have been observed (Chorus and Bartram, 1999; Griffiths
and Saker, 2003; Jochimsen et  al., 1998). Experimental demonstra-
tion of skin tumor–​promoting activity in mice that ingest extracts of
Microcystis aeruginosa (common in freshwater) was reported in 1989
(Falconer and Buckley, 1989), followed by experimental results show-
ing that microcystin-​LR specifically promotes liver tumors in rodents
(Fujiki and Suganuma, 2011; Lian et al., 2006; Nishiwaki-​Matsushima
et al., 1992).
Field results from the endemic HCC region of China have demon-
strated the presence of microcystin in surface water. A series of 989
water samples, tested with an enzyme-​linked immunosorbent assay
(ELISA) (detection limit of 50 pg/​ml) revealed that 17% of pond/​ditch
water samples (average = 101 pg/​ml), 32% of river water samples (160
pg/​ml), and 4% of shallow well water samples (68 pg/​ml) were posi-
tive for microcystin. No microcystin was detected in deep well water
(Ueno et al., 1996). Environmental surveys and epidemiologic studies
of HCC incidence or mortality from this era further implicated micro-
cystin as a risk factor for HCC (Chen and Kensler, 2014; Harada et al.,
1996; Ling, 2000; Yu et al., 2001; Yu and Chen, 1994). Adding to this
evidence is statistical modeling of HCC case-​control data that showed
a multiplicative interaction between consumption of water from ponds
or ditches and infection with hepatitis B virus and aflatoxin ingestion
(Zhao et al., 1994), consistent with the promotional effects of MC-​LR
seen experimentally. Most of the risk from consumption of microcys-
tin results from its joint effect with hepatitis B infection. Compared
to groundwater users negative for hepatitis B antibody (HBab) (OR
[ref] = 1.00), the OR estimate among subjects who were negative for
HBAb but consumed pond/​ditch water was 1.74; among subjects posi-
tive for HBAb who consumed groundwater, the OR was 6.57, and
among subjects who were both HBab positive and consumed ditch
water, the OR was 11.42.
The finding that high-​risk populations consumed water contami-
nated with microcystin, and that this interacted with hepatitis virus
infection to cause HCC, suggests that microcystin is an important risk
factor for HCC. Individual-​level data on dose–​response relationships
are lacking, however. Collecting such information would be difficult,
given the poor predictability and temporal variability of microcystin
blooms and the long induction period for liver cancer. Further research
on whether microcystin interacts with other HCC risk factors would
be valuable.
Studies in China have also found an association between likely
exposure to microcystin in drinking water and elevated risk of colorec-
tal cancer (Chen et  al., 2003; Zhou et  al., 2002). In 2006, an IARC
Working Group classified microcystin-​LR as “possibly carcinogenic
to humans,” microcystis extracts as “not classifiable as to their car-
cinogenicity to humans,” and nodularin also as “not classifiable”
(IARC, 2010).
A limited number of studies have evaluated the association between
cyanobacteria and liver cancer in other populations. In central Serbia,
more than 80% of drinking water reservoirs have experienced cya-
nobacterial blooms over the past 80 years, many with measureable
levels of microcystin-​LR (Svircev et al., 2013). The mean incidence
of HCC was elevated in three Serbian districts where cyanobacterial
blooms occurred annually for the past 25 years. The incidence rate
of HCC in these districts averaged 27/​100,000 in the period 1999–​
2008, nearly four times the rate (7.2/​100,000) in another region of the
country that uses groundwater. The geographic distribution of other
risk factors (hepatitis B virus, hepatitis C virus, and liver cirrhosis,
as measured by mortality), did not explain the localized increases in
risk. An ecologic study in Florida, which evaluated HCC incidence
among people consuming publically-​supplied surface waters with a
history of contamination by microcystins, relative to those who used
uncontaminated groundwater sources, was equivocal (Fleming et al.,
2002). Microcystin-​LR and nodularin are potent inhibitors of protein
phosphatases 1 and 2A; they belong to the okadaic acid class of tumor
promotors (Fujiki and Suganuma, 1994, 2011). Microcystin-​LR upreg-
ulates production of tumor necrosis factor α gene (TNF-​α), which has
tumor-​promoting activity, as well as affecting early-​response genes
such as c-​jun, jun B, jun D, c-​fos, fos B, and fra-​1 (Sueoka et al., 1997).
The World Health Organization in 1998 first recommended a pro-
visional limit for microcystin-​LR in drinking water of 1 µg/​l (WHO,
2011). Many countries have accepted this level and have issued recom-
mendations for its implementation (Burch, 2008). A Health Advisory
issued by the US EPA calls for a limit of 0.3 µg/​l total microcystin
for infants and preschool children and 1.6 µg/​l for older children and
adults (US EPA, 2015). Few countries have issued legally binding lim-
its (Burch, 2008).
Cyanobacteria proliferate rapidly in fresh and marine waters under
suitable environmental conditions. So-​ called “water blooms” are
exacerbated by phosphorus and nitrogen runoff from agricultural and
municipal sources, and by warming of lakes and other drinking water
sources driven by the changing global climate (Elliott, 2012; Heisler
et al., 2008; Newcombe et al., 2012; O’Reilly et al., 2015; Paerl and
Paul, 2012). The public health implications of these combined factors
deserves further study.
COMMUNITIES EXPOSED TO INDUSTRIAL CHEMICALS
IN DRINKING WATER
Here, we describe three settings in which elevated cancer risks have
been observed in communities exposed to water contaminated by
industrial chemicals. Such studies are intrinsically opportunistic. In
one instance (Toms River, NJ), elevated rates of childhood cancers
were observed. The exposure involved poorly defined mixtures and
did not allow the attribution of risk to specific chemical(s). In the other
two scenarios, the predominant chemical exposures were known and
observations of elevated risk of specific types of cancer were consis-
tent with occupational exposures and/​or experimental findings.
Camp Lejeune
At Camp Lejeune, a US Marine Corps Base Camp in coastal North
Carolina, two of eight drinking water systems that served most of
the base’s population (including family members of Marines) were
contaminated by solvents from the 1950s through 1985, as reported
by the US ATSDR (2016). One supply was contaminated by an off-​
base dry cleaner, primarily with perchloroethylene (PCE) (tetrachlo-
roethylene), reaching a maximum measured level of 215 ug/​l; other
contaminants included trichloroethylene (TCE), trans-​1,2-​dichloro-
ethylene, and VC, a degradation product of PCE. Another affected
water supply was contaminated by sources located on the base
320
320 PART III:  THE CAUSES OF CANCER
involving industrial spills, waste disposal sites, and leaking under-
ground storage tanks. The primary contaminant was TCE (maximum
detected level of 1400 ug/​l); levels of PCE were lower (maximum
of 100 ug/​l), and benzene was detectable. A third water supply that
served 2100 family housing units was not contaminated. The US
ATSDR conducted a detailed assessment of exposure and estimated
historical average monthly levels of TCE, PCE, VC, and benzene
exposure in water provided to work areas and housing units on the
base (Maslia et al., 2007, 2013).
Two retrospective cohort studies evaluated the risk of total and
site-​specific cancer mortality. One cohort was comprised of Marines
and Navy personnel who began service in 1975–​1985 (N = 154,932);
another included civilian personnel employed at the base during 1973–​
1985 (N = 4,647). Follow-​up of both cohorts began in 1979 and ended
in 2008 (Bove et al., 2014a, 2014b) The primary comparison was with
uniformed personnel (N = 154,969) and civilian employees (N = 4690),
respectively, at Camp Pendleton, a Marine base of similar size and
demographic composition located in California, with no known his-
tory of comparable drinking water contamination. Among Marines and
Navy personnel, mortality due to all cancers combined was elevated
(hazard ratio [HR] = 1.10; 95% CI: 1.00, 1.20). Hazard ratio estimates
were also increased for cancer sites of “primary interest” (based on
occupational studies or experimental evidence), although these results
were not statistically significant. These included kidney cancer (HR =
1.35; CI: 0.84, 2.16), liver cancer (HR = 1.42; CI: 0.92, 2.20), esopha-
geal cancer (HR = 1.43; CI: 0.85, 2.38), cervical cancer (HR = 1.33; CI:
0.24, 7.32), Hodgkin lymphoma (HR = 1.47; CI: 0.71, 3.06), and multi-
ple myeloma (HR = 1.68; CI: 0.76, 3.72). There was an increasing trend
of risk of kidney cancer mortality with total contaminant level, and of
Hodgkin lymphoma with TCE and with benzene. Increases in risk (not
statistically significant) were also found among the civilian employees
for mortality from all cancer combined (HR = 1.12; CI: 0.92, 1.36),
kidney cancer (HR = 1.92; CI: 0.58, 6.34) and multiple myeloma (HR
= 1.84; CI: 0.45, 7.58). A study of incident cancer is underway (2017).
A separate case-​control study measured mortality from 13 hematopoi-
etic cancers among children born in the interval 1968–​1985 to moth-
ers with household exposure to drinking water at Camp Lejeune. Odds
ratio estimates of 1.6 (CI: 0.5, 4.8) and 1.6 (CI: 0.5, 4.7) were observed
for first trimester exposure to any PCE or any VC, respectively (Ruckart
et al., 2013). Another small case-​control study, of 71 male breast cancer
cases identified from the Department of Veterans Affairs cancer regis-
try, found an adjusted OR of 1.14 (CI: 0.65, 1.97) for ever having been
stationed at Camp Lejeune (Ruckart et al., 2015).
As mentioned, the 95% CI associated with most cancer sites in
the Camp Lejeune studies did not exclude the null hypothesis. When
viewed in isolation, these investigations do not provide evidence of
causal associations for the contaminants involved. However, the
observed risks are consistent with positive epidemiologic evidence
from more highly exposed occupational populations, where the expo-
sure levels are better documented, and there are mechanistic and/​or
experimental data that support a causal relationship. Based on the
overall evidence, primarily from occupational settings, an IARC work-
ing group classified TCE, the contaminant found at highest levels at
Camp Lejeune, as “carcinogenic to humans” (IARC, 2014). The US
EPA has come to a similar conclusion (Chiu et  al., 2013), as has a
draft report from the US National Toxicology Program (National
Toxicology Program, 2015). Vinyl chloride and benzene have been
classified as human carcinogens (IARC, 2012b), and PCE was evalu-
ated by an IARC working group that designated it a “probable” human
carcinogen (IARC, 2014).
Community Exposed to Perfluorooctanoic Acid
(PFOA) and Related Compounds
Perfluorooctanoic acid (PFOA or C8) has been used historically in
the production of Teflon, Gore-​Tex, non-​
stick cookware surfaces,
and other products. Manufacturing using PFOA began at the DuPont
Washington Works on the Ohio-​West Virginia border in 1951. Nearby
populations were exposed, primarily through contaminated drinking
water from private wells and public water supply wells in six nearby
districts. Environmental fate and transport modeling revealed that
extensive contamination of groundwater occurred via deposition of
airborne PFOA from plant stacks and subsequent transport to the aqui-
fer (Shin et al., 2011b). There were also direct releases into the Ohio
River. A  class-​action suit brought by local residents alleging health
damages was resolved by a pretrial settlement agreement calling for
DuPont to fund epidemiologic studies in the surrounding communities
and among plant workers (Frisbee et al., 2009). This was implemented
by the “C8 Science Panel,” composed of three senior chronic disease
epidemiologists who designed and oversaw the studies, reviewed data,
and reported to the court whether selected adverse health outcomes
were “more probably than not” caused by exposure to PFOA. This
criterion is a legal rather than a scientific concept. Any positive results
reported would require DuPont to support continuing medical moni-
toring for the relevant condition(s).
Blood serum measurements of PFOA concentrations by the C8
Health Project in 2005–​2006 revealed an overall median concen-
tration of 28.2 ng/​ml in this population, compared with 4 ng/​ml in
the United States overall, as measured in the National Health and
Nutrition Examination Survey (Steenland et al., 2009). A number
of studies were conducted to evaluate the risk of 55 health out-
comes potentially associated with PFOA. These studies included
individual exposure assessment in a community (N  =  43,449)
(Shin et  al., 2011a, 2013), a survey (including personal medical
information and background) of PFOA concentrations in blood
(serum) and drinking water in the six major contaminated water
districts (Winquist et  al., 2013), a geographic analysis of cancer
incidence in the region (Vieira et  al., 2013), a cohort mortality
study of exposed workers (Steenland and Woskie, 2012), and a
study of incident cancers among adults (Barry et  al., 2013). The
cancer incidence study included 32,254 adult community resi-
dents or plant workers, most of whom had participated in a 2005–​
2006 baseline survey with serum PFOA measurements. Yearly
serum concentrations were estimated for each person from 1952
to 2011 (Shin et  al., 2011a). Subsequent interviews were held in
2008–​2011 to assess health problems (later confirmed by medical
records and/​or cancer registry information). Estimated cumulative
serum PFOA concentrations were positively associated with kid-
ney and testicular cancer. The HR estimates for kidney cancer with
increasing exposure quartiles were 1.0, 1.23, 1.48, and 1.58 (linear
trend test p  =  0.18); those for testicular cancer were 1.0, 1.04,
1.91, and 3.17 (trend p = 0.04).
Based on findings from this study and the literature, the C8 Science
Panel concluded that “there is a probable link between PFOA and both
testicular and kidney cancer” (C8 Science Panel, 2012). The Panel also
concluded, “there is no probable link between PFOA and either thy-
roid cancer or melanoma, for which limited but insufficient evidence
was found.” A working group of the IARC classified PFOA as “pos-
sibly carcinogenic to humans,” based primarily on these epidemiologic
findings (IARC, 2016). The epidemiologic evaluation of the public
health impact of widespread exposure to PFOA played a central role
in responding to the health concerns of the community and in estab-
lishing possible human carcinogenicity, consistent with laboratory
observations that it causes cancer of the testicles, liver, and pancreas in
rodents (Kennedy, 2015).
Toms River, New Jersey
Responding to residents of Toms River, New Jersey, who reported an
unusual number of childhood cancers, the New Jersey Department
of Health and Senior Services (NJDHSS), in collaboration with the
U.S. Agency for Toxic Substances and Disease Registry (ATSDR)
and community organizations, undertook several studies (Maslia
et  al., 2005; NJ Department of Health, 2016). A 1997 analysis of
cancer incidence in Dover Township, the location of Toms River,
found a significant elevation in the incidence of all childhood can-
cers combined (90 observed, 67 expected) for the years 1979–​1995,
based on the New Jersey State cancer registry (Berry, 1997). None
 321
Water Contaminants 321
of the other 32 townships in Ocean County had a significantly
elevated rate. The risk of pediatric cancers was especially elevated
in the Toms River census tracts. Overall, 24 cases were observed,
with 14.1 expected. In females under age 5 years, 10 cases were
observed, with 1.6 expected. The NJDHSS subsequently conducted
two case-​control studies of leukemia and neurological cancers, one
based on an extensive interview of parents and another based on
birth certificates. These used 4 and 10 controls, respectively, per
case, matched on age and gender.
An important element of these studies involved detailed model-
ing by ATSDR of the water distribution system in order to generate
month-​by-​month estimates of potential individual residential expo-
sures during the time period 1962–​1996 for each of several public well
water sources. Two sources were contaminated by chemicals from
separate Superfund sites (Maslia et al., 2001). A former Ciba Chemical
Corporation (later, Ciba-​Geigy) plant opened in 1952 and produced
organic dyes and intermediate products, epoxy resins, and specialty
chemicals. Until 1966, the plant discharged treated wastewater directly
into the Toms River. After 1966, the wastewater was pumped via a 10-​
mile pipeline into the Atlantic Ocean. The pipeline experienced four
major breaks over time, causing local chemical contamination. Tens
of thousands of drums with solid and liquid chemical wastes were dis-
posed on site, resulting in extensive soil and groundwater contami-
nation. A down-​gradient well field of the local water supply (Holly
Street) was contaminated with dyes, nitrobenzene, and other com-
pounds during the mid-​1960s. The other Superfund site is the Reich
Farm, where, for 4 months in 1971, over 4500 drums of toxic waste
from a Union Carbide plant were dumped illegally. These leaked into
the sandy subsoil, forming a plume that contaminated another public
supply well field (Parkway) (Fagin, 2013). A modeling study of public
drinking water reconstructed the monthly well-​field origins of water
provided to each residence during the relevant time period (Maslia
et al., 2000, 2001). However, the residential exposures were estimated
after extensive remediation, when most chemical contaminants were
no longer detectable, obviating the possibility of linking specific
chemicals or mixtures with modeled exposures from individual well
fields. This shortcoming in exposure assessment, and the relatively
small numbers of cases, limited the utility of the case control studies.
Air pollution from the Ciba-​Geigy plant was also modeled and used in
case-​control data analyses.
Parents of 40 children diagnosed with leukemia or nervous system
cancer while residing in Dover Township in 1979–​1996 participated
in the interview study, as did 159 matched controls. Birth mothers and
fathers were interviewed by telephone, providing information on resi-
dence location, volume of water consumed, parents’ occupations, and
several other factors. The focus of most statistical analyses was the
relative level of consumption of water originating in the contaminated
Holly Street or Parkway well fields. No consistent associations were
observed with postnatal exposures (Fagliano et  al., 2003). Prenatal
exposure to water from the Parkway well field in the period 1982–​
1996 was associated with leukemia among female children of all ages
(OR = 3.4; CI:1.1, 10.4). Findings among male children were essen-
tially null. The study, albeit small, was well designed and was sup-
ported by an exposure assessment that was extensive and detailed, but
that lacked important information on specific chemical contaminants.
Cancer risk was not measured in adults in Toms River who consumed
contaminated water. The complex story of the origin and findings of
these studies conducted by NJDHSS and ATSDR and the historical,
social, legal, and political context of water contamination in Toms
River are described by Fagin (2013).
OTHER WATERBORNE EXPOSURES
Classes of waterborne carcinogens not described here are addressed
elsewhere in the current or previous edition of this text (Cantor et al.,
2006). Schistosomiasis is an established infectious cause of bladder
cancer (Chapters 24 and 52); radionuclides such as radon and radium
226 and 228 are naturally occurring contaminants of drinking water
(Chapter 13). For some other waterborne factors, such as asbestiform
particles, metals and metalloids other than arsenic, and water hardness,
the epidemiologic evidence at this time is limited and equivocal.
CLIMATE CHANGE
The capacity of the global atmosphere to hold water increases by about
7% per 1oC warming, leading to increasing water vapor in the air and
more intense precipitation events (Trenberth, 2011). By the year 2015,
average annual global land surface temperature had increased by
0.90oC (1.62oF) above the average for the twentieth century (National
Oceanic & Atmospheric Administration [NOAA], 2015). Climate
change is associated with major perturbations in the hydrologic cycle,
and therefore in the quantity and quality of water available for human
consumption. With respect to its possible effects on carcinogenic water
contaminants, research is currently focused in two areas: (1) increases
in cyanobacterial growth patterns, and (2) elevated levels of disinfec-
tion byproducts. The first is occurring in response to elevated tempera-
tures of freshwater bodies and the release of plant nutrients, especially
nitrate and phosphate, from agricultural regions (Elliott, 2012; Heisler
et al., 2008; Newcombe et al., 2012; O’Reilly et al., 2015; Paerl and
Paul, 2012). Increasing levels of disinfection byproducts may result
from the mobilization of precursor humic and fulvic acids from soils
during more intense rainfall events (Delpla et al., 2016). The design of
most existing water treatment plants predates concerns about climate
change. Increasing attention is now directed on enhancing these facili-
ties to cope with changes in water quantity and quality due to both high
rainfall and, conversely, water shortages (Levine et al., 2016).
EFFECTS OF EXPOSURE MISCLASSIFICATION
IN EPIDEMIOLOGIC STUDIES
The degree to which risk estimates from epidemiologic studies of
cancer reflect “true” risks depends on the accuracy of the exposure
estimates during the relevant exposure period, commonly measured in
decades prior to appearance of a tumor. Relatively small errors in esti-
mating historical exposure can have profound effects on the observed
risk. When a true risk is present and the misclassification of expo-
sure in case-​control studies is non-​differential (similar among cases
and non-​cases), the risk estimate is typically biased toward the null
(Cantor and Lubin, 2007). For example, given a “true” relative risk of
2.0 (an actual 100% risk increase), the observed relative risk would be
decreased to 1.5 (an observed 50% increase) if the correlation coef-
ficient between the actual exposure and the estimated exposure from
the study were 0.6 (Vineis, 2004). This level of exposure misclassi-
fication is common in studies of environmental factors and leads to
special concern in low-​exposure settings, where expected excess risks
are relatively small and the error in exposure estimates can lead to
erroneously missing important risks. Careful consideration of this is
warranted when evaluating the findings of epidemiologic studies of
lower levels of arsenic in drinking water (< 100 ug/​l) and for all studies
of disinfection byproducts and of nitrate in drinking water. A corol-
lary is that when an association between cancer risk and a waterborne
exposure is consistently observed among different populations and
varying circumstances (e.g., bladder cancer and DBP), quantitative
estimates of risk almost certainly underestimate the true risk. When
planning future studies, careful assessment of statistical power issues,
in the face of unavoidable errors in historical exposure assessment,
must be conducted.
FUTURE DIRECTIONS
Inorganic Arsenic
Inorganic arsenic is an established human carcinogen, with most evi-
dence regarding ingested exposure from populations with prolonged
consumption of drinking water at concentrations well over 100 µg/​l. In
the observed range, the dose–​response curve appears to be linear. An
32
322 PART III:  THE CAUSES OF CANCER
unanswered question concerns the level of risk and shape of the dose–​
response curve when exposures are below 100 µg/​l. Addressing this
issue is fraught with many methodologic challenges. The most feasible
approach would be to evaluate risk in populations with exposure in the
50–​100 µg/​l range, if such groups could be identified. Other research
questions concern the mechanism(s) of action and the role of genetic
polymorphisms in arsenic metabolism and cancer risk. Better under-
standing of the mechanism(s) will likely shed light on the effects of
low exposure levels. Elevated MMA in the urine of exposed individu-
als places them at elevated cancer risk and risk of other adverse health
outcomes. The reasons for this observation are not well understood.
Disinfection Byproducts
Considerable evidence implicates exposure to disinfection byproducts
in the risk of bladder cancer, although the specific agents associated
with this risk have yet to be determined. Currently, the data for other
cancer sites are limited and sometimes inconsistent. Well-​designed
studies of colon and rectal cancers, renal cell carcinoma, and brain
cancer would be informative. It may not be possible to determine
which of the compounds in the complex and varying mixtures that
constitute DBPs are most strongly linked to risk. However, it is fea-
sible to refine exposure assessment in future studies to specific types
or classes of DBPs in order to guide mitigation efforts. To that end,
epidemiologic studies should include lifetime residential histories that
can then be linked to public water supply databases in order to esti-
mate long-​term exposures. Of particular importance is the question
of whether risk differs for brominated and chlorinated compounds.
Future work should also investigate the degree of correlation that other
chemical classes have with THMs or HAAs. Direct measurement and
estimation of other classes would be valuable where possible. Another
major knowledge gap is the extent to which inhalation and dermal
routes of exposure are important. Exposure studies suggest that these
routes could result in internal doses of the volatile DBPs much higher
than ingestion. The two epidemiologic studies of bladder cancer that
evaluated these routes of exposure are inconsistent. Further evaluation
is warranted.
Nitrate
Although the number of analytic epidemiologic studies with histori-
cal exposure data has increased since the early 1990s, there remain
few studies of any single cancer site, making interpretation difficult.
The recent analytic studies have generally included historical data of
nitrate levels from public water supplies and have evaluated potential
confounders and factors affecting nitrosation. However, users of pri-
vate wells, which often have higher nitrate levels than public sources
of drinking water, are usually excluded due to a lack of long-​term mea-
surements of nitrate. Recent efforts to model nitrate levels in private
wells for epidemiologic studies using geographic information systems
(Aschebrook-​Kilfoy et al., 2012; Wheeler et al., 2015) will be impor-
tant for understanding the relationship with nitrate ingestion over a
broader range of intake. With the increase in use of nitrogen-​based fer-
tilizers, nitrate levels in water supplies have been increasing in many
areas worldwide; therefore, additional studies, preferably of popula-
tions with well-​characterized and higher exposures, are warranted.
Cyanotoxins
Microcystin is a likely cofactor for elevated rates of HCC in south-
eastern coastal China. The expanding worldwide contamination of
freshwater used for drinking with nitrate and phosphorous, combined
with increased water temperatures, is leading to more blooms of cya-
nobacteria and consequent contamination with microcystin and other
cyanotoxins. Further studies in China and other regions of the world
are warranted and should include other possibly carcinogenic cyano-
toxins such as nodularin and cylindrospermopsin.
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19 Diet and Nutrition
MARJORIE L. MCCULLOUGH AND WALTER C. WILLETT
OVERVIEW
The formal study of diet, nutrition, and cancer is still relatively young,
with most epidemiological studies and randomized controlled trials
(RCTs) having occurred in the past 20–​30 years. Despite the method-
ological challenges of studying diet and cancer in free-​living popula-
tions, there is scientific consensus that overweight and obesity increase
the risk of certain cancers, as well as growing evidence that dietary
patterns rich in vegetables, fruits, and whole grains and low in red
and processed meat are associated with lower risk of colorectal cancer
and total cancer mortality. Although it is more difficult to isolate the
specific components of diet that affect risk, several key factors appear
to play a role. Dietary composition appears to operate by affecting
energy intake and also independent of energy intake. Despite extensive
research, evidence does not support an important impact of the mac-
ronutrient composition of diet on cancer risk. Individual nutrients and
phytochemicals, including folate, vitamin D, calcium, and carotenoids
(such as lycopene), appear to be associated with lower risk of certain
cancers and are under active investigation. However, thus far, RCTs do
not support chemoprevention with high-​dose antioxidant supplements,
and in some cases these may cause harm. The assessment of lifelong
diet and timing of exposures continues to be challenging. Future direc-
tions in diet and cancer research include the examination of early life
exposures in relation to carcinogenicity, the role of the microbiome
in cancer etiology, and risk factors for cancer subtypes defined by the
molecular characteristics of tumors.
INTRODUCTION
The relationship between nutritional factors and human cancer has
been debated for decades, but it is only in the past 20–​30 years that
large epidemiologic studies and RCTs have begun to examine the
issue systematically. Dietary factors are believed to contribute to the
large geographic and temporal variations in cancer rates observed
among human populations and to changes in rates among migrants
who move to countries with higher or lower rates than the country of
origin. A series of ecological reports in the 1970s showed high corre-
lations between specific dietary factors and cancer rates (e.g., fat and
breast cancer, meat and colon cancer) across countries, and stimulated
hypotheses on diet and cancer (Armstrong and Doll, 1975). Initially,
case-​control studies supported a role of these and other dietary factors
in cancer etiology (WCRF/​AICR, 1997). Over time, studies of diet
and cancer became progressively larger, and prospective investiga-
tions, described herein, refuted some but not all of these associations
(WCRF/​AICR, 2007). Meta-​analyses and pooling of individual-​level
data have also improved the precision and reproducibility of risk esti-
mates. Current and future prospective studies using repeated measures
of diet, biological markers, and tumor molecular phenotype will con-
tinue to advance our understanding of the link between diet and cancer
etiology.
This chapter focuses on research regarding dietary composition in
relation to the most common forms of cancer, the most thoroughly
studied exposures, and issues of current interest. Because of the
broad nature of the topic, we will only briefly mention related topics
such as energy balance, obesity and body composition (Chapter 20),
physical inactivity and sedentary behavior (Chapter 21), and alcohol
consumption (Chapter 12). Associations with diet are also covered in
cancer-​specific chapters, where applicable. The goal of this chapter is
to provide a “wide-​angle” perspective on these interrelated factors that
affect cancer.
Other Authoritative Reviews
The World Cancer Research Fund (WCRF) and its American affiliate,
the American Institute for Cancer Research (AICR), have a valuable
series of comprehensive systematic literature reviews of diet, physical
activity, obesity, and alcohol and cancer. These have broader cover-
age of nutritional issues than the reviews by the International Agency
for Research on Cancer (IARC) and are updated more frequently. The
most recent complete WCRF/​AICR report, published in 2007 (WCRF/​
AICR, 2007), synthesized the evidence for 20 cancers and based its
conclusions largely on meta-​analyses. The WCRF/​AICR “Continuous
Update Project (CUP)” follows a staggered schedule for updating the
evidence for each cancer site and more recently for cancer survivors.
An expert panel reviews and judges the evidence according to crite-
ria for inferring causality, classifying relationships as “convincing,”
“probable,” “limited-​suggestive,” “limited-​no conclusion,” and “sub-
stantial effect on risk unlikely.” Throughout this chapter, we will refer
to the WCRF/​AICR reports, in addition to studies of nutritional bio-
markers and dietary patterns (not covered in the reports), and to other
high quality meta-​analyses and individual studies as appropriate.
Estimates of Attributable Fraction
Estimates of the proportion of cancers that can be attributed to
dietary factors varies depending on the definition of “diet,” popula-
tion analyzed (e.g., national, global, individual studies), methodol-
ogy employed, and period of study. Diet is a complex entity that can
be defined narrowly to include only the composition and volume of
food consumed, or more broadly to encompass related factors such as
energy balance, body weight, distribution of body fat, and metabolic
byproducts of digestion. In 1981, Doll and Peto estimated that 35%
of cancer deaths in the United States in the late 1970s could be attrib-
uted to diet, with a range of acceptable estimates of 10%–​70% (Doll
and Peto, 1981). This figure was calculated by summing the estimated
fraction of deaths from specific cancer sites that might be avoided by
practical dietary means (for example, stomach 90%, female breast
50%, bladder 20%, other types 10%) (Doll and Peto, 1981). The Doll
and Peto analysis did not provide separate estimates of the attributable
fractions for body weight and physical inactivity, although the text
stated that “[o]‌vernutrition should perhaps come first rather than last
on a list of aspects of diet which may affect the incidence of cancer,
even though the relevant mechanisms remain obscure.”
In 2015, the WCRF/​AICR proposed new estimates, based on sys-
tematic reviews of the updated literature, and regional data on the
prevalence of known risk factors for various types of cancer. The latest
WCRF/​AICR update estimated that 20 to 22% of all incident cancers
in the United States and United Kingdom were due to the combination
of diet, physical inactivity, and overweight/​obesity; this figure rose to
29% when the analysis was restricted to the 13 most common cancers
(WCRF International, 2015). The estimated fractions of all cancers
preventable by diet in China and Brazil were about 15%, where obesity
329
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330 PART III:  The Causes of Cancer
rates are lower (estimates rose to 19 and 22% for the 13 most common
cancers, respectively). The estimates for the United States were lower
than those of Doll and Peto (1981), probably because WCRF/​AICR
considered only specific dietary factors for which the evidence for cau-
sality was judged to be “convincing” or “probable.”
Other estimates have attempted to separate the effects of dietary
composition from related factors such as overweight/​obesity, physi-
cal inactivity, and alcohol consumption. Colditz and Wei attributed
5.0% of incident cancers in the United States specifically to dietary
composition, largely because of high consumption of red and pro-
cessed meat and low consumption of folate (Colditz and Wei, 2012).
Parkin proposed similar attributable fraction estimates for the United
Kingdom, although consideration was also given to low consumption
of fruit, vegetables, and fiber and high intake of salt as well as meat
(Parkin, 2011). In 2003, the IARC estimated attributable fractions for
low fruit and vegetable intake alone at 5%–​12% (IARC, 2003). Given
that many dietary hypotheses remain unresolved and that the long-​
term impact of early life exposures is largely unexplored, estimates
of the percentage of cancers attributable to dietary composition alone
may continue to change beyond the current estimates of 5%–​12%.
Measures of Dietary Intake
Measurement of diet in free-​living populations is a comprehensive
field of study with specific methodological considerations, and read-
ers are referred elsewhere for a detailed description (Willett WC,
2013). Most epidemiologic studies of cancer risk in humans use
Food Frequency Questionnaires (FFQs) to estimate diet, because
these are designed to assess usual intake efficiently for time periods
of up to 1  year, thereby avoiding the day-​to-​day fluctuations that
affect 24-​hour recalls. FFQs consist of a food list and questions on
frequency of consumption, and some include portion sizes (Willett
WC, 2013). FFQs can be simple or complex, short or long, and are
population specific, reflecting commonly consumed foods and con-
stituents of interest in a study population. Their use has been shown
to be sufficiently valid for assessing intake of foods and nutrients,
and identifying important diet–​disease relationships in large popula-
tion studies (Block et al., 1990; Hu et al., 1999; Rimm et al., 1992;
Willett et al., 1985). FFQs compare well with biochemical indicators
of intake and more detailed questionnaire assessments (Willett WC,
2013). Weighed food records or 24-​hour dietary recalls reflect only
very recent intake. However, if collected repeatedly over a year, they
could approximate usual intake, and have the advantage of measur-
ing exactly what participants eat and drink (assuming an adequately
detailed nutrient database). Whereas serial 24-​hour recalls were pro-
hibitively expensive in the past due to interviewer and training costs,
these methods may prove feasible with technological advancements
(Kirkpatrick et  al., 2014), including applications to smartphones
and tablets. Whether large populations will provide data on a suffi-
cient number of days to provide meaningful assessment of usual diet
remains to be demonstrated. Combining these methods with an FFQ
may lead to improved precision in dietary exposure assessment.
Biomarkers
Biochemical indicators of diet can be useful in some situations, but for
many dietary factors of interest, such as total fat, fiber, and sucrose,
no useful indicators exist. Recently, studies of the food metabolome
have identified potential biomarkers of foods such as red meat (3-​
methylhistidine) (Cross et al., 2011) and whole grains (alkylresorcinols)
(Kyro et al., 2014a, 2014b; Scalbert et al., 2014). To be useful in epide-
miological studies, the within-​person variation of biomarkers will need to
be relatively low (Van Dam and Hunter, 2013). Other biomarkers of inter-
est include DNA specimens that permit the testing of nutritional hypothe-
ses using Mendelian randomization. This approach examines variation in
genes of known function to study the causal effect of a related exposure
on cancer risk in non-​experimental studies (Gray and Wheatley, 1991).
Studies of gene–​diet interactions also hold promise, but these require
very large numbers, and few clear examples exist at present.
Inherent Challenges in Measuring Dietary Intake
Diet is a complex exposure composed of hundreds of nutrients and
non-​nutrient components, some known, some yet to be fully char-
acterized. Dietary behaviors tend to cluster, complicating efforts to
isolate the effects of individual foods. Nutrients and foods are con-
sumed in combinations that may enhance or block their absorption,
metabolism, or physiologic effects. For example, tomatoes consumed
as part of a highly processed diet with large amounts of refined car-
bohydrate may have a different effect on cancer risk than tomatoes
consumed as part of a Mediterranean diet alongside fish, vegetables,
nuts, and olive oil. Food processing (e.g., milling, fermentation), stor-
age (e.g., salting, drying, freezing, bottling) and preparation methods
(e.g., steaming, grilling) can affect nutrient concentration in a food,
and can add carcinogens or unknown substances. The timing of a
nutritional exposure may modify its effects on cancer risk, although
this is seldom recognized in advance. Vitamin supplements are used
by over half the US population (Dickinson et  al., 2014), and some
vitamin formulations provide concentrated, high doses that may have
different physiologic effects than when derived from food. In addi-
tion, individuals eat varied diets formed by individual preference,
cultural models, intolerance, and influenced by lifestyle and avail-
ability. The complexity of diet and the challenge in quantifying intake
in free-​living populations are aptly illustrated in a photojournalistic
series on the typical diet in the week of a family in various parts of
the world (Menzel, 2005).
Dietary Patterns
One method of capturing multiple correlated aspects of diet is to char-
acterize intake in terms of dietary patterns instead of single foods or
nutrients. This is illustrated by contrasts between the “Mediterranean
diet” and the “Western diet,” as discussed in Chapter  20, and is
expanded on later in this chapter.
Study Designs
The study designs most commonly used to examine the relationship of
diet and cancer risk in humans are summarized in Figure 19–​1 (Harris
et  al., 2009). Each design contributes valuable information, but all
have strengths and weaknesses. Ecological studies and migrant studies
play an important role in generating hypotheses about diet and can-
cer, including interest in the 1970s in the fat–​breast cancer and meat–
colon cancer hypotheses (Armstrong and Doll, 1975). Major changes
in disease rates within a population provide key evidence that expo-
sures acquired during life have an important effect on cancer risk in
populations. Through the 1990s, most information on diet and cancer
was obtained from case-​control studies. Subsequently, concern about
recall bias (the diagnosis influencing self-​reported diet) and selection
bias (overly health-​conscious controls being more likely to participate)
has limited their use in studies of diet and cancer. Indeed, many of
the findings from early case-​control studies have not been confirmed
in subsequent research. Public health guidelines for diet and nutrition
tend to place the most weight on RCTs and prospective cohort studies,
which have complementary strengths and weaknesses, and for which
the exposure precedes cancer diagnosis. Although RCTs can reduce
or eliminate confounding, they are expensive and are not always fea-
sible or ethical. For example, an RCT of processed meat in relation
to incident colorectal cancer is both infeasible and unethical, analo-
gous to prohibitions against RCTs of smoking or excess weight gain
and cancer risk. Systematic literature reviews and meta-​analyses can
also contribute importantly to understanding diet–​cancer relationships,
provided that the inclusion or exclusion of individual studies is ade-
quately explained and justified and the definitions of dietary and other
exposures are appropriately harmonized across studies. Publication
bias is a serious concern in meta-​analyses of published studies. Large
pooled analyses of individual-​level data from consortia of prospective
studies have advantages over meta-​analyses, because publication bias
is minimized, original data are harmonized, and a uniform approach
 31
Diet and Nutrition 331
Strength of Evidence
Randomized trials Prospective cohorts
of disease outcomes of disease outcomes
Randomized trials of
physiologic measures
Retrospective case-control
studies of disease outcomes
Ecologic studies Prevalence studies Animal studies
Case series/Case reports
Figure  19–​1.  Hierarchy of quality and strength of evidence of different
study designs for evaluating causation of chronic disease. Studies of physi-
ological endpoints may not fully account for all effects of an intervention;
thus evidence is strongest when derived from well-​conducted studies of
disease endpoints. Well-​controlled prospective observational studies and
well-​performed randomized clinical trials have different, and highly com-
plementary, strengths and limitations. The major strength of randomized
trials is to minimize residual confounding; limitations include potential
lower generalizability to external populations, the inability to evaluate the
effects of many risk factors of interest (e.g., smoking, biomarker levels)
due to ethical or practical limitations, inadequacy of duration and/​or dose
tested, challenges in testing multiple doses, noncompliance, unblinding,
differential loss to follow-​up, and treatment crossover. The major limita-
tion of prospective observational studies is potential residual confound-
ing, whereas major strengths generally include the converse of each of
the major limitations of randomized trials. Thus, evidence is most robust
when studies of both designs provide concordant results. Source:  Harris
WS, et al. (2009).
can be used to define exposure, cut-​points, covariates, and statistical
modeling (Smith-​Warner et al., 2006).
Recognizing these methodologic considerations, the remainder of
this chapter discusses elements of diet that have received particular
attention with regard to cancer risk.
ENERGY BALANCE
There is strong evidence that energy balance has important effects
on the incidence of some cancers, as described in detail in Chapter
20. Experimental studies in animals during the first half of the twen-
tieth century indicated that energy restriction profoundly reduced the
development of mammary tumors (Tannenbaum, 1942; Tannenbaum
and Silverstone, 1953). This finding has consistently been replicated
in a wide variety of mammary and other tumor models (Birt et al.,
1992; Nair et al., 1995; Ross and Bras, 1971; Weindruch and Walford,
1982). For example, 30% restriction in energy intake reduces mam-
mary tumors by as much as 90% (Boissonneault et  al., 1986). In
humans, energy balance is best assessed by determining body size
and composition, or changes in weight or body composition, rather
than by comparing energy intake to expenditure, since both param-
eters are measured with poor precision in free-​living humans (Willett
WC, 2013). The IARC found sufficient evidence that excess body
fat (starting at ≥25 kg/​m2) is associated with increased risk of can-
cers of the gastric cardia, colon and rectum, liver, gall bladder, pan-
creas, breast (post-​menopause), corpus uteri, ovary, kidney (renal
cell), thyroid and multiple myeloma, meningioma, and esophageal
adenocarcinoma (IARC; Lauby-​Secretan, Scoccianti, Loomis, et al.,
2016). The strongest empirical support for mechanisms explaining
these associations involves the endocrine and metabolic effects of
obesity. Hormonal effects primarily involve alterations of peptide
(e.g., IGF, insulin) and steroid (estradiol, testosterone) hormones and
their binding proteins (Calle and Kaaks, 2004). For certain cancers,
such as esophageal adenocarcinoma and gall bladder tumors, chronic
local inflammation from esophageal reflux or recurrent gallstones
plays an important role. Adipose tissue also generates multiple pro-​
inflammatory mediators.
The effects of dietary composition on long-​term weight change
and adiposity are of great scientific interest and public health impor-
tance. In 2007, WCRF/​AICR characterized the evidence as “probable”
that energy-​dense foods, sugary drinks, and fast foods increase risk
(WCRF/​AICR, 2007). A meta-​analysis of 53 randomized clinical trials
found that weight loss was slightly greater with low-​carbohydrate than
with low-​fat diets (Tobias et al., 2015). Many aspects of diet consistent
with a Mediterranean dietary pattern appear to contribute to long-​term
weight maintenance (Mozaffarian et al., 2011). In a 6-​year trial of diet
and weight loss with only 2 years of active intervention, those assigned
to a Mediterranean diet had greater sustained weight loss compared
with those on low-​fat or high-​fat diets (Shai et al., 2008).
MACRO-​AND MICRONUTRIENTS
The relationship of diet to cancer risk can be evaluated in terms of
either individual dietary constituents or broad dietary patterns. This
section of the chapter discusses recent epidemiologic research on
macro-​and micronutrients and their relationship (or lack of relation-
ship) to cancer etiology, biology, and prevention.
Dietary Fat
In the 1980s, dietary fat was postulated to be the most important aspect
of diet with respect to cancer risk. This hypothesis was largely fueled
by the striking international correlations between per capita fat intake
and incidence or death rates from breast, colon, and prostate cancer
(Armstrong and Doll, 1975; Prentice et al., 1988). For breast cancer,
the positive associations seen in some case-​control studies (Howe
et al., 1990; WCRF/​AICR, 1997) have not generally been replicated
in prospective studies (Key et  al., 2011; Smith-​Warner et  al., 2001;
WCRF/​AICR, 2010), although a recent large European study found
a weak positive association of saturated fatty acids with ER+PR+
and HER2-​tumor subtypes (Sieri et  al., 2014). The lack of agree-
ment between the case-​control and cohort studies reinforces concerns
about recall and selection biases in case-​control studies of diet. The
Women’s Health Initiative (WHI) study, designed and implemented
at the end of the previous century (The Women’s Health Initiative
Study Group, 1998), included a randomized clinical trial to test the
effect of a low-​fat diet intervention (by instruction) on breast cancer
incidence. The initial goal was to reduce fat intake among women in
the intervention arm to 20% of calories, and compare this to women
consuming approximately 37% of calories from fat. The actual con-
trast was smaller, however, because women in the intervention arm
reported consuming 27% of calories from fat and the control arm
averaged 33%. No differences were observed in plasma lipid fractions
known to be influenced by dietary fat between the intervention and
control groups, indicating that little or no difference in fat intake was
achieved between the two groups (Willett, 2010). At trial completion,
there was a non-​significantly lower risk of breast cancer in the inter-
vention arm (Prentice RL et al., 2006). In an extended follow-​up after
active intervention, there was no difference in rates of breast or other
cancers between the two randomized groups (Thomson et al., 2014b).
This inability to test the original hypothesis illustrates at least two
serious limitations in using randomized trials to study dietary factors
and cancer etiology. The first is the difficulty of achieving and sustain-
ing the desired contrast in the exposure of interest. The second is that
even a small change in the exposure (in this case dietary fat intake)
32
332 PART III:  The Causes of Cancer
can secondarily change other factors (in this case, weight loss of 1–​2
kg among women on the lower fat diet) (Prentice et al., 2006). Had
there been a statistically significant reduction in the incidence rate of
breast or other cancers, the intervention could not have distinguished
weight loss from reductions in fat intake. In a second large random-
ized trial of dietary fat reduction, conducted among women with high
mammographic density, a non-​significant increase in risk of breast
cancer was seen among those randomized to a low-​fat diet (Martin
et al., 2011).
The debate over dietary fat intake and breast cancer incidence con-
tinues with respect to the timing of exposure, type of fat, and disease
subtypes. Limited data suggest that animal fat intake during young
adulthood may influence risk of premenopausal breast cancer (Farvid
et  al., 2014b). High intake of polyunsaturated fatty acids increases
mammary cancer incidence in rodents, but has not been associated with
increased risk of breast cancer in humans (Smith-​Warner et al., 2001).
The findings regarding total dietary fat intake and prostate cancer
have been inconsistent. Although earlier studies suggested a positive
relationship with animal fat (WCRF/​AICR, 1997), this association
has weakened over time (WCRF/​AICR, 2014b). A  large interna-
tional collaboration including over 5000 prostate cancer cases and >
6600 controls found no strong evidence that circulating specific fatty
acids were important predictors of prostate cancer risk (Crowe et al.,
2014). An unexpected modest positive association was observed
with two omega-​3 fatty acids, eicosapentaenoic and docosapentae-
noic acid. The significance of this finding is unclear, since it conflicts
with meta-​analyses of studies of fish consumption, the major source
of these fatty acids (Szymanski et  al., 2010), which is inversely
associated with prostate cancer incidence (Lovegrove et  al., 2015;
Szymanski et al., 2010). A limitation of this study is that it included
all incident cases of prostate cancer, instead of restricting the end-
point to advanced or fatal cases. Since many cases are diagnosed by
prostate specific antigen (PSA) screening, dietary factors associated
with screening tend to be positively associated with overall incidence
of prostate cancer.
Carbohydrates
Carbohydrates comprise a diverse group of macronutrients that may
differ in their effects on chronic disease risk. For example, carbohy-
drates with a high glycemic index (Wolever and Jenkins, 1986) cause
larger spikes in postprandial blood glucose and insulin concentra-
tions than those with a lower glycemic index (Miller, 1994). High
glycemic carbohydrates also cause higher fasting insulin levels in
insulin-​resistant states (Pereira et  al., 2002). Fasting plasma insu-
lin concentrations are inversely correlated with insulin-​like growth
factor-​binding protein 1 (IGFBP-​1) and thus increase bioactive IGF-​
1 concentrations (Giovannucci, 2001). The glycemic index (GI) of a
carbohydrate reflects its potential to raise blood sugar, whereas the
glycemic load (GL) considers both the GI and the amount of carbo-
hydrate consumed. Neither parameter was associated with the risk of
colorectal or pancreatic cancer in a meta-​analysis (Mulholland et al.,
2009). In contrast, the risk of endometrial cancer is consistently asso-
ciated with increased GL. An increase of 50 units of GL is associated
with a 15% higher risk (WCRF/​AICR, 2013). Endometrial cancer is
also the cancer site most strongly associated with obesity and insulin
resistance. It has not yet been determined whether subsets of people
are at higher cancer risk from dietary GL.
Grain consumption in the United States has increased by 41%
over the past several decades (Wells and Buzby, 2008), concurrent
with national dietary guidelines to reduce total dietary fat intake.
Approximately 15% of total energy intake in the United States is
from added sugars, with soda and energy drinks contributing 36% of
added sugars (Welsh et  al., 2011). Consumption of sugar-​sweetened
beverages correlates with increasing energy intake (Vartanian et  al.,
2007), and contributes to weight gain and increasing prevalence of
overweight and obesity (WCRF/​AICR, 2007). Therefore, excess sugar
consumption, especially as beverages, likely increases risk of cancer
indirectly through weight gain.
Protein
Epidemiologic studies have not found a clear association between an
overall high intake of protein in adulthood and risk of cancer. Most
studies find no evidence of a harmful association with some foods that
are major sources of protein, such as fish, poultry, and plant foods.
Red and processed meat and dairy products are other major protein
sources, discussed later in the chapter.
MICRONUTRIENTS
Vitamin D
Vitamin D is best known for its role in maintaining calcium homeosta-
sis and bone health. It is found naturally in a limited number of foods
(e.g., fatty fish and eggs), and is added to milk and other products in
the United States and many other countries. It is also available from
dietary supplements at a wide range of doses. The most important
source of vitamin D, however, is cutaneous production due to UVB
radiation. The recommended dietary allowance for vitamin D for
adults is 600 IU/​day, with a tolerable upper limit of 4000 IU (Institute
of Medicine, 2011). A cup of milk contains about 100 IU of vitamin
D. In comparison, approximately 10,000–​20,000 IU is produced by a
fair-​skinned adult in a bathing suit who develops a light pink sunburn
from UVB exposure (Holick, 2004). Higher levels of sun exposure
convert the skin precursors of vitamin D to inert metabolites, so that
vitamin D toxicity from sun exposure is highly unlikely. The potential
benefits of sun exposure for vitamin D production need to be balanced
against the harmful effects of UV radiation for skin cancer, however
(see Chapter 62.4). Seasonal variation occurs in the circulating storage
form of vitamin D [25(OH)D], with a peak during summer months and
a nadir in mid-​winter. This variation is accentuated in populations who
live further from the equator (McCullough et al., 2010).
In 1941, Frank Apperly observed lower cancer mortality rates in
North American regions that have higher levels of solar radiation
(Apperly, 1941), an observation later hypothesized to reflect variations
in vitamin D exposure (Garland and Garland, 1980). In vitro and in
vivo animal studies provide strong biological support for a role for
vitamin D in cancer prevention. The active form of the vitamin, 1,25
dihydroxyvitamin D (1,25(OH)2D), also called calcitriol, is the natural
ligand for the vitamin D receptor. This receptor is a nuclear transcrip-
tion factor that modulates expression of over 200 genes, including
some that regulate cell growth, limit inflammation, and reduce levels
of VEGF (Feldman et al., 2014).
The main storage form of vitamin D [25(OH)D] has a half-​life of
3–​4 weeks. Serum concentrations of 25(OH)D reflect input from diet,
supplements, and skin synthesis and are considered the preferred bio-
marker of exposure. Prospective cohort studies with pre-​diagnostic
measures of 25(OH)D provide the strongest support for an inverse
relationship between vitamin D and cancer risk in humans. The most
consistent evidence is for colorectal cancer, where the incidence rate is
approximately one-​third lower in those with high versus low circulat-
ing levels of 25(OH)D (Lee et al., 2011a; Ma et al., 2011). The evi-
dence for other cancers is mixed (Helzlsouer, 2010; Kim and Je, 2014;
Stolzenberg-​Solomon et al., 2009; Wolpin et al., 2012). For prostate
cancer the evidence is highly inconsistent (Ahn et al., 2008; Xu et al.,
2014), although some studies suggest a “U-​shaped” association, with
higher risks at either end of the 25(OH)D distribution (Kristal et al.,
2014). Vitamin D metabolism in the prostate may vary by stage and
grade of the tumor (Tannour-​Louet et  al., 2014), complicating the
interpretation of the role of vitamin D in prostate cancer. Case-​control
studies of breast cancer suggest lower risk with higher 25(OH)D con-
centrations measured after diagnosis (Yin et al., 2010), but the findings
are generally weak or null in prospective studies (Kim and Je, 2014),
suggesting possible disease-​related effects on vitamin D status.
Determining optimal 25(OH)D levels for disease prevention is chal-
lenging because circulating concentrations vary considerably across
populations, and assays differ in their quantification of 25(OH)D
(Binkley et al., 2014). A large, ongoing, international consortium of 21
 3
Diet and Nutrition 333
prospective cohorts (Circulating Biomarkers of Breast and Colorectal
Cancer Consortium) is addressing this issue by calibrating serum
25(OH)D levels to a single laboratory and using the same method
for standardizing serum 25(OH)D concentrations to account for sea-
sonal variation in analyses of prediagnostic vitamin D and breast and
colorectal cancer (Ziegler, et al., 2015). Preliminary results show sta-
tistically significant inverse associations between circulating 25(OH)D
(up to 100 nmol/​L) and colorectal (unpublished), but not breast cancer
risk (Visvanathan et al., 2015).
Results of RCTs of vitamin D supplementation and cancer out-
comes have not definitively confirmed or negated a protective effect
of vitamin D and cancer, due to questions about dose and crossover.
The large Women’s Health Initiative found no reduction in the risk
of colorectal (Wactawski-​Wende et  al., 2006)  or breast (Chlebowski
et  al., 2008)  cancer among women randomized to 400 IU vitamin
D plus 1000 mg calcium compared to the placebo group. However,
400 IU is now considered a low dose of vitamin D, and most women
(including those on placebo) were taking vitamin D by the end of the
study. Secondary analyses of osteoporosis trials reported some lower-
ing of cancer risk, but the number of cases was generally too small to
be conclusive (Avenell et al., 2012; Lappe et al., 2007). No association
with recurrent polyps was observed in a recent trial of 1000 IU vitamin
D and 1200 IU calcium (Baron et al., 2015). Ongoing trials of vita-
min D supplementation and chronic disease risk in the United States
(Manson et al., 2012) and elsewhere (Manson and Bassuk, 2015) are
testing higher doses.
Calcium
Higher calcium intake has been shown to reduce the incidence of
bowel tumors in animals (Lamprecht and Lipkin, 2001), possibly by
precipitating bile acids. Calcium supplementation reduced the recur-
rence of adenomatous polyps by about 20% in one randomized trial
(Baron et al., 1999), but not in a recent trial of similar design (Baron
et al., 2015). In observational studies, a pooled analysis of cohort stud-
ies found a statistically significant 20% lower risk of colorectal cancer
in those with the highest versus lowest total calcium intake (Cho et al.,
2004). Higher calcium intake has been associated with lower breast
cancer risk in some prospective studies (Cui and Rohan, 2006), but not
others (Larsson et al., 2009). The aforementioned randomized trial of
1000 mg calcium and 400 IU vitamin D found no reduction in either
colorectal (Wactawski-​Wende et al., 2006) or postmenopausal breast
cancer incidence (Chlebowski et  al., 2008)  over 7  years of the trial.
It is possible that the generally high calcium intake in both trial arms
limited the ability to detect a modest reduction in risk.
Higher calcium intake (> 2000 mg/​day) from diet and nutritional
supplements was associated with increased risk of total, lethal,
and high-​grade prostate cancer in 24-​years of follow-​up of men in
the Health Professionals Follow-​ up Study (Wilson et  al., 2015).
Phosphorous intake was correlated with calcium and was also associ-
ated with increased risk. In addition, a meta-​analysis of 32 prospective
studies found that dietary calcium, and its major source, dairy product
intake, was significantly associated with higher total prostate cancer
risk, but supplemental calcium intake was the only form significantly
associated with increased risk of fatal prostate cancer (Aune et  al.,
2015). Measured levels of total and ionized serum calcium were asso-
ciated with higher risk of fatal prostate cancer, but only during the
early years of follow-​up, suggesting that serum calcium might be a
marker of extant prostate cancer (Schwartz and Skinner, 2012).
Thus, while evidence supports a modest benefit of higher calcium
intake in colorectal cancer prevention, the practical implications are
presently unclear because high calcium intake or dairy product con-
sumption has been associated with higher risk of prostate cancer
(Kushi et al., 2012).
Folate
Folate deficiency has long been known to cause tumors in animals,
possibly by influencing gene expression through DNA methylation
or by increasing the misincorporation of uracil in DNA (Blount and
Ames, 1994). Considerable evidence from both case-​ control and
cohort studies supports a lower risk of colon cancer with higher folate
intake (Kennedy et al., 2011), and some evidence suggests that higher
folate intake may attenuate the risk of colorectal cancer associated
with alcohol (Nan et al., 2013). An association between a functional
polymorphism in the folic acid metabolizing gene, methylene tetrahy-
drofolate reductase (MTHFR), and incidence of colorectal cancer adds
support for a causal relationship (Zhao et al., 2013). Results of studies
of circulating folate and risk of colorectal cancer have been incon-
sistent, but blood levels of folate are influenced by genetic determi-
nants of metabolism as well as intake. For example, in an analysis that
included folate intake and MTHFR genotype, higher blood levels due
to diet were associated with lower risk of colorectal cancer, but higher
levels due to genotype were associated with higher risk, potentially
due to blockage of a metabolic pathway that reduces risk (Lee et al.,
2012). This illustrates some of the complexity of using biomarkers of
dietary intake. In a randomized controlled trial among patients with
a recent history of colorectal adenomas, folic acid supplementation
increased risk of more advanced adenomas (Cole et  al., 2007), rais-
ing concerns that very high intakes of this vitamin may actually be
carcinogenic. These conflicting observations have been postulated to
reflect different stages of carcinogenesis, whereby high folate intake
might inhibit the initiation of neoplasia but promote the growth and/​
or progression of existing lesions. Reassuringly, recent studies of
folate intake continue to find an inverse association with colorectal
cancer risk, even among older individuals with very high intakes of
folate (Gibson et al., 2011; Stevens et al., 2011). In a detailed analysis
of the timing of folate intake in relation to colorectal adenoma and
cancer, greater folate intake was inversely associated with the risk of
colorectal cancer when exposure occurred before the development
of adenoma (Lee et al., 2011b). Lower risk of colorectal cancer was
observed only after a 12-​year delay. Also reassuringly, mortality due to
colorectal cancer continued to decline steadily after implementation of
folic acid fortification in 1998 in the United States (http://​seer.cancer.
gov/​statfacts/​html/​colorect.html). The role of folate in numerous other
cancers has been studied, but the results are inconsistent and provide
no clear evidence of an association.
Fiber
Interest in the relation between fiber intake and colon cancer was
stimulated by Burkitt’s observation that colon cancer was rare in areas
of Africa where fiber consumption and stool bulk were high (Burkitt,
1971). Fiber has been hypothesized to dilute potential carcinogens and
accelerate transit through the colon. The anti-​carcinogenic mechanisms
of a diet high in fiber and low in fat were explored in a recent study
of the microbiome. In a 2-​week food exchange experiment, O’Keefe
et al. (2015) gave African American men a high-​fiber, low-​fat African-​
style diet and rural Africans a high-​fat, low-​fiber Western-​style diet. In
comparison with their usual diets, the interventions resulted in recipro-
cal alterations in mucosal biomarkers of cancer risk and in aspects of
the microbiota and metabolome related to cancer risk.
In observational studies, dietary fiber was inversely associated
with risk of colorectal cancer in early case-control studies (Howe
et  al., 1992; Trock et  al., 1990), but not consistently in subse-
quent prospective studies. In a prospective US cohort of almost
a half million retired men and women, no association was found
for dietary fiber intake and colorectal cancer risk (Schatzkin et al.,
2007). Similarly, in a large pooled analysis of over 700,000 men
and women from multiple prospective cohort studies, no associa-
tion was seen except a possible small increase in risk in those with
very low fiber intake (Park et al., 2005). In contrast, a 2012 analysis
from the large European Prospective Investigation into Cancer and
Nutrition (EPIC) cohort found statistically significantly lower colo-
rectal cancer risk with higher intake of dietary fiber, including fiber
from fruit, vegetables, and cereals (Murphy et al., 2012). The most
recent WCRF/​AICR update of the epidemiologic evidence for colon
cancer ranks “foods containing dietary fibre” (see http://​www.wcrf.
org/​sites/​default/​files/​Colorectal-​Cancer-​2011-​Report.pdf) to be
34
334 PART III:  The Causes of Cancer
convincingly related to lower risk (WCRF/​AICR, 2011). However,
the inconsistency among large prospective studies remains unex-
plained, and is one of the few examples of important heterogeneity
in findings among such studies. RCTs of supplemental wheat bran
fiber (Alberts et  al., 2000) and isphaghula husk (psyllium fiber)
(Bonithon-​Kopp et al., 2000) failed to reduce the risk of recurrent
adenomatous polyps. A trial that combined instructions for both
high fiber intake and a reduction in total fat also failed to reduce
recurrent adenomatous polyps (Schatzkin et al., 2000).
Higher intake of fiber has also been hypothesized to lower breast
cancer risk by interfering with enterohepatic metabolism of estro-
gens (Gorbach and Goldin, 1987). Although most individual pro-
spective cohort studies have not found a statistically significant
association of breast cancer risk with greater dietary fiber intake,
two meta-​analyses of 10 (Dong et  al., 2011)  and 15 (Aune et  al.,
2012a) prospective cohort studies found a statistically significant
5%–​10% lower risk of breast cancer associated with each 10 g of
increase in dietary fiber intake. In the large EPIC cohort, a weak
inverse relation was seen with fiber from vegetable sources, but not
with fiber from grains or fruits; this inverse association was pri-
marily with estrogen receptor–​negative (ER–​) breast cancer (Ferrari
et  al., 2013). Earlier life exposure to fiber may also impact breast
cancer risk. In a recent study, higher fiber intake during high school
was associated with a 16% lower risk of breast cancer overall, and
a 24% lower risk of premenopausal breast cancer (Farvid et  al.,
2016). Whether fiber or other components of high-​fiber foods, such
as carotenoids, are responsible for this beneficial association is
unclear.
Carotenoids
Carotenoids, ubiquitous in fruits and vegetables, are fat-​soluble pig-
ments that absorb light energy for plant photosynthesis and protect
chlorophyll from damage. Over 700 naturally occurring carotenoids
have been identified, and six (α-​carotene, β-​carotene, β-​cryptoxanthin,
lycopene, and lutein+zeaxanthin) comprise greater than 95% of total
carotenoids in human blood (Maiani et al., 2009). These compounds
are hypothesized to reduce cancer risk by lowering oxidative stress
and inflammation. Pro-​vitamin A carotenoids (α-​carotene, β-​carotene,
and β-​cryptoxanthin) are precursors to vitamin A, which may influence
carcinogenesis by regulating cell differentiation (Maiani et al., 2009).
Preclinical and biomarker-​ based studies in the 1980s (Menkes
et al., 1986; Stahelin et al., 1984) provided evidence for a protective
relationship between carotenoid intake and risk of lung cancer after
controlling for cigarette smoking. Inconsistencies were noted, how-
ever, in that these studies did not show a relationship with preformed
vitamin A (Willett and Colditz, 2013), and a pooled analysis of seven
prospective cohort studies provided little support for a protective
role of β-​carotene intake and lung cancer (Mannisto, Smith-​Warner,
Spiegelman, et  al., 2004). Counter to the hypothesis that β-​carotene
might protect against lung cancer, two large trials in smokers and/​or
asbestos workers, the Alpa-​Tocopherol, Beta-​Carotene (ATBC) (The
Alpha-​ Tocopherol Beta-​ Carotene Cancer Prevention Study Group,
1994) and the CARET (Omenn et al., 1996) trials reported statistically
significant increases in lung cancer occurrence among those random-
ized to 20–​30 mg β-​carotene per day. This is several times the amount
typically present in the diet. However, in mostly non-​smokers, the
Physicians’ Health Study (Hennekens et al., 1996) and the Women’s
Health Study (Lee et al., 1999) observed no effect of β-​carotene sup-
plements on lung or overall cancer incidence. Many explanations have
been offered for the lack of benefit, or even harm, in the randomized
trials, including interference with the metabolism of other beneficial
carotenoids by the relatively high dose of β-​carotene in the supple-
ments, or by induction of carcinogen-​activating enzymes in the highly
oxidized lungs of smokers (Liu et al., 2003; Wang and Russell, 1999).
The lack of benefit from β-​carotene supplements does not exclude
the possibility that other nutrients or biologically active constituents
in fruits and vegetables might prove to be protective in the future.
However, epidemiologic evidence and randomized trials both indicate
no benefit of high β-​carotene intake for lung cancer, and current can-
cer prevention guidelines (Kushi et al., 2012) and the US Preventive
Services Task Force (Moyer and Force, 2014) specifically recommend
against taking β-​carotene supplements.
Neither preformed vitamin A nor carotenoid intake has been con-
sistently associated with risk of colon cancer, although these relation-
ships have been examined in several studies (WCRF/​AICR, 2011).
Similarly, β-​carotene—​as well as vitamins C and E—​did not affect
the recurrence of adenomatous colon polyps (Greenberg et al., 1994).
Recent pooled analyses of prospectively collected blood suggest that
several carotenoids may reduce breast cancer risk (Bakker et al., 2016;
Eliassen et  al., 2015). Both β-​carotene and α-​carotene serum levels
were inversely associated with ER–​breast tumors. These findings are
consistent with a pooled analysis in which vegetable consumption
was associated inversely with ER–​but not ER+ breast cancer (Jung
et al., 2013).
The question of whether lycopene, or tomato products, its major
food source, protect against prostate cancer risk has been studied
extensively in epidemiologic and clinical studies. Lycopene is the
most abundant carotenoid measured in prostate tissue (Arab et  al.,
2001). Although the totality of the evidence for prostate cancer has not
been convincing (WCRF/​AICR, 2014b), a recent large pooled analy-
sis reported statistically significantly lower risk of aggressive prostate
cancer with higher prediagnostic circulating lycopene levels (Key
et al., 2015), adding important support to the possibility of benefit.
Vitamins C and E
Extensive damage to DNA, protein, and lipids can occur from oxidant
byproducts of smoking and normal metabolism. Although DNA repair
mechanisms and antioxidant defenses exist, they are imperfect (Ames
et  al., 1995). Antioxidants may reduce the risk of cancer by neutral-
izing free radicals and reactive oxygen species that can damage DNA.
In humans, vitamin E is the major lipid-​soluble, membrane-​localized
antioxidant, and vitamin C is the major water-​soluble antioxidant.
Vitamin C can interfere with formation of nitrosamines—​carcinogens
formed endogenously from nitrogenous precursors in diet and tobacco
smoke—​in the stomach. However, chemoprevention trials of high-​risk
populations have not provided strong support for a benefit from anti-
oxidants against cancer. Chemoprevention trials of stomach cancer in
high-​risk populations have shown regression of gastric dysplasia from
several antioxidant nutrients (Correa et  al., 2000), but not a specific
benefit from vitamin C supplements (Blot et  al., 1993). A  secondary
analysis of the aforementioned ATBC trial found a 34% lower inci-
dence of prostate cancer in heavy smokers who received supplemental
α-​tocopherol (50 mg/​day), despite no effect on lung cancer (The Alpha-​
Tocopherol Beta-​Carotene Cancer Prevention Study Group, 1994). The
Selenium and Vitamin E Cancer Prevention Trial (SELECT), initiated
partly because of the ATBC trial results for vitamin E, found no ben-
efit from selenium for prostate cancer, and an unexpected borderline
adverse effect among men randomized to vitamin E alone (400 IU/​
day vitamin E of all rac α-​tocopheryl acetate) or in combination with
selenium (200 µg/​d of L-​selenomethionine). This adverse effect was
sustained and became statistically significant during post-​trial follow-​
up (Klein et al., 2011). The SELECT trial tested a higher dose of vita-
min E than ATBC. However, an RCT using a similar vitamin E dose in
mostly non-​smokers found no effect of the vitamin on prostate cancer
(Gaziano et al., 2009). Overall, epidemiologic studies and RCTs have
not supported a role of vitamin C or vitamin E in cancer prevention
(Fortmann et al., 2013; WCRF/​AICR, 2007). Despite the lack of dem-
onstrated benefit, any aspect of diet that acted by blocking the initial
steps in carcinogenesis would need to be present at that time, presum-
ably two or three decades earlier in the case of smoking and lung can-
cer. This is far longer than the duration of any of the intervention trials.
Selenium
Selenium defends against oxidative stress through selenoproteins,
including selenium-​dependent glutathione peroxidases. The amount
 35
Diet and Nutrition 335
of selenium in food may vary up to 10-​fold, depending on the sele-
nium content of soil where the plant was grown or where the ani-
mal was raised. This variability makes food composition databases
for selenium unreliable (Panel on Dietary Antioxidants and Related
Compounds, 2000). Therefore, most epidemiologic evidence on sele-
nium and cancer risk is from randomized trials and biomarkers of
selenium exposure. For example, several prospective studies have
reported inverse associations between selenium levels and prostate
cancer incidence and progression using measures of selenium in toe-
nails (Vogt et al., 2003; Yoshizawa et al., 1998), as a marker of sele-
nium intake over the past year, or in the plasma or serum (Brooks
et  al., 2001; Li et  al., 2004; Nomura et  al., 2000). Selenium was
strongly associated with reduced prostate cancer risk as a second-
ary endpoint in one small trial of selenium supplementation and skin
cancer (Clark et al., 1996). However, the SELECT trial (Klein et al.,
2001), the aforementioned large randomized placebo controlled trial
with selenium (200 µg) and vitamin E (400 IU) was ended 4  years
early, with the study showing no protective effect of selenium on total
prostate cancer incidence (Lippman et  al., 2009). This interpreta-
tion of this trial was limited because it included only one fatal case
of prostate cancer. Recent research suggests that polymorphisms in
genes that code for selenoproteins should be considered when exam-
ining the relationship between selenium biomarker concentrations
and prostate cancer risk (Xie et al., 2016).
Vitamin and Mineral Combinations
Few trials have tested combinations of multivitamins and/​or minerals
in relation to cancer incidence. In a nutritionally depleted population
in Linxian, China, a trial of over 25,000 men and women found that
a cocktail of 50 μg selenium, 30 mg vitamin E, and 15 mg β-​carotene
reduced total mortality, cancer-​specific mortality, and gastric cancer,
compared to placebo (Blot et  al., 1993). Ten-​year post-​trial follow-​
up showed sustained benefits (Qiao et al., 2009). In contrast, as noted
earlier, most vitamin and/​or mineral supplement trials in nutritionally
replete populations have not shown benefit (Fortmann et  al., 2013),
although benefits among subgroups with less than optimal diet cannot
be excluded. Recently, two RCTs conducted in populations presumed
to be nutritionally replete found reduced incidence of all cancers com-
bined in individuals randomized to relatively low-​dose, multi-​nutrient
supplements. In the Physicians’ Health Study (Gaziano et al., 2012),
randomization of adult men to a Centrum Silver multivitamin, which
contained 26 nutrients at the US RDA level (recommended level from
diet for most US adults), was associated with a significant, 8% lower
incidence of all cancers combined. A  similar study in US women is
ongoing. The French SUVIMAX study of men and women (Hercberg
et  al., 2004)  reported a statistically significant 31% lower risk of all
cancers combined in men, but not women, who were randomized to
an antioxidant mix (120 mg of ascorbic acid, 30 mg of vitamin E, 6
mg of β-​carotene, 100 μg of selenium, and 20 mg of zinc) versus pla-
cebo. Women in that trial had higher baseline plasma antioxidant status.
Based on the preponderance of data on RCTs of high-​dose, individual
supplements, several organizations recommend against taking antioxi-
dant or other supplements for cancer prevention (Kushi et  al., 2012;
WCRF/​ AICR, 2007), or prevention of chronic diseases (Fortmann
et al., 2013). However, a possible modest benefit of lower dose supple-
ments in cancer prevention deserves further study, especially in groups
with suboptimal diets.
Sodium
Foods preserved in salt or other sources of sodium are thought to con-
tribute to a higher risk of gastric cancer in Asia and South America,
where salting fish and/​or brining vegetables is common practice. High
concentrations of salt irritate the gastric epithelium, especially in the
context of Helicobacter pylori (H. pylori) infection (see Chapter 31).
In the United States and other Western countries, dietary salt or
sodium has not been associated with increased risk of stomach or other
cancers. Because salt preservation is an issue in certain populations,
however, global cancer-​
prevention guidelines recommend limiting
sodium intake (WCRF/​AICR, 2007).
Plant Polyphenols
Polyphenols are secondary metabolites widely distributed in plant
foods. There are four main classes:  flavonoids, lignans, phenolic
acids and stilbenes. Polyphenols are of considerable interest in anti-
cancer research because of their antioxidant, anti-​inflammatory, anti-​
estrogenic, and anticarcinogenic properties (Adolphe et  al., 2010).
Advances in measurement and reporting of the polyphenol content of
foods (Harnly et al., 2006; Rothwell et al., 2013) facilitate population
studies of these compounds. Herein, we focus on evidence for lignans
and flavonoids.
Lignans
Lignans, found primarily in flaxseed and other seeds, berries, tea, and
wine, comprise one of three main groups of plant compounds classi-
fied as phytoestrogens, the other two being isoflavonoids and coumes-
tans (Webb and McCullough, 2005). Studies in humans, animals, and
cell culture provide support for a chemopreventive action of lignans,
potentially through anti-​ estrogenic, anti-​ angiogenic, proapoptotic,
and antioxidant mechanisms. The two primary lignans, matairesinol
(MAT) and secoisolariciresinol (SEC), are converted by intestinal
microflora to the biologically relevant mammalian lignans, enterodiol
(EDL) and enterolactone (ENL). These latter two compounds, mea-
sured in blood and urine, reflect only very recent intake. Some studies
support an inverse association of these biomarkers with risk of post-
menopausal breast (Velentzis et al., 2009) and bladder (Zamora-​Ros
et al., 2014) cancer. While evidence is inconsistent for dietary lignan
intake and prostate cancer risk (Saarinen et al., 2010), a recent meta-​
analysis supports an inverse association with circulating enterolactone
(He et al., 2015). The short half-​life of these circulating compounds
and the large between-​individual variability in metabolism present
challenges to research in this area.
Flavonoids
Flavonoids are bioactive, polyphenolic non-​nutrient constituents in
plants. Common classes of flavonoids include anthocyanidins, flavo-
nols, flavanones, flavones, flavanols, proanthocyanidins, and isofla-
vones, the latter being the most thoroughly studied. Isoflavones, found
primarily in soy foods, have weak estrogenic activity and are therefore
of interest in relation to hormone-​dependent cancers. Because isofla-
vones were shown to increase estrogenic markers in MCF-​7 cells, an
ER+ breast cancer cell line, and to produce estrogenic effects in rodent
reproductive tissues (Messina and Wood, 2008), there has been con-
cern among medical professionals and the general public that eating
soy food could fuel breast cancer growth. However, soy is metabolized
differently in humans than it is in mice and rats, so findings in rodents
may not apply to people (Setchell et al., 2011). A meta-​analysis of soy
feeding studies in humans does not support effects of soy consumption
on circulating estrogen (Fritz et al., 2013).
Another meta-​analysis of 14 prospective studies showed that in
Asian women, those who ate the most (compared to the least) soy iso-
flavones had a 24% lower risk of incident breast cancer, while there
was no association in Western countries such as the United States
(Dong and Qin, 2011). However, consumption levels in US women
would typically correspond to levels in the reference group from stud-
ies in Asian countries. A systematic review concluded that soy intake
equivalent to 2–​3 servings daily (25–​50 mg/​d, similar to the traditional
Japanese diet) may reduce breast cancer risk (Fritz et al., 2013). It is
also important to consider differences in lifelong soy exposure in Asian
and Western countries when comparing associations between soy and
breast cancer across these populations. In Chinese women, consistently
higher soy consumption during adolescence and adulthood was asso-
ciated with 60% lower risk of pre-​menopausal breast cancer, but not
with postmenopausal breast cancer (Lee SA et al., 2009). Isoflavone
exposure in utero may likewise be important (Nagata, 2010). For
prostate cancer, dietary intake and serum biomarkers of daidzein and
36
336 PART III:  The Causes of Cancer
genistein (major isoflavone types), but not total isoflavones, were asso-
ciated with a significantly lower risk of total prostate cancer in a recent
meta-​analysis (He et al., 2015). Inter-​individual variability in the abil-
ity of gut microbiota to convert daidzein to equol may explain some of
the inconsistencies in the literature on soy and cancer (Lampe, 2009;
Vastag, 2007). Of note, few studies have comprehensively evaluated
whether soy supplements or isolated soy proteins (found in energy
bars and other processed foods) influence cancer risk.
Flavonoid classes other than isoflavones are more commonly con-
sumed in Western populations. Despite considerable interest in these
other flavonoids with respect to human cancer, the evidence remains
limited, in part because flavonoid databases have only recently permit-
ted comprehensive analyses of these compounds in relation to cancer
risk (Peterson et al., 2015). Also, flavonoid content varies by plant spe-
cies and can be affected by factors such as processing method. Food
sources of these compounds include green tea (flavanols), black tea
(theaflavins and thearubigins), vegetables (flavonols), berries (antho-
cyanidins), celery and garlic (flavones), citrus fruits (flavanones), and
cocoa (proanthocyanidins), among others. Emerging studies from
European and US cohorts support a cancer protective role of flava-
nols in relation to hepatocellular cancer risk (Zamora-​Ros et al., 2013),
flavonols and urothelial cell carcinoma (Zamora-​Ros et  al., 2014),
anthocyanidins, flavonols, flavones, flavanols, and total flavonoids
and gastric cancer (Zamora-​Ros et  al., 2012), and flavonols and fla-
vanones and ovarian cancer (Cassidy et  al., 2014). However, not all
studies are consistent (Wang et al., 2009), and some even suggest harm
(Romagnolo and Selmin, 2012).
Food Contaminants
A comprehensive review of potentially carcinogenic food and bever-
age contaminants is beyond the scope of this chapter. Herein we focus
on some key contaminants that are established or suspected cancer
risk factors.
Aflatoxins are mycotoxins produced primarily by the common fun-
gus Aspergillus flavus and the closely related species A. parasiticus,
and found primarily in corn, peanuts, cottonseed, and tree nuts, in
tropical or semitropical areas (IARC, 2012b). They are classified as
Group 1 carcinogens by the IARC (IARC, 2012b), and are an estab-
lished cause of liver cancer. Presence of the hepatitis B virus sensitizes
liver cells to the mutagenic effects of aflatoxin, and recent studies doc-
ument decreases in liver cancer incidence in high-​risk areas in China
coinciding with lower aflatoxin biomarkers in urine and blood (Chen
et  al., 2013; Sun et  al., 2013). Reductions in aflatoxin exposure are
currently the main reason for the decrease in liver cancer at older ages
in these high-​risk areas. Neonatal vaccination against hepatitis B will
become more important as vaccinated cohorts age (Sun et al., 2013).
An industrial chemical, acrylamide, has been classified as “prob-
ably carcinogenic” in humans (Group 2A) by IARC since 1994, based
primarily on genotoxicity experiments in animals (IARC, 1994).
Discovery in the first decade of the 2000s that acrylamide could be
formed in (mostly) carbohydrate-​containing foods during high-​heat
cooking stimulated a surge of research into the association of esti-
mated acrylamide intake and cancer risk. Dietary acrylamide assess-
ment using an FFQ was shown to correlate moderately (r  =  0.34)
with hemoglobin adducts of acrylamide and its metabolite, glycidam-
ide (Wilson et  al., 2009). Two large meta-​analyses (Pelucchi et  al.,
2011; Virk-​Baker et al., 2014) found no association between dietary
acrylamide and risk of several cancers. Potential for confounding by
tobacco (an important source of acrylamide) and difficulty in assess-
ing exposure in a rapidly changing marketplace remain challenges in
studying the health effects of this compound.
Bisphenyl A  (BPA) is an industrial chemical used in materials
intended to come into contact with food (e.g., reusable plastic bot-
tles, feeding-​bottles, microwave ovenware, storage containers, etc.),
whereas the epoxy resins are used for internal coating of food and
beverage cans (European Food Safety Authority, 2006). First pro-
duced in 1891, its estrogenic potential was hypothesized in the
1930s (Dodds and Lawson, 1936). Because of its ability to activate
the human estrogen receptor, it is classified as an endocrine disruptor
(Geens et al., 2012). Although BPA is not thought to be a direct car-
cinogen, studies in rodents show that it sensitizes mammary tissue to
effects of chemical carcinogens (Rochester, 2013). BPA exposure may
have significant implications for human health and fertility, especially
exposure at developmental ages, and in sensitive populations. In 2012,
the FDA banned its use in baby bottles and sippy cups (FDA, 2012a,
2012b).
Pesticides and genetic modification of crops to resist pests or
improve crop yield are frequently the focus of public concern. Studies
of the effects of herbicides and pesticides in humans are complicated,
however, because the amounts in foods are highly variable and not
known to the consumer. For many of these compounds, no practical
biomarker of exposure has been identified. The IARC (Guyton et al.,
2015) and the state of California (State of California, 2015) have con-
cluded that glyphosate (Roundup), an extensively used herbicide, is a
class II carcinogen. This is troublesome because Roundup use is cur-
rently widespread for commercial and non-​commercial purposes.
Cadmium, used in nickel-​cadmium batteries and for stabilizing
plastics, is a heavy metal that enters the food supply from water con-
taminated by landfills. It bioacumulates in the liver and kidney, and has
a half-​life of 7–​16 years (Kjellstrom and Nordberg, 1978). Since 1993,
the IARC has classified cadmium as a Group 1 carcinogen, citing suf-
ficient evidence in humans for the carcinogenicity of cadmium and
cadmium compounds (IARC, 2012a). Cadmium is thought to influ-
ence cancer risk through increasing oxidative stress and reducing DNA
damage repair. It is also considered an endocrine disrupter since it has
the potential to mimic estrogens and androgens in the body. Studies
generally find no association of dietary estimates of cadmium with
breast cancer risk (Wu et al., 2015), potentially because of difficulty
estimating exposure. A  meta-​analysis of mostly case-​control studies
reported a significant increased risk of breast cancer with higher uri-
nary cadmium concentrations (Larsson et al., 2015).
SPECIFIC FOODS AND BEVERAGES
Fruits and Vegetables
Fruits and vegetables contain numerous constituents thought to influ-
ence carcinogenesis, including vitamins, phytochemicals, and dietary
fiber (IARC, 2003). Based largely on case-​control studies, the 1997
WCRF/​AICR report designated the evidence “convincing” that fruits
and vegetables lower the risk of several cancers (WCRF/​AICR, 1997).
Ten years later, the 2007 WCRF/​AICR report concluded that the evi-
dence for fruits, vegetables, and cancer risk was “probable,” primar-
ily for gastrointestinal cancers (WCRF/​AICR, 2007). This shift was
chiefly due to weaker findings from prospective cohort studies, which
are not subject to the recall and selection biases of case-​control studies.
Nevertheless, fruits and vegetables may influence cancer risk in
more nuanced ways. A  higher vegetable intake was associated with
a significantly lower risk of ER–​breast cancer in two large prospec-
tive analyses (Emaus et al., 2016; Jung et al., 2013), including a pool-
ing project of 20 cohort studies (Jung et al., 2013) (Figure 19–​2). In
another pooled analysis of 13 prospective cohort studies, intake of
fruits and vegetables was inversely associated with risk of renal cell
cancer (Lee JE et al., 2009), although the WCRF CUP for kidney can-
cer considered the totality of the evidence to be limited (WCRF/​AICR,
2015a). In a meta-​analysis of published studies, intake of fruits and
vegetables was associated with a nonlinear lower risk of colorectal
cancer, with higher risk reported among those with the lowest intakes,
and a flattened association at higher intake levels (Aune et al., 2011).
Fruits and vegetables are consistently inversely associated with can-
cers of the esophagus and other aerodigestive tract sites, although
this is based largely on case-​control studies (WCRF/​AICR, 2007). As
described later in this chapter, overall diet patterns higher in fruits and
vegetables are associated with lower risk of certain cancers, cancer
mortality, cardiovascular diseases (CVD), and death from all causes.
It is worth noting that fruits and vegetables are highly heteroge-
neous in composition, and some types of fruits and vegetables may
 37
Diet and Nutrition 337
1.2
1 P-trend, 0.06
0.8 P-trend, < 0.001
Relative Risk
0.6
ER-positive
0.4
ER-negative
0.2
0
Q1 Q2 Q3 Q4 Q5
Quintile of Vegetable Intake
Figure  19–​2. Association of vegetable intake and RR of breast cancer
by hormone receptor status. The study included 993,466 women from 20
prospective cohort studies, with 19,869 estrogen receptor positive (ER+)
and 4821 ER− breast cancers diagnosed during 11–​20 years of follow-​up.
Source: Jung S, et al. (2013).
have potential deleterious effects. Potatoes and some fruit juices, for
example, have a high glycemic load and increase insulin secretion. In
the United States, potatoes and orange juice are the most commonly
consumed vegetables and fruit, respectively, and broccoli and legumes
are among the least frequently consumed vegetables (Produce for
Better Health Foundation, 2015). Therefore, careful attention should
be paid to the types of foods that contribute to risk estimates.
Red and Processed Meat
The IARC Monographs Programme recently reviewed the evidence on
red and processed meat in relation to cancer, and classified processed
meat (e.g., hot dogs, bacon, sausage, deli meats, etc.) as a Group 1 car-
cinogen, based on sufficient evidence in humans for colorectal cancer
(Bouvard et  al., 2015). Consumption of unprocessed red meat (e.g.,
beef, pork, lamb) was classified as probably carcinogenic to humans
(Group 2A), based on limited evidence in humans for colorectal can-
cer, and strong mechanistic evidence supporting a carcinogenic effect
(Bouvard et al., 2015). These conclusions are consistent with those of
the WCRF/​AICR Continuous Update Report (WCRF/​AICR, 2011),
which considered the association between red and processed meats
and colorectal cancer to be “convincing.” A meta-​analysis of prospec-
tive cohort studies reported 17%–​18% higher risk of colorectal cancer
for each 100 g of red or 50 g of processed meat consumed per day
(Chan et al., 2011). The IARC noted that consumption of processed
meat is also positively associated with stomach cancer; consumption
of red meat is positively associated with pancreatic and prostate cancer
(Bouvard et  al., 2015). Because the relationships for colorectal can-
cer appear linear up to 140 g/​day (Chan et  al., 2011), the evidence
does not allow for a determination of a safe level of consumption. The
American Cancer Society’s cancer prevention guidelines recommend
reducing consumption in general, rather than indicating a specific
amount (Kushi et al., 2012).
The timing when meat is consumed may be important. For example,
a large pooled analysis of eight cohort studies observed no association
between breast cancer and consumption of red or total meat in adult-
hood (Missmer et al., 2002). However, the consumption of red meat
during high school was associated with higher risk of breast cancer in
young women (Farvid et al., 2014a). It was considered plausible that
breast tissue would be most susceptible to carcinogens during adoles-
cence. Furthermore, modeling substitution of red meat with poultry,
fish, or legumes and nuts was associated with 14%–​24% lower risks of
overall or postmenopausal breast cancer.
There are several mechanisms by which the consumption of red
and processed meats could influence colorectal carcinogenesis. The
formation of nitrosamines in the gut is catalyzed by heme iron, result-
ing in oxidative DNA damage (Joosen et  al., 2009). Polycyclic aro-
matic hydrocarbons (PAHs) and heterocyclic aromatic amines (HCA
or HAA) are carcinogens formed during high-​heat cooking of meat
(Sinha et al., 1998a, 1998b). In a study from the NIH-​AARP Cohort
including 300,948 US men and women (Cross et al., 2010) in which
dietary intakes were linked with a meat carcinogen database, a posi-
tive association was observed for heme iron, nitrate from processed
meats, and heterocyclic amine intake, specifically 2-​amino-​3,8-​dime-
thylimidazo[4,5-​f]quinoxaline (MeIQx) and 2-​amino-​3,4,8-​trime-
thylimidazo[4,5-​f]quinoxaline (DiMeIQx). Not all studies of specific
meat carcinogens are consistent (Ollberding et  al., 2012). The 2015
US Dietary Guidelines Advisory Committee report recommended that
individuals reduce their intake of red and processed meat (regardless
of fat content) because of its associations with cancer and other dis-
eases and the environmental impact on agriculture and greenhouse
gasses (US Dietary Guidelines Advisory Committee, 2015). However,
this recommendation did not survive opposition from industry lobby-
ists and Congress (US Department of Health and Human Services and
US Department of Agriculture, 2015).
Grains
Whole-​grain foods, made from the entire grain seed, are much higher
in fiber and many vitamins, minerals, and other phytochemicals than
processed (refined) flour products. While research on whole grains
in relation to cancer risk has generally been inconsistent, some stud-
ies support an inverse association with gastrointestinal cancers. In
the NIH-​AARP Diet and Health Study of 291,988 men and 197,623
women, whole-​grain foods were associated with a significant 20%
lower risk of colorectal cancer (Schatzkin et al., 2007), and a statisti-
cally borderline inverse association with rare small intestinal tumors
(Schatzkin et al., 2008). The evidence for other cancers, including pan-
creatic (Chan et al., 2007) and breast (Egeberg et al., 2009), is incon-
clusive. Whole-​grain foods are strongly protective against CVD (Cho
et al., 2013) and diabetes (de Munter et al., 2007). As described later
in this chapter, dietary patterns rich in whole grains, nuts, vegetables,
fruits, and low in red and processed meat are associated with lower risk
of certain cancers.
Dairy Products
In the United States, dairy products are the major source of dietary
calcium and vitamin D.  Consistent with the evidence for calcium
and vitamin D, epidemiologic evidence supports an inverse associa-
tion between dairy products and colorectal cancer (Cho et al., 2004).
A  recent meta-​ analysis further suggests that milk and total dairy
products (but not cheese) lower the risk of colon but not rectal cancer
(Aune et al., 2012b).
High consumption of milk during childhood and adolescence is
associated with increased height (Berkey et al., 2009), which in turn is
associated with multiple forms of cancer (WCRF/​AICR, 2007). Milk
consumption also increases blood levels of IGF-​1 (Cadogan et  al.,
1997; Rich-​Edwards et  al., 2007), which have been associated with
higher risks of breast and prostate cancer (Key et al., 2010; Neuhouser
et al., 2013; Rowlands et al., 2009). Prospective studies of breast can-
cer risk in relation to dairy intake have been inconsistent and mostly
null (Missmer et al., 2002), although some studies suggest that breast
cancer incidence may be lower with higher intakes of low-​fat dairy
products during mid-​and later life (Cui and Rohan, 2006; Shin et al.,
2002). In contrast, high intake of dairy products has been associated
with an increased risk of other hormonally related cancers, includ-
ing prostate (Aune et al., 2015), ovary (Genkinger et al., 2006), and
endometrium, especially among women not using hormone therapy
(Ganmaa et al., 2012). Evidence on milk and dairy consumption dur-
ing childhood and cancer risk in adulthood remains limited; in one
report, adolescent milk consumption was not significantly associated
with future risk of breast cancer (Linos et al., 2010).
38
338 PART III:  The Causes of Cancer
Soy
Soy foods (such as tofu, tempeh, edamame, miso, many veggie
burgers, and other products made with soy flour) contain isoflavones
which, as described earlier, have weak estrogenic activity and can act
as anti-​estrogens by competitive inhibition for the estrogen receptor
(Nagata, 2010). Because of this, soy foods have been hypothesized
to reduce the risks of breast and other hormonally related cancers.
In a recent meta-​analysis including 14 epidemiologic studies, Asian
women who ate the most (compared to the least) soy isoflavones
had a 24% lower risk of developing breast cancer, while there
was no association in Western countries such as the United States
(Dong and Qin, 2011). The benefit of soy has been observed primar-
ily with consumption during childhood or early adult life (Lee SA
et al., 2009).
Coffee
In addition to caffeine, coffee contains multiple biologically active com-
pounds such as chlorogenic acid, kahweol, and N-​methylpyridinium,
which in animals and in vitro induce apoptosis, inhibit inflammation,
angiogenesis, and metastasis, and regulate genes involved in DNA
repair and detoxification processes (Bohn et al., 2014).
In 1991, an expert Working Group organized by the International
Agency for Research on Cancer (IARC) Monographs Program clas-
sified coffee as a 2B carcinogen, concluding that “[c]‌offee is possibly
carcinogenic to the human urinary bladder” (IARC Working Group on
the Evaluation of Carcinogenic Risks to Humans, 1991); however, a
2016 review by IARC concluded that coffee drinking was considered
unclassifiable as to its carcinogenicity to humans (Group 3) (Loomis
et al., 2016). Most of the studies considered in the 1991 IARC review
were case-​control studies, which are susceptible to recall and selec-
tion biases. A 2012 meta-​analysis of coffee consumption and bladder
cancer risk continued to show positive associations for case-​control
studies, but estimates from five prospective cohort studies were null
(Zhou et al., 2012). Further, coffee consumption is generally associ-
ated with smoking, which is strongly related to bladder cancer and
difficult to control for.
The potential for residual confounding due to smoking is a concern
for the relationship of coffee consumption with other cancers as well.
In the AARP cohort, there was a two-​fold increased risk of mortality
due to cancer in age-​adjusted models for both men and women; after
controlling for smoking and other risk factors, risk estimates were
substantially attenuated and were no longer statistically significant in
any category of consumption, although the trend remained statistically
significant in men only (Freedman et  al., 2012). Significant interac-
tions by smoking status were observed (p < 0.01), with weak inverse
trends in never smokers and either a positive or no trend in current and
former smokers.
The WCRF/​ AICR CUP considers the protective association
between coffee consumption and endometrial cancer to be “probable”
(WCRF/​AICR, 2013) although a recent meta-​analysis concluded that
there is no association (Yang TO et al., 2015). Of 12 cancers examined
in relation to coffee consumption in the Prostate, Lung, Colorectal, and
Ovarian (PLCO) screening cohort, a statistically significant inverse
association was observed only for endometrial cancer; the association
was non-​statistically significantly inverse when limiting the analysis to
never smokers (Hashibe et al., 2015).
Despite methodologic limitations, coffee consumption has been
strongly and consistently related to lower risk of hepatocellular cancer
(HCC) (Bravi et al., 2013), and the 2014 WCRF/​AICR Liver Cancer
CUP considers it “probable” that coffee consumption protects against
liver cancer (WCRF/​AICR, 2015b). In a recent pooling project of nine
US cohorts including over 1 million persons, higher coffee consump-
tion was associated with lower risk of HCC (relative risk for > 3 cups/​
day vs. non-​drinker = 0.73; 95% CI: 0.53, 0.99, P, trend cups/​day =
< 0.0001) (Petrick et al., 2015). The relative risk was stronger for caf-
feinated coffee than for decaffeinated coffee, although the confidence
interval for the latter was wide. In the European EPIC cohort, the
relative risk for drinking 4 or more cups per day compared with less
than 2 cups per day was 0.25 (95% CI: 0.11, 0.62); this was weakened
after control for biomarkers of hepatocellular injury and inflamma-
tion, suggesting that these mechanisms may underlie the association
(Aleksandrova et al., 2015). Whether coffee is related to a lower risk
of cancers of the kidney (Lee et al., 2007), breast (Bhoo-​Pathy et al.,
2015), colon and rectum (Li et  al., 2013), or prostate (particularly
lethal or advanced forms) (Wilson et al., 2011) is the subject of con-
tinued research.
The 2016 IARC Expert Review Committee also reviewed the evi-
dence for maté (a traditional South American caffeine-​rich infused
drink), and beverage temperature. The IARC concluded that drink-
ing very hot beverages at above 65 degrees Centigrade (149 degrees
Fahrenheit), including maté, was “probably carcinogenic to humans”
(Group 2A) (Loomis et al., 2016). As most of the evidence in humans
is from case-​control studies, it will be important to confirm these find-
ings in additional prospective studies.
Tea
Tea is rich in polyphenols and other compounds with antioxidant and
anti-​cancer properties. Green tea, more commonly consumed in Asian
countries, is particularly rich in catechins, a type of flavonoid. In con-
trast, black tea, more commonly consumed in Western countries, is
higher in theaflavins and thearubigens (Yuan et al., 2011). Case-​control
studies of tea consumption and cancer risk generally find stronger
inverse associations than prospective studies. A  meta-​analysis of 57
prospective studies (including 20 from the US and 22 from Asia) that
included over 8 million individuals and almost 50,000 incident cancer
cases found tea consumption to be inversely associated with oral can-
cer (RR 0.72; 95% CI: 0.54, 0.95, high vs. low tea consumption), but
with none of the other cancers examined (gastric, colon, rectum, lung,
liver, pancreas, breast, prostate, ovarian, bladder, or glioma). Thus, the
evidence to date suggests that the relationship between tea and can-
cer is likely to be minimal, but additional large studies of oral cancer
would be valuable to confirm this finding.
Alcohol
As described in Chapter  12, alcohol is considered a Group  1 car-
cinogen by the IARC (IARC, 2010), and an established cause of
cancers of the upper gastrointestinal tract, liver, colorectum, and
breast (female). In contrast, there is evidence for lack of carcino-
genicity for kidney cancer and non-​Hodgkin lymphoma. For pan-
creatic cancer, risk begins to increase at greater than 3 servings/​day
(Gapstur et al., 2011), whereas the increase for breast cancer begins
at as few as 3 servings/​week (Chen et al., 2011; Smith-​Warner et al.,
1998). On the other hand, alcohol is associated with lower CVD
risk and mortality (Thun et  al., 1997), and is an integral part of
certain healthful dietary patterns, such as the Mediterranean diet
(Trichopoulou et  al., 2003). Dietary recommendations for cancer
prevention advise limiting alcohol consumption among those who
drink to no more than one drink/​day for women and two drinks/​day
for men (WCRF/​AICR, 2007).
DIETARY PATTERNS
Characterizing “diet” as an overall diet pattern provides a more com-
plete picture of dietary intake than studies of single foods or nutri-
ents. Dietary patterns also potentially reflect additive and synergistic
effects of the components of diet on disease risk. This approach may
be particularly useful in the study of cancer etiology, where associa-
tions with certain dietary risk factors may be small and difficult to
detect in isolation.
The two most common approaches to characterize dietary patterns
in observational studies involve either statistically driven empirical
methods, such as factor analysis, or creation of a priori dietary indexes
or scores (Hu, 2002), as described later in this chapter.
 39
Diet and Nutrition 339
Vegetarians
Levels of vegetarianism range from complete exclusion of all animal
products (including fish and dairy; “vegan”) to lacto-​ovo vegetarian
(includes eggs and dairy), to pescovegetarian (includes fish). In the
Adventist Health Study II, compared to non-​ vegetarians, vegetar-
ians of any type—​defined according to protein sources reported on a
FFQ—​had a statistically significant 28% lower risk of colorectal can-
cer (Orlich et al., 2015). Likewise, in a recent British study (Key et al.,
2014), vegans, vegetarians, and pescovegetarians had a significantly
lower risk of several cancers, compared to meat eaters.
Mediterranean Diet
Probably the most studied dietary pattern has been the Mediterranean
diet, characterized by high consumption of olive oil (or unsaturated
fats in some scoring systems), fruits, vegetables, nuts, legumes, and
unprocessed cereals, low consumption of meat and meat products, low
consumption of dairy (with the exception of long preservable cheeses),
and moderate intake of alcohol, usually wine consumed with meals
(Trichopoulou et  al., 2014). A  meta-​analysis of 11 cohort studies
found that higher (vs. lower) scores reflecting a Mediterranean-​like
diet were associated with a lower risk of all cancers combined (relative
risk = 0.87; 95% CI: 0.81, 0.93), and specific cancer sites (colorectum,
breast, prostate, stomach, liver, pancreas, head and neck, and respira-
tory cancers) (Schwingshackl and Hoffmann, 2015). This conclusion
was further supported by a recent analysis of three cohort studies in
which adherence to a Mediterranean diet, calculated using identical
scoring methods, was associated with lower all-​cancer mortality (Liese
et  al., 2015). The Spanish PREDIMED randomized trial random-
ized participants to three diet pattern interventions: a Mediterranean
diet (via instruction) with supplementary nuts, a Mediterranean diet
with supplementary extra virgin olive oil, or a control (low-​fat) diet
(Estruch et al., 2013). Both Mediterranean diet groups had unequivo-
cal health benefits for CVD; although based on a small number of
cases, the group randomized to extra virgin olive oil had a substantially
lower risk of breast cancer compared to the control group (RR = 0.32;
95% CI: 0.13, 0.79) (Toledo et al., 2015).
Other Diet Patterns
Empirically derived patterns, which use statistical approaches to
extract unique correlated eating behaviors within a population, typi-
cally identify two or three such patterns, each explaining up to 5%–​
10% of the variation in diet. As expected, patterns vary across study
populations, but two have been commonly identified across interna-
tional borders:  the first, a so-​called “Western” pattern, is higher in
red and processed meat, potatoes, sugar, and lower in vegetables and
whole fruit; the second, a “Prudent” pattern, is higher in fruits, veg-
etables, poultry, fish, and nuts, and low in high-​fat dairy, meat, and
sugar. The “Western” pattern is positively associated with colon can-
cer incidence (Magalhaes et al., 2011) and with cancer recurrence and
mortality among colorectal cancer patients (Meyerhardt et al., 2007).
Although the Prudent pattern is associated with lower colorectal can-
cer risk, it appears that this is not as strong as avoiding a Western-​type
diet (Fung et al., 2003).
A priori indices, such as those used to study the Mediterranean diet,
quantify the degree of dietary concordance with hypothesized healthy
diet patterns using a set of criteria, with low scores generally reflect-
ing poor concordance, and high scores reflecting high concordance to
multiple dietary components. Healthy diet scores have been based on
dietary guidelines, hypothesized general or disease-​specific diets, cul-
turally defined healthful models of eating, and specific mechanisms
mediated by diet, such as its antioxidant or anti-​inflammatory poten-
tial. Recently, associations of four hypothesized healthful diet patterns
were examined in relation to cause-​specific mortality using a uniform
approach to diet score calculations and analysis across three prospec-
tive cohort studies (Liese et al., 2015). Scores reflecting dietary con-
cordance with the Mediterranean diet, the Dietary Approaches to Stop
Hypertension (DASH) diet, the Healthy Eating Index (reflecting US
Dietary Guidance), and an Alternate Healthy Eating Index (reflecting
the Harvard Healthy Eating Plate & Food Guide Pyramid) were each
associated with an approximate 20% statistically significant reduction
in cancer mortality, comparing the highest to lowest quintile (Liese
et al., 2015). These diet scores share several commonalities, including
being rich in a variety of plant foods and generally higher in healthy
protein sources, and lower in sugar and saturated and trans fat, but vary
in the specific fatty acids, protein sources, and alcohol recommenda-
tions. Of individual cancers, diet scores have tended to be most con-
sistently inversely associated with gastrointestinal cancers. Despite the
many advantages of studying diet patterns, such exposures are more
complex to interpret, as they may mask subcomponents that are mini-
mally or maximally predictive of disease outcome.
Cancer Prevention Guidelines
Dietary guidelines focused on cancer prevention emphasize not only
healthy diet, but also behaviors that affect body weight, physical
activity, and alcohol consumption (Kushi et al., 2012; WCRF/​AICR,
2007). These recommendations encourage diets that are mostly plant-​
based, high in non-​starchy vegetables, whole fruit, and whole (vs.
refined) grains, and low in red and processed meat. Scores reflecting
the diet, physical activity, body weight, and alcohol recommendations
of cancer prevention guidelines have been developed and examined
in relation to cancer incidence (Kabat et al., 2015; Romaguera et al.,
2012; Thomson et al., 2014a) and mortality (McCullough et al., 2011;
Vergnaud et  al., 2013). Lifelong non-​ smokers whose dietary pat-
terns, weight, and physical activity more closely correspond with the
American Cancer Society (ACS) guidelines have a 24%–​30% lower
death rate from cancer, and a 42% lower all-​cause mortality rate,
compared to those whose patterns are least consistent (McCullough
et al., 2011). Another large study of the AARP cohort reported that,
in analyses controlling for smoking, the incidence rates for 14 out of
25 cancer sites were significantly lower in study participants whose
behaviors were consistent with the ACS guidelines than in those who
were not (Kabat et al., 2015). In the Women’s Health Initiative cohort,
significant inverse associations with cancer incidence and death rates
were reported among white, black, and Hispanic postmenopausal
women, with stronger associations appearing in the last two racial/​eth-
nic groups (Thomson et al., 2014a). In models with mutual adjustment,
the individual score components, including diet, generally remained
independently associated with lower cancer risk. Results using the
global WCRF/​AICR score, with different weighting for lifestyle fac-
tors, found qualitatively similar inverse associations with cancer risk
and mortality (Romaguera et al., 2012; Vergnaud et al., 2013). Overall,
these studies underscore the significant potential for cancer prevention
through combined health behaviors including diet, physical activity,
and healthy body weight.
Effects of Diet on Cancer Survival
Approximately 14.5 million children and adult cancer survivors were
alive on January 1, 2014 (American Cancer Society, 2014). Compared
to the evidence base on diet and cancer prevention, the study of diet
in relation to cancer recurrence, cancer-​specific survival, and overall
survival is in its infancy. Therefore guidelines on nutrition and physi-
cal activity for cancer survivors also recommend following cancer
prevention guidelines (Rock et al., 2012). Timing is a central issue in
studies of diet and cancer survival. For a cancer patient, the relevant
time is after the diagnosis, and many of the existing studies assessed
diet before diagnosis. Optimally an epidemiologic study should have
dietary assessments both before and after diagnosis because these tend
to be correlated, and we would want to know their independent con-
tribution to survival. Only a few randomized trials of dietary inter-
ventions and cancer survival have been conducted, as described in the
following paragraph.
Breast cancer survivors comprise over 3.1 million survivors in the
United States, larger than any other group (American Cancer Society,
340
340 PART III:  The Causes of Cancer
2014). A report based on a systematic and quantitative literature review
found no convincing or probable dietary factors associated with recur-
rence, cause-​specific, or total mortality for breast cancer survivors
(WCRF/​AICR, 2014a), although limited support exists for soy foods,
high dietary fiber, and low saturated fat. A limitation is that many stud-
ies contributing to this report only examined diet prior to diagnosis. In
Western diets where soy consumption is less common, lignans are the
predominant phytoestrogen. A  recent population-​based case-​control
study showed that pre-​diagnostic dietary lignan intake was associ-
ated with statistically significantly lower risk of breast cancer mortal-
ity (McCann et al., 2010). The Women’s Intervention Nutrition Study
(WINS) trial, a low-​fat dietary intervention trial, found a 24% mar-
ginally significant lower risk of recurrence (Chlebowski et al., 2006);
however, because women on the low-​fat arm also lost weight, it is
possible that the effect was due to weight loss and not because of a
reduction in dietary fat per se (Gapstur and Khan, 2007). The Women’s
Healthy Eating and Living (WHEL) study found no difference in
breast cancer outcomes between women counseled on a high fruit,
vegetable, fiber, low-​fat diet versus those counseled on eating “five
a day” (fruits and vegetables) (Pierce et al., 2007). As breast cancer
patients typically have a relatively good prognosis, they are subject to
the same diseases as the general population and actually tend to be at
higher risk of other chronic diseases, including CVD, relative to non-​
cancer survivors (Rock et al., 2012). Thus, understanding the potential
role of diet on both cancer and non-​cancer outcomes in this patient
group has strong clinical and population health relevance. As would
be expected, a growing literature in breast cancer survivors from pro-
spective cohort studies suggests that women who consume healthy diet
patterns (assessed via diet scores) rich in a variety of plant foods and
whole grains and low in red and processed meat after diagnosis have
lower risk of non-​breast-​cancer causes of death (George et al., 2014;
Inoue-​Choi et al., 2013; Izano et al., 2013; Kim et al., 2011); however,
none of the diet scores examined was associated with breast cancer–​
specific mortality.
For colorectal cancer survivors, post-​diagnostic dietary intake from
two cohorts suggests a deleterious effect of a Western dietary pat-
tern, high red and processed meat intake, and a high glycemic load
diet on colorectal cancer recurrence or survival (Van Blarigan and
Meyerhardt, 2015). In another type of analysis, post-​diagnostic data
were used to predict plasma vitamin D status. In turn, higher predicted
vitamin D was associated with lower colorectal cancer-specific and
overall mortality (Ng et al., 2009).
Like breast cancer, clinical recurrence and death often occur many
years after a prostate cancer diagnosis, thus providing a wide time
window for potential dietary and lifestyle influences on the outcome
(Chan et  al., 2014). Although the data on post-​diagnostic diet and
survival are limited, a higher prostate-​specific mortality with higher
intake of saturated fat and a lower total mortality with higher intake
of vegetable fats were observed in a recent report from the Physician’s
Health Study (Van Blarigan et  al., 2015). Similar findings were
observed in another population of men with prostate cancer (Richman
et al., 2013). Adherence to a Western dietary pattern has been associ-
ated with higher prostate-​specific and total mortality, and adherence
to a Prudent dietary pattern was associated with lower total mortality
(Yang M et al., 2015). Numerous short-​term interventions have been
conducted with changes in PSA or other surrogate variables as out-
comes; possible benefits have been seen with several combinations of
nutritional supplements, but clinical outcomes are lacking (Hackshaw-​
McGeagh et al., 2015).
The available evidence supports the same recommendations for can-
cer survival as for cancer prevention (Rock et al., 2012). Fortunately,
these recommendations also apply to the prevention of CVD, and thus
provide broad benefits for the prevention of chronic disease.
GENE–​DIET INTERACTIONS
Nutrigenomics seeks to identify genetic polymorphisms and epigen-
etic alterations that modify individual response to nutrients (Teegarden
et al., 2012; Zeisel, 2007). The underlying goal is to identify individuals
who might benefit most from increased or decreased exposure to
specific dietary factors. The same concept underlies “personalized
medicine” or “personalized prevention.” The potential for practical
applications of this concept has weakened, especially for prevention,
with the realization that the effects of common genetic variants on
disease risk are considerably smaller than anticipated 15  years ago.
Apart from this application, the identification of gene–​environment
interactions can be of value in etiologic studies if Mendelian random-
ization supports a particular mechanism for a diet and disease relation-
ship that cannot be tested in a randomized clinical trial (Willett W,
2013). Furthermore, the identification of a subset of individuals who
are uniquely responsive to the effects of a particular dietary factor can
increase the statistical power of observational studies of this relation-
ship. The study of gene–​diet interactions in relation to cancer risk has
evolved from studies of single nucleotide polymorphisms (SNPs) in
candidate genes to genome-​wide association studies (GWAS) using
a more agnostic approach. A  recent systematic literature review of
gene–​diet interactions and colorectal cancer risk in candidate gene
studies found suggestive evidence for interactions between meat, cru-
ciferous vegetables, dietary fiber, calcium, vitamins, and alcohol and
SNPs in the ABCB1, NFKB1, GSTM1, GSTT1, CCND1, VDR, MGTM,
IL10, and PPARG genes (Andersen et  al., 2013). More recently, a
comprehensive GWAS approach examined diet–​ gene interactions
with colorectal cancer risk in over 9000 cases and 9000 controls from
10 studies (Figueiredo et al., 2014). The study uncovered strong evi-
dence for a gene–​diet interaction and colorectal cancer risk between
a genetic variant (rs4143094) on chromosome 10p14 near the gene
GATA3 and processed meat consumption (p = 8.7E-​09), although the
functional significance of this interaction is still unknown (Figueiredo
et al., 2014).
The impact of epigenetic modifications can vary from full gene
silencing to complete expression, and the effect may be permanent
or transient (Teegarden et al., 2012). Multiple bioactive food compo-
nents, including folate, selenium, polyphenols, isothiocyanates, and
others, have been shown to affect epigenetic processes in vitro; how-
ever, more evidence is needed from animal and human studies (Ong
et al., 2011). At present, no gene–​environment interactions involving
nutritional factors and cancer have been identified with sufficient cer-
tainty and impact to have clinical application.
SUMMARY
Methodologic Considerations
Existing methodologic approaches have identified important rela-
tionships between nutrition and cancer, especially regarding dietary
patterns, anthropometric measures, and alcohol consumption.
Diet composition can be reasonably well characterized by food
frequency questionnaires, repeated measures of short-​term intake
(e.g., multiple food records and recalls), and biological markers
of dietary intake. The methods of assessing diet composition con-
tinue to improve as nutrient databases are expanded, technologies
are adapted and/​or developed to measure dietary intake more pre-
cisely, new biomarkers are discovered, and metabolites that medi-
ate between food intake and biological effects on cancer risk are
identified. Further improvements in these methodologies will likely
increase the precision of estimates of absolute or relative risk. New
biomarkers are needed to assess aspects of diet that cannot be evalu-
ated from self-​report; markers of food processing and contaminants
would be particularly useful. It is inherently difficult to separate
the effects of highly correlated nutrients and foods in observational
studies; distinguishing among them may be facilitated by Mendelian
randomization studies and short-​ term randomized studies with
intermediate endpoints. These issues become unimportant in studies
of overall dietary patterns.
No single type of study is likely to resolve most hypothesized diet
and cancer relationships. Large randomized trials of diet and cancer
incidence may be definitive if “positive,” but are not a gold standard, as
they may be unable to detect important effects due to poor adherence
  341
Table 19–1.  Relationship of Dietary Factors with Risk of Selected Individual Cancer Sitesa

Dietary Factor Colorectum Breast Prostate Lung Stomach Esophagus Pancreas Liver Ovary Endometrium All Cancers

Macronutrients/​energy balance
Obesity ↑↑ ↑↑˅ ↑˅ ↑↑˅ ↑↑˅ ↑↑ ↑↑ ↑ ↑↑ ↑↑

Abdominal fatness ↑↑ ↑
Carbohydrates/​sugars ↑§

Glycemic Load ↑

Height ↑↑ ↑↑ ↑ ↑ ↑↑ ↑ ↑

Nutrients (from food unless

otherwise specified)
Vitamin D [25(OH)D] ↓ φ Non-​linear Conflicting

Calcium ↓ ↑ §

Folate ↓§

Fiber ↓↓

Carotenoids ↓˅ Lycopene↓§ ↓

ß-​carotenesupplements φ ↑↑˅

Vitamin E supplements φ §

Selenium supplements φ

Antioxidant (combin​ation) ϕ φ
supplements
Salt preservation ↑↑

Contaminants ↑↑arsenic in ↑↑Aflatoxin

drinking water
Foods

Fruits ↓** ↓ ↓^

Vegetables ↓˅ ↓**
↓^

Red meat ↑↑ ↑§
↑† ↑†

Processed meat ↑↑ ↑↑ †
↑^

Other protein sources, fish, ↓§

↓
poultry, nuts
Whole grains ↓

Dairy or milk ↓ ↑˅§

Soy ↓˅

Coffee φ ↓↓§ ↓

(continued)
 342
Table 19–1. Continued

Dietary Factor Colorectum Breast Prostate Lung Stomach Esophagus Pancreas Liver Ovary Endometrium All Cancers

Tea φ

Alcohol ↑↑˅ ↑↑ ↑↑ ↑↑ ↑§ ↑↑ ↑↑

Diet patterns*
Empirical diet patterns

“Western” diet ↑↑

“Prudent” diet ↓ ↓˅

Dietary indices

Mediterranean diet ↓ ↓§ ↓˅ ↓ ↓

“DASH” diet ↓ ↓

USDA Healthy Eating Index ↓ ↓ ↓ ↓ ↓ ↓

Harvard “Alternate” Healthy ↓ ↓ ↓

Eating Index
Dietary Inflammatory Index ↑

Cancer lifestyle guidelines‡

ACS guidelines ↓ ↓ ↓˅ ↓ ↓ ↓˅ ↓˅ ↓ ↓↓
WCRF/AICR Guidelines ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓↓

a
Two arrows denotes convincing or consistent evidence; One arrow denotes probable association; Grey arrow denotes only one or limited studies; ϕ mark=unlikely to be an association; ˅ denotes lower risk in subgroups, e.g. obesity and
postmenopausal (not premenopausal) breast cancer, aggressive prostate, gastric cardia and esophageal adenocarcinoma; vegetables, carotenoids and ER-​breast cancer; beta-​carotene supplements and lung cancer in smokers; processed meat and
gastric cardia cancer; fruit, vegetables, processed meat and squamous cell esophageal cancer; dairy and aggressive prostate cancer; soy and breast cancer primarily in Asian countries; alcohol and colorectal cancer risk convincing in men, probable in
women. For diet patterns, prudent diet related to lower risk of ER-​breast tumors, Mediterranean diet associated with esophageal squamous cell cancer; ACS guidelines related to lower liver, lung and pancreatic cancer in men only. § denotes author
conclusions (note: breast cancer and red meat includes early life exposure); † also noted in IARC 2015 conclusions *Evidence on diet patterns is based on a limited number of studies. ‡ In addition to food-based recommendations, the ACS and
WCRF/​AICR scores also include body mass index, physical activity and alcohol consumption. Sources: WCRF/​AICR 2007 report or CUP reports if available; **This association may be confounded by smoking.
 34
Diet and Nutrition 343
(especially with complex dietary patterns), limited duration, and diffi-
culty blinding the intervention. For most hypotheses, the best evidence
will probably come from replicated cohort studies in combination with
short-​term randomized trials with intermediate biomarkers.
Estimates of Attributable Fraction
The population attributable fraction for diet and all cancers, based
on more precise estimates for relationships that are established with
reasonable certainty, is about 20% overall, which is weaker than
previously estimated, and much of this is related to overweight and
inactivity. This also does not include the contribution of dietary com-
position to adiposity, which has become better established in recent
years. The proportion contributed by dietary composition independent
of adiposity is unclear because some dietary factors have yet to be
identified or established with sufficient certainty, and associations are
likely underestimated because of measurement error or misspecifica-
tion of temporal relationships. Estimates based on reasonably docu-
mented relationships suggest an etiologic contribution of 5%–​12%,
but this could be appreciably higher.
Specific Diet and Cancer Relationships
Progress in diet and cancer prevention over the past 30+ years has
been slow compared to accrual of knowledge relating diet to CVD and
diabetes, but several findings come into focus:
1. Individual nutritional supplements in high doses are unlikely to
prevent cancer and may even be harmful, but evidence suggests a
modest benefit of RDA-​level multi-​nutrient supplements that may
be most important in subsets with suboptimal diets.
2. Certain constituents (nutrients, phytochemicals) may significantly
reduce the risk of various cancers. Low folate intake likely contrib-
utes to colon and possibly other cancers, and considerable evidence
supports a role of plant foods, lycopene, vitamin D, and constitu-
ents of coffee in human cancer.
3. Processed and red meat consumption is likely to increase risk of
colorectal and possibly other cancers, and dairy foods are likely
to influence risk of colorectal and prostate cancers in opposite
directions.
4. Alcohol consumption increases the risk of breast, colorectal, esoph-
ageal, and other cancers but is unlikely to increase risk of kidney
cancer or non-​Hodgkin lymphoma.
5. Several culturally or a priori defined diet patterns, including the
Mediterranean diet, are associated with lower cancer risk and mor-
tality in prospective epidemiological studies. These diet patterns
are higher in plant foods (vegetables, fruits, cereals, vegetable pro-
tein) and fish, and lower in processed meat and red meat and gener-
ally moderate in dairy and alcohol (Table 19–​1).
FUTURE DIRECTIONS
The precision of dietary estimates can be improved by combining sev-
eral different approaches to exposure measurement, including the use
of biomarkers, food frequency questionnaires, and multiple 24-​hour
recalls or food records. Pooled analyses of dietary intakes or biomark-
ers in relation to cancer outcomes across multiple prospective stud-
ies can minimize variation due to chance and biases from selective
recall and publication. This is optimal if measurements of absolute
intake and biomarker concentration are standardized and/​or calibrated
across studies. Probably the greatest limitation of currently available
evidence is that it derives mainly from diets assessed in mid-​or later
life with follow-​up of less than 15 years. Dietary assessments earlier in
life, including in utero and during puberty, combined with long follow-​
up using repeated dietary assessments, may uncover exposures that
are relevant.
Technological advancements in biomarker analysis permit com-
prehensive examination of an individual’s metabolome, microbiome,
genome, and epigenome. Use of these methods to assess internal
exposures and identify subsets of individuals who are particularly
responsive to the dietary factor being investigated could increase our
ability to detect diet and cancer relationships and to provide targeted
interventions. Cohort studies with prospectively collected archived
stool, blood, and urine samples will be positioned to evaluate proposed
biomarkers from “omics” studies in relation to cancer risk.
Molecular characterization is increasingly used in oncology and
cancer epidemiology to identify tumor subtypes that differ in their
clinical characteristics and etiology. As with the identification of gene–​
environment interactions, identifying biologically relevant exposures
and pathways related to specific cancer subtypes can increase the abil-
ity to detect relationships and to develop support for causality. This
work will benefit from collaborative efforts to provide the large num-
bers of study participants and cases required.
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20 Obesity and Body Composition
NANA KEUM, MINGYANG SONG, EDWARD L. GIOVANNUCCI,
AND A. HEATHER ELIASSEN
OVERVIEW
In 2014, an estimated 1.9 billion adults were either overweight (BMI
25–​29.9) or obese (BMI ≥30), worldwide. The so-​called obesity epi-
demic began in high-​income, English-​speaking countries in the early
1970s, but soon spread globally; worldwide, more than one-​third (38%)
of all adults and 600,000 children under age 5 are overweight or obese,
as are two-​thirds (69%) of adults in the United States. Excessive body
fat is a major cause of type 2 diabetes, hypertension, and cardiovascu-
lar and liver disease, among other disorders, and has been designated
a definite cause of at least 14 cancer sites:  breast (postmenopausal),
colorectum, endometrium, esophagus (adenocarcinoma), gallblad-
der, kidney (renal cell), pancreas, gastric cardia, liver, ovary, pros-
tate (advanced tumors), multiple myeloma, thyroid, and meningioma.
A  causal association is considered possible for leukemia and lym-
phoma. Estimates of the proportion of cancers attributable to over-
weight and/​or obesity globally range from 6% for rectal cancer to 33%
for esophageal cancer in men and from 4% for rectal cancer to 34% for
endometrial cancer in women. Mechanisms by which adipose tissue
are thought to promote tumor growth include the endocrine and met-
abolic effects of fat on sex hormones, growth factors, and inflamma-
tion, as well as local chemical or mechanical injury of gastrointestinal
organs. Because of the high prevalence of excess adiposity world-
wide and the difficulty that most individuals have in losing substantial
amounts of weight and maintaining that weight loss, population-​based
approaches will require policies and community actions that help indi-
viduals avoid excessive weight gain throughout life.
INTRODUCTION
The hypothesis that excess energy intake may contribute to cancer
risk originated from experimental studies of animals in the 1940s, in
which mice fed ad libitum developed larger and more numerous mam-
mary tumors than mice on energy-​restricted diets (Sellers et al., 2007;
Tannenbaum, 1940a, 1940b). As noted in Chapter 19, this finding has
consistently been replicated in a wide variety of mammary and other
tumor models (Birt et al., 1992; Nair et al., 1995; Ross and Bras, 1971;
Weindruch and Walford, 1982); a 30% restriction in energy intake
since birth reduces mammary tumors in laboratory animals by as much
as 90% (Boissonneault et al., 1986).
Epidemiologic studies, beginning in the 1970s, reported that over-
weight women were more likely to develop breast and endometrial
cancer (Blitzer et  al., 1976; de Waard and Baanders-​van Halewijn,
1974). Large prospective studies subsequently observed associations
between excess body weight and increased mortality from multiple
types of cancer (Calle et al., 2003; Lew and Garfinkel, 1979). During
the last 15–​20 years, the literature on cancer in relation to obesity and
body composition has expanded exponentially. This chapter will focus
primarily on epidemiologic studies published in the last 10–​15 years
and on advances in understanding the relationship of obesity and body
composition to cancer since the publication of the corresponding
chapter in the third edition of Cancer Epidemiology and Prevention
(Ballard-​Barbash et al., 2006).
MEASURES OF BODY FAT AND BODY COMPOSITION
Individuals vary in their size and shape. Because of this variation, it
is not surprising that no single measure of adiposity and body com-
position is ideal in all circumstances. The so-​called gold s​tandard
approaches for measuring the amount and distribution of body fat in
clinical settings involve imaging with computed tomography (CT) or
magnetic resonance imaging (MRI). While these provide the most
accurate measurements, the devices are expensive to transport and
operate, limiting their use in large-​scale population studies. Various
anthropometric measures have been developed that use self-​reported
or measured information on height and weight and/​or waist and hip
circumference to assess different aspects of body composition. These
are widely used because of their simplicity and low cost. It is impor-
tant to understand the specific significance of these measures, as well
as their limitations, since they serve as the exposure variable(s) in epi-
demiologic studies.
Body Mass Index (BMI)
BMI is the most commonly used measure of overall body fatness.
BMI is defined as weight in kilograms (kg) divided by height in
meters squared (m2). The advantages of BMI are that it provides a sin-
gle measure of adiposity that is independent of height and that can be
compared across populations (Gallagher et al., 1996). BMI is highly
correlated (r = 0.82–​0.91) with absolute fat mass, calculated from
percent body fat measured by densitometry, even after accounting for
extraneous variations caused by age and sex (Spiegelman et al., 1992;
Willett, 2013). Densitometry has long been considered a gold standard
for measuring total body fat.
The World Health Organization (WHO) has established criteria to
classify individuals according to their BMI (WHO, 2015). Adults (age
>18 years) with a BMI <18.5 are considered underweight; those with
BMI 18.5–​<25 are judged to have normal weight; those with BMI
≥25 are considered overweight, and those with BMI ≥30 are desig-
nated obese. The latter category can further be separated into obese
class I (30–​<35), class II (35–​<40) and class III (≥40). Currently the
same categories are used for men and women and all ethnicities. It
will be important to determine whether the standard WHO BMI clas-
sifications for adults are universally applicable to diverse populations
in predicting cancer risk. The criteria used to define overweight and
obesity in children are discussed later in the chapter.
The two major disadvantages of BMI are that it does not specify
where the fat is located, nor does it account for variations in lean body
mass. The location of fat is important, because accumulation around
the waist (abdominal obesity, or “apple-​shape”) is more closely related
to metabolic syndrome than is excess fat distributed on the hips and
thighs (“pear-​shape”) (Lebovitz, 2003). Moreover, visceral adipose
tissue (VAT) that accumulates inside the peritoneum is a more potent
cause of insulin resistance and metabolic syndrome than subcutaneous
adipose tissue (SAT) located beneath the skin (Donohoe et al., 2011;
Riondino et al., 2014). The extent to which studies that rely on BMI
alone may misclassify visceral obesity is illustrated by MRI images
that show wide variation in fat deposits around organs such as the
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352 PART III:  THE CAUSES OF CANCER
liver, pancreas, and kidney in individuals with the same BMI (Thomas
et al., 2012).
The dependence of BMI on assumptions about lean body mass is
also important, particularly for the elderly, males, African Americans,
and highly muscled individuals. In the elderly, variations in weight
(and thus BMI) are substantially affected by the loss of lean body
mass (Willett, 2013). Furthermore, for a given BMI, percent body fat
is usually lower in men than in women (Gallagher et al., 1996; Garn
et al., 1986; Hu, 2008a), and lower in blacks but higher in Asians than
in whites (Deurenberg et al., 2002; Hu, 2008a). Consequently, varia-
tions in the risk of adiposity-​related cancers in people with the same
BMI level may partly reflect variation in lean body mass by age, sex,
and race.
In many large epidemiologic studies, BMI is calculated using
self-​reported height and weight, rather than technician-​measured
height and weight. Due to individuals’ tendency to overreport height
and underreport weight (Willett, 2013), BMI calculated from self-​
reported data may be underestimated, which could lead to an under-
estimation of obesity prevalence. However, self-​reported BMI is
highly correlated with measured BMI (r > 0.90) with a relatively
small mean difference (Willett, 2013). Thus, measurement error
in BMI does not introduce substantial bias in epidemiologic mea-
sures of association, at least for young and middle-​aged adults, and
the accuracy of BMI based on self-​reported data is considered suf-
ficient to investigate the relationship between adiposity and cancer
(Willett, 2013).
Waist Circumference (WC) and
Waist-​to-​Hip Ratio (WHR)
Waist circumference (WC) and waist-​to-​hip ratio (WHR) are other
measures commonly used in large epidemiologic studies to reflect
central adiposity and intra-​abdominal visceral fat. As noted earlier,
abdominal obesity and visceral fat are metabolically more detrimen-
tal than fat distributed on the hips and thighs (Donohoe et al., 2011;
Lebovitz, 2003; Riondino et al., 2014).
WC is measured at the midpoint between the lowest rib margin and
the iliac crest (i.e., top of hip), roughly in line with the umbilicus.
WHR further accounts for frame size by dividing WC by hip cir-
cumference, which is typically measured at the widest circumference
around the buttocks. The US Department of Agriculture recommends
maintaining WC ≤40 inch (102 cm) for men and ≤35 inch (88 cm) for
women; the recommendations for WHR are ≤0.95 for men and ≤0.88
for women (US Department of Agriculture, 1990). As is the case with
BMI, the recommended cutpoints are currently the same for men and
women of all ethnicities.
Both WC and WHR are more pertinent to abdominal adiposity than
BMI (Hu, 2008a) and thus are increasingly used in epidemiologic
research. Furthermore, WC is generally preferred over WHR for sev-
eral reasons. First, WHR requires measures of both waist and hip cir-
cumference and is therefore more burdensome for study participants
and more subject to measurement error. Second, the interpretation of
WHR is complicated, since hip circumference reflects not only fat
mass but also gluteal muscle mass and bone structure. A high WHR
may indicate increased abdominal obesity and/​ or reduced gluteal
muscle mass (Hu, 2008a). Third, when WC and WHR were compared
with total abdominal fat as measured by CT, the correlation was stron-
ger for WC (r = 0.90–​0.91) than for WHR (r = 0.60–​0.73) (Clasey
et al., 1999).
However, when used alone, WC also has limitations. Like BMI,
WC cannot distinguish visceral from subcutaneous fat (Willett,
2013), and individuals with the same WC may have very different
amounts of VAT (Thomas et  al., 2012). Second, study participants
tend to underreport WC, especially since the location of the waist is
less clearly demarcated than is the calculation of BMI. Despite these
limitations, the correlation between self-​reported WC and technician-​
measured WC was generally high (r = 0.7–​0.9) in validation studies
(Hu, 2008a). There is some evidence that BMI and WC measured
together may provide complementary information about VAT. At least
one study has shown that the combination of BMI and WC explains
a greater proportion of variability in VAT than either alone (Janssen
et al., 2002).
Timing of Weight Change
The age at which study participants gain or lose weight is of great
interest in epidemiologic studies. Excess body weight in childhood
reflects exposure during a critical period of development and suscep-
tibility. Weight gain in adulthood reflects the cumulative increase in
fat mass over several decades. Weight loss during the most recent 10–​
15 years may indicate involuntary rather than voluntary weight loss.
Involuntary weight loss can be caused either by the condition being
studied (reverse causation), or wasting due to age or illness. Either can
mimic a protective effect of excess weight. This issue has not been
thoroughly studied with respect to the conditions that cause it and
the time period over which it occurs, complicating studies of weight
change and disease.
Adult Weight Gain
Although there is wide variability among individuals, adults gain
weight at an average of 0.5 kilograms annually (Malhotra et al., 2013).
Weight gain in adults largely represents the accumulation of abdomi-
nal fat, especially in men (Ballard-​Barbash, 1994). Because the weight
gain usually reflects increases in fat rather than lean body mass, it pro-
vides a longitudinal marker of the trajectory in fat mass during the
decades when most adult cancers develop. People can usually remem-
ber their approximate weight at the end of adolescence (i.e., between
ages 18 and 25  years). This can be compared to their weight at the
time of enrollment into an epidemiologic study. Weight change during
other periods of life, such as before and after menopause or during
the previous 10  years, is also potentially informative. The potential
for measurement error increases with the number of measurements.
Underreporting of weight tends to be larger when recalled for periods
earlier in life than self-​reported current weight. The extent of underre-
porting is greater among women than men and increases with increas-
ing current weight (Niedhammer et al., 2000; Palta et al., 1982; Perry
et al., 1995; Stevens et al., 1990). Despite these problems, self-​reported
information on weight and weight gain is informative in epidemiologic
research (Hu, 2008a; Willett, 2013). Subjects who underreport their
weight are likely to do so for both current and past weight, partially
offsetting the error.
Adiposity in Early Life
Emerging evidence suggests that excess body fat in early life (i.e.,
in childhood and adolescence, ages 2–​19  years) may be especially
important for the risk of developing certain cancers later in life.
Anthropometric classification is more complicated for children and
adolescents than for adults, however, since the categories are based
on age-​and sex-​specific distributions, rather than absolute cutoffs,
to account for growth (Hu, 2008b; Krebs et al., 2007). In the United
States, growth charts for children and adolescents are published by
the Centers for Disease Control and Prevention (CDC) (Centers for
Disease Control and Prevention, 2015). National data for the year
2000 are used as the reference, with individuals at <5th percentile of
the BMI for age and sex classified as underweight, at 5th–​84.9th per-
centile as normal weight, at 85th–​94.9th percentile as overweight, and
≥95th percentile as obese (Centers for Disease Control and Prevention,
2015). The CDC categories for overweight and obesity in children do
not correspond exactly to the BMI categories for adults when applied
to adolescents. Some adolescents who would be classified as over-
weight by the adult BMI categorization (25≤ BMI <30) would not
meet the CDC criterion for overweight in children (85th–​94.9th per-
centile for age and sex) (Hu, 2008b).
Assessment of Childhood Adiposity.  Since it is usually dif-
ficult for adults to recall their weight during childhood, an alternative
approach is to use a visual aid, such as a pictogram, that depicts dif-
ferent body shapes. For example, Stunkard and colleagues developed
 35

Obesity and Body Composition 353

a set of nine images, ranging from underweight to obese, from which
study participants can choose the image that corresponds most closely
to the shape they recall from childhood (Stunkard et al., 1983). In a
validation study of adults ages 71–​76 years, the correlation between
recalled body shape at early ages (e.g., 5, 10, and 20), assessed by the
pictogram, and measured BMI at approximately the same ages ranged
between 0.60 and 0.75 (Must et al., 1993). Analyses of body size in
childhood based on pictograms have identified associations with can-
cer (Baer et  al., 2010; Fagherazzi et  al., 2013; Palmer et  al., 2007;
Suzuki et al., 2011; Weiderpass et al., 2004; Zhang X et al., 2015a).
United States, using CDC Growth Charts from 2000, the prevalence of
overweight children and adolescents aged 2–​19 years increased from
9.2% in 1980 to 14.9% in 2012, and the prevalence of obesity tripled,
from 5.5% to 16.9% (Figure 20–​2) (Fryar et  al., 2014a). Globally,
across a similar time period, the prevalence of overweight and obesity
increased from 10% to 14% (Ng et al., 2014). These trends potentially
affect cancer rates in two ways. First, childhood and/​or adolescent adi-
posity may have a direct impact on carcinogenesis through metabolic
and hormonal influences during a susceptible developmental period.
Second, obesity in early life correlates strongly with excess adiposity
in adulthood as populations age (Cunningham et al., 2014).

EPIDEMIOLOGY OF EXCESS BODY WEIGHT

The prevalence of overweight and obesity has been increasing world-
wide, beginning in high-​income, English-​speaking countries in the
early 1970s and subsequently in many other industrialized and/​or
middle-​income countries (Ng et al., 2014). Excess body fat also affects
subgroups of the population in low-​income countries where overnutri-
tion coexists with famine. Globally, the prevalence of BMI levels ≥25
increased from 28.8% to 36.9% in men and from 29.8% to 38.0% in
women from 1980 to 2013 (Ng et al., 2014).
The patterns of weight gain vary in severity as well as timing among
countries. In the United States, the prevalence of BMI ≥25 increased
from 56% in 1980 to 69% in 2012, with all of the increase in adults
occurring in the obese category of BMI >30 (Figure 20–​1) (Fryar
et al., 2014b). The prevalence of obesity increased by approximately
8% per decade from 1980 to 2000. While the overall prevalence of
obesity in adults appears to have stabilized at about 35.5% in men in
the United States in the last 10 years (Flegal et al., 2002, 2010, 2012,
2016), it has continued to increase in women, reaching 40.4% in 2014
(Flegal et al., 2016).The greatest proportional increase has been in the
prevalence of severe obesity (Class III).
In certain geographic regions, such as among men and women in
some Pacific Islands and women in several Middle Eastern coun-
tries, the estimated prevalence of obesity exceeds 50% (Ng et  al.,
2014). Except in the United States, the increase has been greater for
overweight than for obesity. Currently, more than two-​thirds (69%)
of adults in the United States are overweight or obese, compared to
over one-​third (38%) globally. In 2014, an estimated 1.9 billion adults
worldwide had a BMI ≥25. Nearly one-​third of these (about 600 mil-
lion adults) were obese, including about 11% of men and 15% of
women (WHO, 2015).
Secular increases in adiposity also have occurred among child-
ren and adolescents in the United States and internationally. In the
TYPES OF CANCER CAUSED BY EXCESS ADIPOSITY
Obesity is associated with increased risk of multiple types of cancer.
Several organizations, including the International Agency for Research
on Cancer (IARC), the World Cancer Research Fund/​American Institute
for Cancer Research (WCRF/​AICR), and the National Institutes of
Health (NIH), have periodically evaluated the evidence regarding spe-
cific cancer sites in relation to excess body fat. The WCRF/​AICR and
the IARC classify the evidence as “definite” that obesity is causally
related to cancers at 10 anatomic sites: female breast (postmenopausal),
colorectum, endometrium, esophagus (adenocarcinomas), gallbladder,
kidney (renal cell), pancreas, gastric cardia, liver, and ovary (Table
20–1). For cancer of the prostate (advanced), the WCRF/​AICR classi-
fies the evidence as “definite” (WCRF/​AICR, 2014b), while the most
recent IARC report includes multiple myeloma, thyroid cancer, and
meningioma (Lauby-​Secretan et al., 2016). Obesity is considered as a
“possible” causal factor for leukemia and lymphoma. The associations
with cervix, lung, melanoma, and bladder have not been classified.
Compared to BMI, which reflects both lean and fat mass, adult
weight gain largely reflects an increase in body fat independent of
BMI, and thus may better reflect adiposity and its metabolic conse-
quences. Weight gain commonly occurs throughout early and middle
adulthood in Western societies, and this measure is associated with
several cancers. As noted earlier, the distribution of body fat is also
thought to affect the metabolic consequences of adiposity. Measured
by WC or WHR, higher abdominal adiposity in adulthood is associ-
ated with several cancers.
The relationship between obesity in early life (i.e., in utero or dur-
ing childhood and adolescence) and subsequent cancer risk, inde-
pendent of adult weight, is of considerable research interest. Obesity
18

16
40
14
Age-adjusted Prevalence (percent)

35
Prevalence (percent)

12
30
10
25
8
20
6
15
4
10
2
5
0
0
74

80

94

00

02

04

06

08

10

12
19

19

19

20

20

20

20

20

20

20
74

2
98

99

00

00

00

00

00

01

01

–
19

71

76

88

99

01

03

05

07

09

11
–1

–1

–2

–2

–2

–2

–2

–2

–2
–

19

19

19

19

20

20

20

20

20

20
71

76

88

99

01

03

05

07

09

11
19

19

19

19

20

20

20

20

20

20

Years
Years
Overweight Obese
Overweight Obese

Figure  20–​2.  Prevalence of overweight and obesity among children and

Figure 20–​1.  Age-​adjusted prevalence of overweight and obesity among adolescents aged 2–​19 years: United States (1971–​2012).
adults aged 20–​74: United States (1971–​2012). Source: Fryar et al. (2014a).
Source: Fryar et al. (2014b).
354

354 PART III:  THE CAUSES OF CANCER

in childhood has similar metabolic consequences to exposure in
adulthood, but these occur during a critical developmental period.
Given the long delay between the initiation of many exposures and
the diagnosis of an invasive cancer, it is plausible that obesity that
begins in childhood or adolescence may independently affect cancer
risk later in life.
The evidence linking excess body weight and body composition to
individual cancer sites is discussed in detail in the site-​specific chapters
in this volume. In the following, we summarize for specific cancers the
associations with adult adiposity, weight gain, body fat distribution,
and early life adiposity.
Cancers Definitely Caused by Excess Adiposity
Female Breast (Postmenopausal)
Adiposity Measured After Menopause.  Numerous obser-
vational studies have established that excess body fat affects breast
cancer risk, and that this effect varies depending on the timing of
adiposity in relation to menopausal status. Women with a high BMI
after menopause have increased risk of postmenopausal breast can-
cer, specifically ER+/​PR+ tumors (positive for estrogen receptor
[ER] and progesterone receptor [PR]). The opposite relationship
exists for premenopausal women, in whom a high BMI decreases
the risk of premenopausal breast cancer (WCRF/​AICR, 2010a) (see
Chapter 45).
In postmenopausal women, a 5  kg/​m2 increase in BMI increases
breast cancer incidence by about 13% (95% CI:  1.08, 1.19)
(Table 20–​1), based on a systematic review of prospective cohort stud-
ies in which height and weight were self-​reported or measured (WCRF/​
AICR, 2010a). This positive relationship was confirmed in a secondary
analysis of postmenopausal women in the Women’s Health Initiative
(WHI) clinical trials, where weight and height were measured at base-
line and annually. The WHI trial protocol also required mammography,
thereby minimizing the possibility of ascertainment bias (Neuhouser
et al., 2015). Postmenopausal women with a BMI higher than 35 had
58% (95% CI: 1.40, 1.79) higher risk of invasive breast cancer, com-
pared to women with a BMI less than 25.
Childhood and Premenopausal Adiposity. In contrast,
women who were most overweight during childhood and adolescence,
compared to those who were lean, have 20%–​50% lower risk of both
premenopausal (Baer et  al., 2010; Fagherazzi et  al., 2013; Palmer
et  al., 2007; Suzuki et  al., 2011; Weiderpass et  al., 2004)  and post-
menopausal (Baer et al., 2010; Fagherazzi et al., 2013; Kawai et al.,
2010; Palmer et al., 2007; Suzuki et al., 2011; van den Brandt et al.,
1997) breast cancer. This association persists with adjustment for adult
BMI, suggesting that an independent, lifelong reduction in risk occurs
among girls who are overweight. The inverse association is apparent
for both ER+ and ER–​breast cancer (Baer et al., 2010). Although most
studies were conducted among Caucasian women (Ahlgren et  al.,
2004; Baer et al., 2010; Fagherazzi et al., 2013; Hilakivi-​Clarke et al.,
2001; van den Brandt et al., 1997; Weiderpass et al., 2004), this inverse
association has been confirmed in African American (Bandera et al.,
2013; Palmer et  al., 2007), Hispanic (Sangaramoorthy et  al., 2011),
and Asian (Kawai et al., 2010; Suzuki et al., 2011) women.
In a systematic literature review and dose-​response meta-​analysis
of cohort studies published in 2008 by the WCRF/​AICR, relative risk
(RR) of breast cancer decreased with higher BMI in premenopausal
women (RR = 0.93; 95% CI: 0.88, 0.98 with a 5 kg/​m2 increase in
BMI). Lower BMI was characterized as a “convincing” risk-​reduc-
ing factor (WCRF/​AICR, 2008). This conclusion was upheld in a
subsequent meta-​analysis of 16 studies conducted the WCRF/​AICR
Continuous Update Project, which reported a significant 3% decrease
in risk per 2 kg/​m2 increase in BMI (WCRF/​AICR, 2010a).
The inverse relationship between excess body fat and risk of pre-
menopausal breast cancer does not alter the recommendation that
women should maintain a healthy body weight throughout life. Excess
adiposity in childhood increases the likelihood of obesity in adulthood,
as well as increasing the risk of multiple obesity-​related diseases. It
is extremely difficult for most people to lose substantial amounts of
weight voluntarily and then maintain this weight loss.
Weight Gain During Adulthood.  Weight gain that occurs
after age 18  years is also consistently associated with higher risk
of postmenopausal breast cancer (Table 20–​2) (Ahn et  al., 2007;
Alsaker et  al., 2013; Eliassen et  al., 2006; Feigelson et  al., 2004;
Kawai et  al., 2010; Keum et  al., 2015; Krishnan et  al., 2013;
Lahmann et  al., 2005; Palmer et  al., 2007; Radimer et  al., 2004;

Table 20–​1. Association Between Adiposity and Specific Cancers, RR (95% CI) per 5 kg/​m2 Increase in BMI

Cancer Type Association RR (95% CI) Reference

Breast (postmenopausal) Definite 1.13 (1.08, 1.19) (WCRF/​AICR, 2010a)

Colorectum Definite 1.10 (1.05, 1.16) (WCRF/​AICR, 2011)
Endometrium Definite 1.50 (1.42, 1.59) (WCRF/​AICR, 2013)
Esophagus (adenocarcinoma) Definite 1.48 (1.35, 1.62) (WCRF/​AICR, 2016b)
Gallbladder Definite 1.25 (1.15, 1.37) (WCRF/​AICR, 2015a)
Kidney (renal cell) Definite 1.30 (1.16, 1.46) (WCRF/​AICR, 2015b)
Pancreas Definite 1.10 (1.07, 1.14) (WCRF/​AICR, 2012)
Gastric cardia Definite 1.23 (1.07, 1.40) (WCRF/​AICR, 2016a)
Liver Definite 1.30 (1.16, 1.46) (WCRF/​AICR, 2015c)
Ovary Definite 1.06 (1.03, 1.11) (WCRF/​AICR, 2014c)
Prostate (advanced) Definite* 1.08 (1.04, 1.12) (WCRF/​AICR, 2014b)
Multiple myeloma Definite* 1.12 (1.07, 1.18) (Wallin and Larsson, 2011)
Thyroid Definite* 1.06 (1.02, 1.10) (Kitahara et al., 2016)
Meningioma Definite* Obese =1.51 (1.25, 1.82)^ (Niedermaier et al., 2015)
Leukemia Possible 1.13 (1.07, 1.19) (Larsson and Wolk, 2008)
Lymphoma Possible HL: Obese = 1.41 (1.14, 1.75)^ (Larsson and Wolk, 2011)
NHL: 1.07 (1.04, 1.10)
Cervix Inconsistent (Lacey et al., 2003)
Lung Inconsistent (WCRF/​AICR, 2007)
Melanoma Inconsistent (Sergentanis et al., 2013)
Bladder No association (WCRF/​AICR, 2007)

* Designations of “definite*” correspond to cancers determined to be causally related to obesity by either WCRF/​AICR or IARC, but not by both organizations.
^ Association with BMI was non-​linear, with no increased risk observed among overweight
 35
Obesity and Body Composition 355
Table 20–​2. Summary of Meta-​analysis Findings on the Association of Cancer Risk with Weight Gain (per 5 kg) from Young Adulthood
(Age 18–​25 Years) to Study Enrollment
Cancer Type RR (95% CI)
Breast (postmenopausal) Overall: 1.08 (1.06, 1.10)
MHT users: 1.01 (0.99, 1.02)
MHT non-​users: 1.11 (1.08, 1.13)
Endometrium Overall: 1.16 (1.12, 1.20)
MHT users: 1.09 (1.02, 1.16)
MHT non-​users: 1.39 (1.29, 1.49)
Ovary 1.02 (0.96, 1.09)
Colorectum Overall: 1.04 (0.99, 1.09)
Women: 1.01 (0.96, 1.08)
Men: 1.09 (1.01, 1.18)
Pancreas 1.40 (1.13, 1.72)*
Prostate Overall: 0.98 (0.94, 1.02)
Localized: 0.96 (0.92, 1.00)
Advanced: 1.04 (0.99, 1.09)
Abbreviation: MHT = menopausal hormone therapy
*The estimate was calculated by comparing BMI gain of >10 kg/​m2 to BMI change ≤2 kg/​m2 in a pooled analysis of 14 cohort studies.
Sweeney et al., 2004; van den Brandt et al., 1997; White et al., 2012).
In a recent meta-​analysis, each 5 kg of adult weight gain was associ-
ated with an 11% (95% CI: 1.06, 1.13) increase in risk of postmeno-
pausal breast cancer (Keum et al., 2015). The association with adult
weight gain is stronger for tumors that are ER+/​PR+ than for ER–​/​
PR–​tumors (Alsaker et al., 2013; Kawai et al., 2010; Tamimi et al.,
2012; Vrieling et al., 2010). Weight gain in later adulthood, specifi-
cally after menopause, is also associated with postmenopausal breast
cancer risk (Eliassen et al., 2006).
For premenopausal breast cancer, although a high BMI at age 18
is inversely associated with risk, it is not clear how additional weight
gain before menopause affects this risk. An increased risk has been
reported for short-​term weight gain (i.e., over 4 years) during premen-
opausal adulthood, particularly for ER+/​PR–​and ER–​/P ​ R–​tumors
(Rosner et al., 2015). Other studies have not found an association with
weight gain or loss before menopause (Lahmann et al., 2005; Michels
et al., 2012; Palmer et al., 2007).
Effect Modification by  Menopausal Hormone
Therapy.  Numerous observational studies have suggested that the
association between obesity and increased breast cancer risk among
postmenopausal women may be limited to those who have never taken
menopausal hormone therapy (MHT) (reviewed in Kabat et al., 2015;
Munsell et al., 2014; WCRF/​AICR, 2008). This finding was not con-
firmed by the WHI clinical trials, however (Neuhouser et al., 2015).
Body Fat Distribution.  It is unclear whether the specific distri-
bution of body fat affects breast cancer risk, beyond its contribution to
total fat mass. In a meta-​analysis of seven cohorts of postmenopausal
women, higher WC was associated with an increased risk of breast
cancer (RR = 1.07; 95% CI: 1.04, 1.10 per 8 cm increase) in analyses
not adjusted for BMI (WCRF/​AICR, 2010a). However, in three stud-
ies, adjustment for BMI attenuated this association (RR = 1.04; 95%
CI: 1.00, 1.06). The contribution of fat mass to estrogen synthesis in
postmenopausal women is not thought to depend on its location in the
body, unlike the greater effect of abdominal obesity on insulin and
other metabolic peptide hormones.
Colorectum
Adult Adiposity. In a meta-​analysis published by the WCRF/​
AICR, colorectal cancer risk increased by 10% (95% CI: 1.05, 1.16)
for every 5 kg/​m2 increase in adult BMI, with slightly stronger associa-
tions observed for men than for women (Table 20–​1) (WCRF/​AICR,
2011). The association was also stronger for colon cancer (per 5 kg/​m2
increase RR  =  1.16; 95% CI:  1.10, 1.22) than for rectal cancer
(RR = 1.10; 95% CI: 1.05, 1.16).
Reference
(Keum et al., 2015)
(Aune et al., 2015b; Keum et al., 2015)
(Aune et al., 2015a)
(Chen Q et al., 2014)
(Genkinger et al., 2011)
(Moller et al., 2013)
Adult Weight Gain. Weight gain between early and middle
adulthood (usually somewhere between ages 30 and 65 years) is con-
sistently associated with higher risk of colorectal cancer in observa-
tional studies (Table 20–​2) (Aleksandrova et al., 2013; Bassett et al.,
2010; Hughes et al., 2011; Laake et al., 2010; Oxentenko et al., 2010;
Renehan et al., 2012; Song et al., 2015b; Steins Bisschop et al., 2014;
Thygesen et al., 2008). Like the association with BMI, this relation-
ship is stronger in men than in women (Bassett et al., 2010; Hughes
et  al., 2011; Laake et  al., 2010; Renehan et  al., 2012; Song et  al.,
2015b) and for colon than for rectum cancer (Aleksandrova et  al.,
2013; Hughes et al., 2011; Laake et al., 2010; Renehan et al., 2012;
Steins Bisschop et al., 2014). It is especially stronger for tumors in the
distal rather than in the proximal colon (Bassett et al., 2010; Laake
et al., 2010; Oxentenko et al., 2010). Weight gain at older ages (after
mid-​life) has not been associated with colorectal cancer risk, although
the number of studies is limited (Karahalios et al., 2015; Song et al.,
2015b).
Body Fat Distribution.  While weight and weight gain are posi-
tively associated with colorectal cancer, the association with abdomi-
nal adiposity is particularly strong. Risk increases by 3% (95%
CI: 1.02, 1.04) per 2.5 cm increase in WC. This association persists in
analyses adjusted for BMI (WCRF/​AICR, 2011). Similarly, WHR is
positively associated with risk of colorectal cancer. Risk increases by
17% (95% CI: 1.09, 1.25) per 0.1 increase in WHR. Furthermore, the
association with adult weight gain is particularly strong in women who
also increase their WC (Aleksandrova et al., 2013; Song et al., 2015c),
supporting an adverse effect of abdominal adiposity on colorectal can-
cer. The stronger association with adiposity for men than for women
may relate to gender differences in fat distribution, given that men are
more likely to accumulate intraabdominal fat than women (Despres,
2006; Geer and Shen, 2009).
Early Life Adiposity.  While adult obesity is an established risk
factor for colorectal cancer, few studies have examined the association
between body size in early life and colorectal cancer risk in adulthood.
In the most recent, and largest, analysis of two prospective cohorts,
body fatness in childhood and adolescence was associated with
increased risk of colorectal cancer in women, but not men (Zhang X
et al., 2015a). Specifically, compared to the smallest body size, as mea-
sured by somatotype pictogram (Stunkard et al., 1983), women who
were in the top category of body fatness in childhood had a 28% (95%
CI: 1.04, 1.58) higher risk of developing colorectal cancer. The asso-
ciation between childhood body size and colorectal cancer was inde-
pendent of adult BMI. Excess body fat in childhood is also positively
associated with colorectal adenomas among women, independent of
adult BMI (Nimptsch et al., 2011a).
356
356 PART III:  THE CAUSES OF CANCER
Endometrium
Adult Adiposity.  The association of excess adiposity with endo-
metrial cancer is among the strongest and most consistent relationships
between body fat and any cancer. Each 5 kg/​m2 increase in adult BMI
results in a 50% (95% CI: 1.42, 1.59) increase in the incidence of uter-
ine cancer (Table 20–​1) (WCRF/​AICR, 2013). Mendelian randomiza-
tion analyses have reported positive associations between genetic risk
scores for BMI and the risk of endometrial cancer (Nead et al., 2015;
Prescott et al., 2015).
Adult Weight Gain.  Endometrial cancer is also strongly asso-
ciated with adult weight gain (Canchola et  al., 2010b; Chang et  al.,
2007; Dougan et al., 2015; Friedenreich et al., 2007; Han et al., 2014;
Jonsson et al., 2003; Nagle et al., 2013; Park et al., 2010). This asso-
ciation is stronger in women who do not use MHT than in those who
do (Table 20–​2) (Keum et  al., 2015)  and is stronger for endometri-
oid cancer than for other histologic subtypes (Nagle et  al., 2013).
Corroborating the dominant effect of adiposity in later life, most stud-
ies have shown that the positive association of BMI at age 18–​20 years
with endometrial cancer risk is substantially weakened in analyses that
adjust for current BMI (Canchola et  al., 2010b; Chang et  al., 2007;
Dal Maso et al., 2011; Dougan et al., 2015; Levi et al., 1992; Swanson
et al., 1993; Xu et al., 2006; Yang et al., 2012).
Body Fat Distribution.  Abdominal adiposity, as measured by
WC, has been positively associated with endometrial cancer risk (per
5 cm increase, RR = 1.13; 95% CI: 1.08, 1.18), as has WHR (per 0.1
increase, RR = 1.21; 95% CI: 1.13, 1.29) (WCRF/​AICR, 2013). The
association with WC was not attenuated by adjustment for BMI, sug-
gesting that the distribution of the fat mass may independently affect
the risk of endometrial cancer.
Esophagus (Adenocarcinoma)
Adult Adiposity. Like the association between adiposity and
endometrial cancer, the association with esophageal adenocarcinoma
is particularly strong. For every 5 kg/​m2 increase in BMI, the risk of
esophageal adenocarcinoma increases by 48% (95% CI: 1.35, 1.62)
(WCRF/​AICR, 2016b). This association has been confirmed by a
Mendelian randomization analysis of a genetic risk score for BMI in
relation to the risk of esophageal adenocarcinoma (Thrift et al., 2014).
Body Fat Distribution.  Abdominal adiposity is more strongly
associated with esophageal adenocarcinoma than fat elsewhere on the
body. Many studies have reported strong positive associations between
WC and risk. A recent study of esophageal adenocarcinoma in Europe
found that the association with WC remained strong after adjustment
for BMI, whereas the association with BMI was largely attenuated
by adjustment for WC (Steffen et al., 2015). The higher incidence of
esophageal cancer incidence in men than women may partly reflect the
greater prevalence of abdominal adiposity in men (Lagergren et  al.,
1999; Singh et al., 2013).
Gallbladder
Adult Adiposity. A meta-​analysis of eight studies, included in
the WCRF/​AICR report, showed a significant positive association
between BMI and gallbladder cancer (WCRF/​AICR, 2015c). Risk
increased by 25% (95% CI: 1.15, 1.37) per 5 kg/​m2 increase in BMI.
The association was similar in men and women. There are limited data
on the association of weight gain and body fat distribution with gall-
bladder cancer.
Kidney (Renal Cell)
Adult Adiposity.  A meta-​analysis of 23 studies found that each
5  kg/​m2 increase in BMI in adulthood was associated with a 30%
increase (95% CI:  1.25, 1.35) in the risk of renal cell carcinoma
(WCRF/​AICR, 2015b).
Adult Weight Gain. Adult weight gain has been associated
with a higher risk of renal cell cancer in several studies (Adams et al.,
2008; Chow et al., 2000; Luo et al., 2007; van Dijk et al., 2004), espe-
cially among individuals with a low BMI in adolescence (Adams
et al., 2008).
Body Fat Distribution. WC is associated with higher risk of
renal cell carcinoma independent of BMI. Each 10 cm increase in WC
is associated with an 11% increase in the risk of renal cell carcinoma
(95% CI:  1.05, 1.19) in analyses adjusted for BMI (WCRF/​AICR,
2015b). WHR also is positively associated with risk (per 0.1 increase,
RR  =  1.26; 95% CI:  1.18, 1.36), with no attenuation observed after
adjustment for BMI.
Pancreas
Adult Adiposity.  Higher BMI is positively associated with pan-
creatic cancer risk (per 5 kg/​m2 increase, RR = 1.10; 95% CI: 1.07,
1.14). This association is similar for men and women (WCRF/​
AICR, 2012).
Adult Weight Gain.  Although overweight and obesity throughout
adulthood are associated with both increased risk of pancreatic cancer
and younger age at diagnosis (Genkinger et  al., 2011; Stolzenberg-​
Solomon et al., 2013), the influence of weight change on risk remains
unclear (Genkinger et al., 2011; Isaksson et al., 2002; Patel et al., 2005;
Stolzenberg-​Solomon et al., 2013). In a pooled analysis of 14 cohort
studies, study participants who gained ≥10  kg/​m2 between ages 18–​
21 years and age at enrollment had increased risk of pancreatic cancer
compared to those with BMI change ≤2 kg/​m2, as did those who lost
>2 kg/​m2 during this period (Genkinger et al., 2011). These associations
were adjusted for history of diabetes, and persisted even after excluding
cases diagnosed within the first 5 years of follow-​up. Further studies are
needed to better understand these associations.
Body Fat Distribution. In the WCRF/​AICR report, WC was
positively associated with pancreatic cancer risk. Risk increased by
11% (95% CI: 1.05, 1.18) per 10 cm increase in WC (WCRF/​AICR,
2012). A pooled analysis of cohort studies observed a similar, although
not statistically significant, increase in risk (RR = 1.16; 95% CI: 0.92,
1.46), but this was attenuated with adjustment for BMI (RR = 1.04;
95% CI:  0.73, 1.47) (Genkinger et  al., 2011). WHR was positively
associated with risk in both the WCRF/​AICR meta-​analysis (per 0.1
increase, RR = 1.19; 95% CI: 1.09, 1.31) and in the pooled analysis
of cohort studies (RR  =  1.35; 95% CI:  1.03, 1.78). Adjustment for
BMI did not attenuate this association in the pooled analysis. Further
replication of these findings is needed to determine whether abdominal
adiposity is a risk factor for pancreatic cancer, independent of general
adiposity.
Gastric Cardia
The WCRF/​AICR summary meta-​analysis found a significant positive
association between increasing BMI and risk of gastric cardia cancer,
but not non-​cardia gastric cancer. The relative risk increased by 23%
(95% CI: 1.07, 1.40) per 5 kg/​m2 increase (WCRF/​AICR, 2016a). The
association appeared to be non-​linear, with a greater increase in risk
observed at higher levels of BMI.
Liver
A meta-​analysis of 12 studies shows a positive association between
BMI and risk of hepatocellular carcinoma. The incidence rate
increased by 30% (95% CI: 1.16, 1.46) per 5 kg/​m2 increase in BMI in
men and women (WCRF/​AICR, 2015a). The meta-​analysis provided
evidence of non-​linearity, with risk increasing more steeply at higher
BMI levels.
 357
Obesity and Body Composition 357
Ovary
The combined evidence from 25 studies shows a modest positive
association between BMI and ovarian cancer risk, with a 6% (95%
CI: 1.02, 1.11) increase in risk per 5 kg/​m2 increase in BMI (WCRF/​
AICR, 2014c). Whether risk is associated with body fat distribution is
not clear (WCRF/​AICR, 2014c). Weight gain in adulthood has been
associated with risk of ovarian cancer in some (Canchola et al., 2010a;
Ma et al., 2013), but not most (Aune et al., 2015a; Fairfield et al., 2002;
Jonsson et al., 2003; Kotsopoulos et al., 2010; Lahmann et al., 2010;
Schouten et al., 2003) prospective studies.
Prostate (Advanced)
No significant association has been observed between BMI and the
overall incidence of prostate cancer (per 5 kg/​m2 increase, RR = 1.00;
95% CI: 0.97, 1.03). However, it may be that excess body weight
increases the risk of advanced prostate cancer, but decreases the risk
of non-​advanced tumors. The incidence of advanced prostate cancer
increases by 8% (95% CI: 1.04, 1.12) per 5 kg/​m2 increase in BMI, as
does the incidence of high-​grade prostate cancer (RR = 1.08; 95% CI:
1.01, 1.15) (WCRF/​AICR, 2014b). Weight gain is also associated with
increased risk of aggressive or fatal disease in some studies (Bassett
et  al., 2012; Keum et  al., 2015; Wright et  al., 2007), but not others
(Chamberlain et  al., 2011; Littman et  al., 2007; Moller et  al., 2013;
Rodriguez et al., 2007). Both WC and WHR are positively associated
with advanced prostate cancer (e.g., per 10 cm increase in WC, RR =
1.12; 95% CI: 1.04, 1.21), but not with total prostate cancer risk (RR =
1.01; 95% CI: 0.90, 1.12) (WCRF/​AICR, 2014b).
In contrast, an inverse association between excess body fat and
non-​advanced prostate cancers has been observed in multiple stud-
ies. In the WCRF/​AICR meta-​analysis, the risk of non-​advanced dis-
ease decreased by 5% (95% CI:  0.92, 0.98) per 5  kg/​m2 increase in
BMI (WCRF/​AICR, 2014a). Subsequent studies have confirmed this
inverse relationship with adult BMI (Moller et  al., 2016)  and adult
weight gain (Keum et al., 2015).
Multiple Myeloma
A meta-​analysis reported a significant positive association between
BMI and multiple myeloma, with a 12% (95% CI: 1.08, 1.16) increase
in risk per 5 kg/​m2 increase in BMI (Wallin and Larsson, 2011), and
the recent IARC report considers the evidence “sufficient” (Lauby-​
Secretan et al., 2016).
Thyroid
In a large pooled analysis of 22 prospective studies of thyroid cancer,
BMI was associated with an increased risk (per 5 kg/​m2, RR = 1.06;
95% CI: 1.02, 1.10), which was marginally stronger in men (RR = 1.17;
95% CI: 1.06, 1.28) than in women (RR = 1.04; 95% CI: 1.00, 1.09)
(Kitahara et al., 2016). The recent IARC report considers the evidence
“sufficient” for a causal association between adiposity and thyroid
cancer (Lauby-​Secretan et al., 2016).
Meningioma
The IARC also considers the evidence “sufficient” for a causal associa-
tion between adiposity and meningioma (Lauby-​Secretan et al., 2016),
with a meta-​analysis of six cohort studies reporting a significantly
increased risk for BMI ≥30 (RR  =  1.51; 95% CI:  1.25, 1.82). The
association with BMI was significantly non-​linear, with no significant
association observed with BMI 25–​<30 (Niedermaier et al., 2015).
Cancers Possibly Caused by Excess Adiposity
Accumulating evidence suggests possibly causal associations between
excess adiposity and leukemia (see Chapter 38) and lymphomas (see
Chapters 39, 40). In a meta-​analysis of nine cohort studies, a positive
association was reported between BMI and leukemia, with a 13% (95%
CI: 1.07, 1.19) increase in risk per 5 kg/​m2 increase in BMI (Larsson
and Wolk, 2008). For Hodgkin lymphoma, increased risk was observed
for BMI ≥30 (RR = 1.41; 95% CI: 1.14, 1.75), but the association was
non-​linear, with no apparent increase in risk among the overweight. For
non-​Hodgkin lymphomas, significant positive associations with BMI
were observed in a meta-​analysis (per 5kg/​m2 increase, RR = 1.14;
95% CI: 1.04, 1.26) (Larsson and Wolk, 2011). More recent analyses of
the UK Million Women Study reported associations between BMI and
both Hodgkin lymphoma and non-​Hodgkin lymphomas (Murphy et al.,
2013). Replication is needed to confirm or refute these associations.
Cancers Inversely Related to Excess Adiposity
Inverse associations have been reported between increasing adiposity
and cancers of the lung (sese Chapter 28), oral cavity (see Chapter 29),
and esophagus (squamous cell) (see Chapter 30). As yet, no biologi-
cally plausible mechanisms have been proposed to account for these
associations, which could plausibly reflect confounding or reverse
causation (WCRF/​AICR, 2007). Cancer at all of these sites is strongly
associated with tobacco use, and tumors could potentially interfere
with eating and/​or breathing. Indeed, a genetic risk score for obesity in
the GAME-​ON consortium was positively associated with lung can-
cer, suggesting that the observed inverse associations with BMI may
be non-​causal (Gao et al., 2016).
CANCERS ASSOCIATED WITH HEIGHT
Numerous studies have found that adult height is positively associated
with cancer risk. The UK Million Women Study represents the larg-
est prospective study on height and cancer. The analyses of height and
cancer included 1,297,124 women and 97,376 incident cancer cases
(Green et al., 2011). Total cancer risk increased by 16% for each 10 cm
increase in adult height. A positive association of height with total can-
cer incidence or mortality was observed for both men and women in a
meta-​analysis that included this study and 10 other prospective studies
(Green et al., 2011). The Million Women Study also examined the rela-
tionship separately for 17 cancer sites; significant positive associations
were observed with 10 anatomic sites (colon, rectum, melanoma, breast,
endometrium, ovary, kidney, central nervous system, non-​ Hodgkin
lymphoma, leukemia), accounting for multiple testing. The increase
in risk per 10  cm increase in adult height ranged from 14% for rec-
tal cancer to 32% for malignant melanoma. Subsequent meta-​analyses
reported positive associations with cancers of the pancreas (Aune et al.,
2012) and thyroid (Jing et al., 2015). Height has also been associated
with advanced or high-​grade prostate cancer (Giovannucci et al., 1997;
Zuccolo et al., 2008). Associations with adult height have generally not
been seen with smoking-​related cancers (Green et al., 2011).
The presence of similar associations with height across different
cancer sites suggests that a common underlying mechanism might be
involved. Adult height per se is unlikely to be the causative exposure.
It is more plausible that height reflects some underlying exposure that
may increase both height and cancer risk. Adult height is determined
by a complex interplay between inherited genetic traits and early-​life
environmental factors, including nutrition and/​or illness (Giovannucci
et al., 2004). Insulin-​like growth factor-​1 (IGF-​1) is known to influ-
ence adult height (Albanes, 1998; Giovannucci et al., 2004) and has
mitogenic and anti-​apoptotic hormonal effects (see later discussion in
this chapter for more detail) (Aaronson, 1991). IGF-​1 is influenced
by both genetic and nutritional factors. Thus, adult height has been
hypothesized to reflect circulating exposure to IGF-​1 in early life,
which modifies cancer risk later in life.
Although early-​life IGF-​1 level is more strongly associated with
leg length than other components of height, evidence supporting the
superiority of leg length compared to total height in predicting cancer
risk has not been consistent (Gunnell et al., 2001; Lawlor et al., 2003;
Mellemkjaer et al., 2012). Another potential mechanism involves the
greater number of cells in taller individuals, increasing the opportunity
to acquire genetic and epigenetic alterations that drive cancer develop-
ment (Albanes and Winick, 1988; Trichopoulos and Lipworth, 1995).
It is worth noting that lower adult height was associated with
increased risk of non-​cardia gastric cancer in the NIH-​AARP Diet and
Health Study (Camargo et al., 2015) and with head and neck cancer
358
358 PART III:  THE CAUSES OF CANCER
in a pooled analysis (Leoncini et  al., 2014). Biological mechanisms
underlying this inverse association are not clear, although short height
may be a marker of poor health status (e.g. infectious illness, poor
nutritional status) in early life.
EXPOSURE PARAMETERS THAT INFLUENCE RISK
Menopausal Hormone Therapy Use
As mentioned, the associations between obesity and both breast and
endometrial cancers in postmenopausal women vary in some studies
depending on MHT use (reviewed in Munsell et  al., 2014; WCRF/​
AICR, 2008; and Kabat et  al., 2015). Adipose tissue is the primary
source of estrogens after menopause in women who are not taking
MHT. For women who use exogenous hormones, however, MHT
could obscure the contribution of adipose tissue to circulating hor-
mone levels (Key et al., 2003). Thus, the effect of obesity on breast and
endometrial cancers would be easier to detect in women who do not
use MHT. If all of the studies supported this finding, it would strongly
implicate estrogen production by fat tissue as the principal mediator of
risk for endometrial and postmenopausal breast cancer. As mentioned,
however, the WHI clinical trials report did not support the hypothesis
of effect modification by MHT (Neuhouser et al., 2015).
Smoking
Tobacco use, especially cigarette smoking, is a major modifier of the
association between adiposity and cancer risk. This influence is thought
to involve multiple mechanisms that relate directly or indirectly to
smoking (Song and Giovannucci, 2016). First, smoking-​related can-
cers in general (particularly lung cancer and upper aerodigestive can-
cers) may be less likely to be obesity-​related cancers. Smokers have
proportionally more cancers of the lung and upper aerodigestive tract
than non-​smokers, and thus have proportionately fewer obesity-​related
cancers. Smoking is also a major cause of many illnesses (e.g., chronic
obstructive pulmonary disease) that can cause weight loss or limit
weight gain through pathophysiologic mechanisms. In epidemiologic
studies, this phenomenon would enrich the categories of lower weight
individuals with unhealthy individuals who suffer more severe conse-
quences of long-​term smoking. The cancer risk for these individuals
with low body weight may be different from that of normal healthy
lean individuals. Controlling for smoking may not fully eradicate
confounding because smokers who are lean may be unhealthier than
smokers who maintain a higher body mass. Such a scenario would
result in intractable residual confounding.
More broadly, smoking has direct consequences for body weight.
These relationships may be quite complex. Over the short term, the
nicotine from smoking increases energy expenditure and may reduce
appetite. This relationship may explain why smokers tend to have a
lower BMI than non-​smokers, though underlying illness also may
contribute. Furthermore, smoking cessation is frequently followed by
weight gain. For example, recent quitters in two large cohorts of men
and women had a 5.17 pound weight gain over a 4-​year period, con-
trolling for other factors (Mozaffarian et al., 2011). On the other hand,
among smokers, those who smoke heavily tend to have a higher BMI
than lighter smokers. This association is surprising given the effect of
smoking on energy expenditure and appetite suppression. A potential
explanation for this association is that heavy smokers have multiple
unhealthy behaviors, including poor diet, heavy alcohol intake, and
lower physical activity (Chiolero et  al., 2008). The combination of
these may offset the mechanisms by which smoking usually limits
weight gain.
A final consideration is that smoking is associated with central fat
accumulation, so that smokers are at increased risk of metabolic syn-
drome and insulin resistance. Smoking appears to increase the WHR,
independently of BMI; the phenotype of a high WHR with relatively
low BMI is more common in smokers than in non-​smokers (Chiolero
et al., 2008). In fact, smoking may be associated with increased VAT
by CT scan, even though BMI or traditional circumference measures
may not capture this relationship (Kim et  al., 2012). The relation
between smoking and visceral accumulation of adipose tissue, pos-
sibly mediated by an increase in cortisol, may account for the dose-​
dependent association between smoking and insulin resistance and
hyperinsulinemia (Cena et al., 2011).
Though the biologic underpinnings of these complex relationships
are incompletely understood, it is clear that adiposity in smokers dif-
fers from that in never-​smokers. The effects of smoking may involve
a mixture of traditional confounding, effect modification, and reverse
causation. Arguably, it may be unjustifiable to examine associations
between measures such as BMI or WC in relation to cancer in mixed
study populations of smokers and non-​smokers. Analyses that stratify
on smoking status are critical for obtaining valid information. This
is particularly true for cancer sites that are most strongly associated
with smoking, such as lung cancer, where either smoking or smoking-​
induced lung disease may cause weight loss. It is also true for other
cancers for which the metabolic consequences of smoking and excess
adiposity may overlap. Renehan and colleagues have noted that stron-
ger associations are observed between adiposity and various cancers
in non-​smokers (preferably never smokers) than in smokers (Renehan
et al., 2008).
EFFECT OF WEIGHT LOSS
Although excess body weight and weight gain are considered
causally related to at least seven types of cancer, the evidence
regarding whether weight loss reverses these risks is less certain.
Observational studies of weight loss and cancer are limited by the
relatively small number of people who have voluntarily lost sub-
stantial amounts of weight and have maintained this weight loss.
It is difficult to distinguish voluntary from involuntary weight loss
in observational studies (Birks et  al., 2012). Randomized trials of
dietary or exercise interventions with durations of 4–​12  months
have demonstrated favorable changes in metabolic biomarkers, but
have not yet confirmed any reduction in cancer risk. Surgical inter-
ventions effectively reduce weight, improve metabolic biomarkers,
and decrease the risk of type 2 diabetes and cardiovascular disease,
but have not yet provided a sufficient sample size to evaluate site-​
specific cancer risk. Thus, the data currently available to evaluate
the extent to which weight loss affects the risk of specific cancer
sites remain sparse and inconclusive.
Intentional Weight Loss
The results from observational studies of intentional weight loss and
cancer have been inconsistent. In the Iowa Women’s Health Study,
researchers compared cancer risk among women who reported inten-
tional weight loss of >20 pounds to that in women who reported never
achieving this level of voluntary weight loss. The incidence rate of
all cancer sites combined was 11% lower (HR = 0.89; 95% CI: 0.79,
1.00) among the women who reported this level of weight loss; breast
cancer risk was 19% lower (HR = 0.81; 95% CI: 0.66, 1.00); colon
cancer 9% lower (HR = 0.91; 95% CI: 0.66, 1.24); and endometrial
cancer 4% lower (HR = 0.96; 95% CI: 0.61, 1.52). The risk was lower
by 14% for all obesity-​related cancers combined (HR  =  0.86; 95%
CI: 0.74, 1.01) (Parker and Folsom, 2003). In contrast, two other stud-
ies reported no significant association between intentional weight loss
and risk of all-​cancer mortality (Williamson et al., 1999) except among
women with preexisting obesity-​related health conditions (Williamson
et al., 1995).
Other observational studies that have examined the relationship
between weight loss and colon cancer also characterized weight loss
by a single category, due to the limited number of cases. A statisti-
cally significantly lower risk of colon cancer associated with weight
loss was reported in only one (Rapp et  al., 2008)  of nine studies
(Aleksandrova et  al., 2013; Bassett et  al., 2010; Campbell et  al.,
2007; Han et  al., 2014; Hughes et  al., 2011; Laake et  al., 2010;
 359
Obesity and Body Composition 359
Oxentenko et al., 2010; Renehan et al., 2012; Steins Bisschop et al.,
2014). The study in which lower risk was observed (Rapp et  al.,
2008) found that weight loss of more than 0.1 kg/​m2 BMI per year
over 5–​9  years was associated with 50% lower risk of colon can-
cer in men after 9 years of follow-​up. No association was observed
in women, however. Recently, a detailed dose–​response analysis
of weight change in relation to risk of colorectal cancer used data
from two large prospective studies that compared weight in young
adulthood to current weight reported throughout 24–​34  years of
follow-​up (Song et  al., 2015b). Weight loss during adulthood was
associated with a suggestively lower risk of colorectal cancer in
men, but not women. Compared to men who maintained a stable
weight, those who lost 4–​8  kg and ≥8.0  kg between age 21  years
and baseline enrollment (median age = 52 years) had 27% and 39%
lower risk of colorectal cancer, respectively.
For postmenopausal breast cancer, weight loss has been associ-
ated with a decreased risk in some (Eliassen et  al., 2006; Harvie
et al., 2005) but not all (Teras et al., 2011) prospective studies. In the
Nurses’ Health Study, weight loss of ≥10 kg since menopause was
associated with a suggestive 23% decrease in risk (95% CI:  0.56,
1.08), although this was not statistically significant (Eliassen et al.,
2006). Weight loss of 10 kg or more among women who had never
used MHT was significantly associated with lower risk (HR = 0.63;
95% CI: 0.38, 1.05; p-​trend for weight loss = 0.04), as was sustained
weight loss of ≥10 kg of weight after menopause (HR = 0.43; 95%
CI:  0.21, 0.86; p-​trend for weight loss  =  0.01). Weight loss was
inversely associated with ER+/​PR+ tumors, whereas no associations
seen for ER–​/​PR–​ tumors.
Bariatric Surgery
Bariatric surgery is the most effective therapeutic approach for patients
with morbid obesity. Bariatric surgery has been shown to improve
metabolic biomarkers and reduce the risk of type 2 diabetes and car-
diovascular disease (Adams et al., 2012; Sjostrom et al., 2004, 2012).
Recent evidence from four observational studies (Adams et al., 2009;
Christou et al., 2004, 2008; McCawley et al., 2009) and one interven-
tion trial (Sjostrom et al., 2009) suggests that gastric bypass surgery
may decrease risk of all cancers combined. At this point, the studies
of surgical weight loss have insufficient follow-​up to assess effects
on individual cancer sites. In the largest observational study to date,
6,596 morbidly obese patients who underwent bariatric surgery had a
significantly lower total cancer incidence than their counterparts who
received conventional care (HR = 0.76; 95% CI: 0.65, 0.89) (Adams
et al., 2009). Similarly, cancer mortality was 46% lower in the patients
treated with surgery than in the controls (HR = 0.54; 95% CI: 0.37,
0.78). It is interesting that the reduction in mortality was seen for all
cancers combined, whereas the reduction in incidence was limited to
obesity-​related cancers (esophagus [adenocarcinoma only], colorec-
tal, pancreas, postmenopausal breast, corpus and uterus, kidney,
non-​Hodgkin lymphoma, leukemia, myeloma, liver, and gallbladder)
(Adams et al., 2009). These results were supported by three other stud-
ies (Adams et  al., 2007; Flum and Dellinger, 2004; Sjostrom et  al.,
2007) that reported reductions in all-​cause and all-​cancer mortality in
morbidly obese patients who received gastric bypass surgery, com-
pared to those who did not.
The Swedish Obese Subjects cohort, a prospective, controlled
intervention trial (Sjostrom et al., 2009), found that individuals who
had bariatric surgery had a hazard ratio of 0.67 (95% CI: 0.53, 0.85)
for overall incident cancers when compared to participants who
received conventional treatment. Of note, an interaction with gender
was observed:  bariatric surgery was associated with reduced cancer
incidence in obese women (HR = 0.58; 95% CI: 0.44, 0.77) but not
in obese men (HR  =  0.97; 95% CI:  0.62, 1.52). These results were
consistent with previous observational findings that lower cancer inci-
dence and mortality associated with gastric bypass surgery were seen
only in women (Adams et al., 2009), although surprisingly, in the latter
study breast cancer risk did not differ between the surgery and control
groups.
As the use of bariatric surgery continues to increase (Santry et al.,
2005) and larger numbers of participants can be followed for longer, it
will become feasible to assess the long-​term effects of surgical inter-
vention on specific cancer sites.
Changes in Biomarkers with Weight Loss
In randomized trials of dietary or exercise interventions with duration
of 4–​12 months, weight loss has produced favorable changes in a wide
range of metabolic biomarkers, as mentioned earlier. Changes have
been observed in the circulating levels of steroid hormones, inflam-
matory markers, and metabolic hormones, mostly in postmenopausal
women (Byers and Sedjo, 2011). For example, the levels of estradiol,
estrone, and testosterone decreased by 10%–​20% among individuals
who lost >2% of body fat (Campbell et al., 2012; Fabian et al., 2013;
Kaaks et al., 2003; McTiernan et al., 2004a, 2004b; van Gemert et al.,
2015). In contrast, sex hormone binding globulin levels were increased
after weight loss. These relationships appeared to be dose-​dependent,
with stronger associations with sex hormones with greater weight
loss. Reductions in inflammatory biomarkers have also been observed
after weight loss, with more consistent evidence for C-​reactive protein
(CRP) and interleukin-​6 (IL-​6) (Esposito et  al., 2003; Fabian et  al.,
2013; Harvie et al., 2011; Imayama et al., 2012; Madsen et al., 2008;
Ryan and Nicklas, 2004; Tchernof et al., 2002) than tumor necrosis
factor-​α (TNF-​α) (Fabian et al., 2013; Ryan and Nicklas, 2004). An
increase in adiponectin concentrations and decrease in leptin levels
have been observed with weight loss (Abbenhardt et al., 2013; Esposito
et al., 2003; Fabian et al., 2013; Madsen et al., 2008); some studies
suggest that >10% weight loss is needed to increase adiponectin levels
significantly (Fabian et  al., 2013; Madsen et  al., 2008). Weight loss
as low as 2.5%–​5% of body weight has been shown to lower insulin
levels and improve insulin sensitivity (Fabian et al., 2013; Kaaks et al.,
2003; Lofgren et  al., 2005; Mason et  al., 2011; Ryan and Nicklas,
2004). The evidence for IGF-​1 is inconsistent (Kaaks et  al., 2003;
Mason et al., 2013).
MECHANISMS OF CARCINOGENESIS
Various mechanisms have been proposed by which excess body fat
could affect cancer risk (Figure 20–​3). These can be classified broadly
as hormonal (endocrine) effects from both sex steroid hormones and
peptide metabolic hormones and the effects of chronic inflammation.
Systemic and local inflammation can result from the hormonal effects
of adipose tissue, or it can be caused by the chemical or mechanical
injury, as in the context of gastroesophageal reflux or chronic gall-
stones. The effects of obesity on metabolic hormones are thought
to affect multiple types of cancers. Effects on steroid hormones are
thought to be more specific, affecting breast and endometrial can-
cer (and perhaps prostate and colon as well); local inflammation has
been implicated at some, but not all, cancer sites. Fat cells secrete and
receive endocrine signals and are a major site for the metabolism of
sex steroids. It is difficult to separate the metabolic and endocrine
functions of adipose tissue, since these pathways overlap.
Metabolic Peptide Hormones
Insulin and IGF-​1
Insulin and IGF-​1 are closely related metabolic protein (peptide) hor-
mones that are thought to mediate some of the effects of excess body
fat on cancer risk. Excess adiposity, particularly visceral fat (Donohoe
et  al., 2011; Wajchenberg, 2000), induces insulin resistance. The
resulting hyperinsulinemia suppresses hepatic production of hormone
binding proteins (e.g., insulin-​like growth factor binding proteins
[IGFBPs]) (Kaaks et al., 2002a). This increases the concentration of
bioavailable IGF-​1, especially that which is not bound to IGFBP-​3
(van Kruijsdijk et al., 2009). The net consequence of excess adipos-
ity on metabolic hormones is to increase concentrations of circulating
360
360 PART III:  THE CAUSES OF CANCER
Aromatase
Excessive Free Fatty Acids
Calorie Central Leptin
Intake Adiposity
Adiponectin
Figure 20–​3.  Proposed mechanisms by which excess adiposity affects cancer risk.
insulin and bioavailable IGF-​1 (Kaaks et al., 2002a). Normal and can-
cerous cells express receptors for insulin and IGF-​1 (Pollak, 2008).
Peptide hormones such as insulin and bioavailable IGF-​1 promote car-
cinogenesis by enhancing cell proliferation and inhibiting apoptosis
(van Kruijsdijk et al., 2009). It should be noted that IGF-​1 elicits stron-
ger mitogenic and anti-​apoptotic responses than insulin. Insulin may
act primarily through enhancing the bioavailability of IGF-​1, rather
than through direct ligand activity (Nimptsch and Giovannucci, 2012).
Cancer cells may reactivate the expression of insulin receptor isoform
A, which is normally expressed primarily in embryonic/​fetal tissue.
The A  isoform is more mitogenic than the B isoform of the insulin
receptor, which is typically expressed in adults (Pandini et al., 2003).
Yu and Rohan have comprehensively reviewed the role of the IGF
family on cancer development and progression (Yu and Rohan, 2000).
Based on epidemiologic evidence, the insulin and/​or IGF-​1 pathways
appear to be particularly relevant to cancers of the colorectum, breast,
endometrium, and prostate.
Indirect evidence linking IGF-​1 to colorectal cancer comes from
the observation that taller individuals, who potentially had greater
exposure to IGF-​1 during adolescent growth, are consistently associ-
ated with an increased risk of colorectal cancer (Green et al., 2011).
Epidemiologic studies based on direct measurement of IGF-​1 are lim-
ited to measurements made in adults. Recent meta-​analyses of obser-
vational studies found that higher levels of circulating IGF-​1 levels in
adulthood are associated with an increased risk of both colorectal can-
cer (Rinaldi et al., 2010) and high-​risk adenomas (Yoon et al., 2015a).
Of note, adult IGF-​1 levels are an imperfect surrogate for adolescent
IGF-​1 levels. Whereas height is strongly correlated with IGF-​1 lev-
els in adolescence, it is only weakly correlated with levels in adults.
However, Yoon and colleagues have inferred that both early-​life and
later-​life IGF-​1 levels may contribute to the development and progres-
sion of colorectal cancer (Yoon et al., 2015b).
Strong evidence supports a role for insulin in colorectal carcino-
genesis. Studies of this issue have generally measured C-​peptide, a
marker of insulin secretion, rather than insulin itself, because the lon-
ger half-​life of C-​peptide provides a more accurate marker of insu-
lin activity. In a recent meta-​analysis of eight prospective studies,
higher C-​peptide levels were associated with an approximately 40%
increased risk of colorectal cancer (Chen et al., 2013). Furthermore,
an elevated risk of colorectal neoplasia is associated with disorders
that involve hyperinsulinemia, such as insulin resistance (as marked
by high HOMA-​IR or by hypertriglyceridemia) and diabetes mellitus
(Grundy, 1999; Yao and Tian, 2015; Yoon et al., 2015b). Interestingly,
in some studies, individuals who have elevations in both C-​peptide and
IGF-​1 levels have the same level of increased risk of colorectal cancer
as those who have elevated levels of only one biomarker (Wei et al.,
Bioavailable
Sex Hormones
SHBG
Insulin
Proliferation
Insulin
Resistance Apoptosis
IGFBPs
Bioavailable Genomic
IGF-1 Instability
Inflammation
2005; Wu et  al., 2011). This finding, if confirmed, suggests a com-
mon carcinogenic pathway shared by insulin and IGF-​1, whereby high
levels of either insulin or IGF-​1 may be sufficient to achieve maximal
effect. For example, colorectal cancer may possess hybrid insulin and
IGF-​1 receptors, which can be stimulated and saturated by either insu-
lin or IGF-​1.
Adult height is also associated with breast cancer risk (Zhang B et al.,
2015), potentially implicating the IGF-​1 pathway in the pathogenesis
of breast as well as colorectal cancer. The Nurses’ Health Study was
the first prospective study to examine prediagnostic concentrations of
circulating IGF-​1 in relation to breast cancer risk. A  strong positive
association was observed only in women who were premenopausal
at the time of blood collection (Hankinson et al., 1998). In contrast,
a pooled analysis of 17 prospective studies reported increased risk
of breast cancer in women with higher circulating IGF-​1 concentra-
tions, regardless of menopausal status at the time of blood collection.
In fact, the positive association was stronger among postmenopausal
than premenopausal women (Endogenous Hormones Breast Cancer
Collaborative Group, 2010). Both this analysis and a subsequent study
conducted in the European Prospective Investigation into Cancer and
Nutrition (EPIC) cohort (Kaaks et  al., 2014)  observed the positive
association with IGF-​1 only with ER+ breast cancer. This difference
by ER status is supported by accumulating evidence of the presence of
synergistic cross-​talk in mammary cells between IGF-​1 and estrogen
signaling pathways (Yee and Lee, 2000).
The role of insulin in breast cancer etiology remains unclear. Given
that estrogens have a dominant influence on breast cancer (Colditz,
1998), it has been hypothesized that insulin may promote breast cancer
by suppressing hepatic production of sex hormone binding globulins
(SHBG), thereby increasing the bioavailability of estrogens (Singh
et al., 1990). However, no overall association was observed between
insulin or C-​peptide and breast cancer in a recent meta-​analysis of 10
prospective studies (Autier et al., 2013) Six of these studies measured
insulin (Eliassen et al., 2007; Gunter et al., 2009; Kaaks et al., 2002b;
Kabat et  al., 2009; Mink et  al., 2002; Sieri et  al., 2012); five mea-
sured C-​peptide (Cust et al., 2009; Eliassen et al., 2007; Keinan-​Boker
et al., 2003; Toniolo et al., 2000; Verheus et al., 2006). Contrary to the
hypothesis that estrogen mediates the increased risk, the most recent
prospective study that examined the relationship between C-​peptide
and subtypes of breast cancer found a stronger association with ER–​
than ER+ cancer (Ahern et al., 2013). Thus, the mechanism by which
hyperinsulinemia increases breast cancer risk remains unclear.
The relationship between excess body fat and endometrial cancer is
thought to be driven by primarily by estrogen (Schmandt et al., 2011),
although insulin may also play a role. Epidemiologic evidence sup-
porting the link between insulin resistance and endometrial cancer
 361
Obesity and Body Composition 361
risk is comprehensively reviewed by Mu and Zhu (Mu et al., 2012).
A recent meta-​analysis found an approximately 2-​fold increased risk
of endometrial cancer among women with type 2 diabetes mellitus
compared with non-​diabetic women (Liao et al., 2014). In a Mendelian
randomization study that provides evidence for causality, single nucle-
otide polymorphisms (SNPs) for fasting insulin and SNPs for post-​
challenge insulin were linked to an elevated endometrial cancer risk
(Nead et al., 2015).
A recent meta-​analysis of studies of height and prostate cancer
observed a modest positive association between adult attained height
and prostate cancer risk (Zuccolo et  al., 2008). A  pooled study of
12 prospective studies that measured IGF-​1 concentrations in adults
found a positive relationship between IGF-​ 1 and prostate cancer
(Roddam et  al., 2008). The results are inconsistent, however, with
respect to the association by stage and grade of prostate cancer. IGF-​
1 appears to be more strongly associated with low-​grade than high-​
grade tumors (Chan et  al., 2002; Nimptsch et  al., 2011b; Roddam
et  al., 2008), whereas the opposite is observed for both height and
obesity in adulthood.
Only a few prospective studies have examined the association
between prediagnostic levels of circulating IGF-​1 and insulin and pan-
creatic cancer risk, and the results are conflicting (Giovannucci and
Michaud, 2007). However, numerous studies have investigated the
relationship between history of type 2 diabetes and pancreatic cancer
risk. A recent meta-​analysis reported an elevated risk associated with
type 2 diabetes, regardless of the duration of diabetes prior to cancer
diagnosis (RR = 1.5, 95% CI: 1.3, 1.8 for 5–​9 years; RR = 1.5, 95%
CI: 1.2, 2.0 for 10+ years) (Huxley et al., 2005).
Adiponectin
Another peptide hormone, adiponectin, possesses significant anti-​
inflammatory and insulin-​ sensitizing effects (Tilg and Moschen,
2006), and has been postulated to mediate the relationship between
obesity and several cancers (Vansaun, 2013). Although predominantly
secreted by white adipose tissue (Maeda et  al., 1996), adiponec-
tin expression is reduced in obesity because of complex factors that
suppress transcription, including adipocyte hypertrophy, inflamma-
tion, and oxidative stress (Kadowaki et  al., 2006; Kim et  al., 2015;
Maury and Brichard, 2010). Lower levels of adiponectin have been
linked to the development of metabolic syndrome and type 2 diabetes
(Kadowaki et al., 2014; Li et al., 2009; Matsuzawa, 2006). The insulin-​
sensitizing effect of adiponectin may be mediated, at least in part, by
an increase in fatty-​acid oxidation via activation of AMP-​activated
protein kinase (AMPK) and peroxisome proliferator-​activated recep-
tor (PPAR)-​ α, which bind to adiponectin receptors AdipoR1 and
AdipoR2, respectively (Yamauchi et  al., 2002, 2003). Synthetic
AdipoR agonist has been shown to ameliorate diabetes and prolong
the life span in mice who are either genetically obese or become so
on a high-​fat diet, suggesting that adiponectin can be a promising
therapeutic target for metabolic disorders (Okada-​Iwabu et al., 2013).
Given the well-​established role of inflammation and insulin resistance
in carcinogenesis, adiponectin has been hypothesized to lower obesity-​
related cancer risk. In addition, experimental evidence suggests that
adiponection may directly control malignant potential by regulating
metabolic, inflammatory, and cell cycle signaling pathways (Fujisawa
et  al., 2008; Moon et  al., 2013; Sugiyama et  al., 2009). Despite the
strength of experimental data, epidemiologic studies have reported
inconsistent findings on the relationship of prediagnostic adiponectin
with risk of several specific cancers.
Six prospective case-​control studies have studied the relationship
between adiponectin and colorectal cancer. Three of these reported no
association (Chandler et al., 2015; Lukanova et al., 2006; Stocks et al.,
2008), whereas three others reported mixed results (Aleksandrova
et al., 2012; Ho et al., 2012; Song et al., 2013b). In the Women’s Health
Initiative, while high plasma adiponectin was associated with lower
colorectal cancer risk, this association disappeared after adjusting for
insulin levels, suggesting that insulin could be on the causal pathway
(Ho et al., 2012). This notion was not supported by EPIC, however, in
that the high molecular weight fraction of adiponectin, which is most
strongly associated with insulin sensitivity and diabetes (Heidemann
et al., 2008; Oh et al., 2007), was not more strongly associated with
colorectal cancer risk (Aleksandrova et al., 2012).
Similarly intriguing, a sex difference has been observed in an
analysis of the Nurses’ Health Study and the Health Professionals
Follow-​up Study, where the inverse association between adiponectin
and colorectal cancer risk was confined to men (Song et al., 2013b).
Of note, women generally had higher levels of adiponectin than men
(median:  8.2 vs. 5.3 μg/​mL). The gender difference in plasma lev-
els appears to be independent of fat mass or distribution, and may
result from the influence of sex steroid hormones (Cnop et al., 2003;
Lanfranco et al., 2004; Yarrow et al., 2012). Thus, the sex heteroge-
neity in the adiponectin–​colorectal cancer association may reflect a
distinct influence of altered estrogen and testosterone concentrations
related to adiposity (Giovannucci, 2007; Koo and Leong, 2010).
A Mendelian randomization study of SNPs associated with circulat-
ing adiponectin levels (Dastani et al., 2012; Ling et al., 2009; Richards
et al., 2009) did not report consistent, strong associations with a variety
of outcomes, including colorectal cancer (Song et al., 2015a), although
the SNPs explain only a small fraction of variation in adiponectin lev-
els. However, low circulating levels of adiponectin have been primar-
ily linked to the increased risk of KRAS-​mutant cancer (Inamura et al.,
2016), and a larger Mendelian randomization study would be needed
to assess whether adiponectin-​related SNPs are associated with any
particular subtypes of colorectal cancer.
For breast cancer, although retrospective case-​control studies have
generally reported lower adiponectin levels in cases than in controls
(Macis et  al., 2014), this finding was replicated in only two (Macis
et  al., 2012; Tworoger et  al., 2007)  of the seven prospective studies
(Cust et al., 2009; Gaudet et al., 2010; Gunter et al., 2015; Macis et al.,
2012; Ollberding et  al., 2013; Touvier et  al., 2013; Tworoger et  al.,
2007). However, the two studies differ in that adiponectin was associ-
ated with breast cancer risk in premenopausal women in one study
(Macis et  al., 2012), but only with postmenopausal breast cancer in
the other (Tworoger et  al., 2007). Similarly, for endometrial cancer,
prospective studies have produced inconsistent findings. While an
early study reported that prediagnostic adiponectin level, independent
of BMI and other metabolic biomarkers, was associated with a lower
risk of postmenopausal endometrial cancer (Cust et  al., 2007), this
finding was not replicated in three subsequent studies (Dallal et  al.,
2013; Luhn et al., 2013; Soliman et al., 2011), except for an inverse
association noted in one study only among non-​current MHT users
only (Luhn et al., 2013).
For prostate cancer, higher adiponectin levels were associated with
lower risk of high-​grade or lethal prostate cancer in the Physicians’
Health Study (Li et  al., 2010), and this finding was further corrob-
orated by genetic studies demonstrating that SNPs related to lower
adiponectin levels were associated with higher prostate cancer risk
(Dhillon et al., 2011). However, such findings have not been consis-
tently replicated in other studies (Baillargeon et al., 2006; Moore et al.,
2009; Touvier et al., 2013). For pancreatic cancer, a pooled analysis of
five prospective cohort studies observed a common inverse association
between adiponectin and pancreatic cancer risk among smokers and
non-​smokers (Bao et al., 2013). Higher levels of circulating adiponec-
tin were inversely associated with multiple myeloma risk (Hofmann
et al., 2012), and also have been associated with a lower risk of pro-
gression from monoclonal gammopathy of undetermined significance
(MGUS) to myeloma (Fowler et al., 2011; Reseland et al., 2009).
For primary liver cancer, four prospective studies have consistently
shown that high adiponectin is associated with increased risk among
patients with chronic hepatitis C (Arano et al., 2011), among patients
with hepatitis B or C infection (Chen CL et al., 2014; Michikawa et al.,
2013), or among participants with low infection rate (Aleksandrova
et  al., 2014). This positive association appears to be stronger for
non-​HMW adiponectin (Aleksandrova et al., 2014; Michikawa et al.,
2013). Although these findings seem to contradict those for other can-
cers, circulating adiponectin has been found to be elevated in patients
with chronic hepatitis C or with high hepatitis B viral load (Chen CL
et al., 2014; Wong et al., 2010), suggesting that adiponectin may rise
as a result of reduced degradation by the liver due to virus-​induced
inflammation and injury. Furthermore, higher adiponectin levels
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362 PART III:  THE CAUSES OF CANCER
among patients with newly diagnosed or recurrent hepatocellular car-
cinoma have been linked to increased mortality (Siegel et al., 2015).
Interestingly, the phenomenon of adiponectin-​ associated increased
mortality, known as the “adiponectin paradox,” has also been reported
in patients with colorectal cancer (Chong et al., 2015), prevalent car-
diovascular disease (Cavusoglu et al., 2006), and heart failure (Kistorp
et al., 2005), and among the elderly (Karas et al., 2014; Kistorp et al.,
2005; Kizer et  al., 2012; Laughlin et  al., 2007; Poehls et  al., 2009;
Wannamethee et al., 2007). Although there is evidence suggesting that
increased adiponectin concentrations may represent a response to an
underlying disease process, this paradox has not been explained and
warrants further studies to elucidate the complex pathophysiology of
adiponectin (Sattar and Nelson, 2008).
Sex Steroid Hormones
Contributing to the role of adipose tissue as an endocrine organ, body
fat is a major site for the synthesis of sex steroid hormones, and con-
tributes to the bioavailability of these hormones. Steroid hormone
synthesis occurs as a result of adipocyte expression of the aromatase
enzyme. In men and postmenopausal women, the primary source of
circulating estrogens is the conversion of androgens (testosterone and
androstenedione) to estrogens (estradiol and estrone) by adipose tissue.
Less active forms of these hormones (androstenedione, estrone) are
converted to more active forms (testosterone, estradiol) by the enzyme
17B-​hydroxysteroid dehydrogenase, expressed in adipocytes. Adipose
tissue contributes to increased bioavailability of sex hormones through
the inhibition by insulin of the synthesis of SHBG in the liver (Crave
et al., 1995). Lower SHBG levels result in higher concentrations of free
estradiol and free testosterone, which are more readily taken up by cells
in target organs. Combining the strengths of several nested case-​control
studies of circulating hormones and breast cancer risk, a large collab-
orative study of BMI and circulating hormones was conducted recently,
including more than 6000 postmenopausal women (Endogenous
Hormones Breast Cancer Collaborative Group, 2011). Compared to
thin women (BMI ≤22.5), obese women (BMI >30) had 47% higher
circulating estradiol and estrone levels. In addition, obese women had
46% lower SHBG levels, contributing to significantly higher circulat-
ing free estradiol (89%) and free testosterone (72%) levels.
Steroid hormones play an important etiologic role in cancers of the
breast, endometrium, ovary, and prostate. Circulating hormone levels
have been consistently associated with postmenopausal breast cancer
(Kaaks et al., 2005; Key et al., 2002; Zhang X et al., 2013). In a pooled
analysis of nine prospective studies, including 663 breast cancer cases
and 1765 controls, higher circulating levels of estrogens, including
estradiol, estrone, estrone sulfate, and free estradiol, were associ-
ated with higher subsequent risk of breast cancer (e.g., top vs. bot-
tom quintile estradiol, RR = 2.0; 95% CI: 1.5, 2.7) (Key et al., 2002).
Adipose tissue may also affect breast cancer risk locally, given that
adipocytes in breast stromal tissue likely contribute to estrogen levels
in the microenvironment.
In endometrial carcinogenesis, the interplay between peptide and sex
steroid hormones appears to be critical (Kaaks et al., 2002a). Higher insu-
lin and IGF-​1 levels in obese women increase ovarian androgen produc-
tion. In premenopausal women, ovarian androgen production interferes
with ovulation, which decreases production of progesterone. Normally,
progesterone provides a check on estrogen-​induced proliferation in the
uterus (Key and Pike, 1988). Therefore, decreases in progesterone pro-
duction in premenopausal women, and increases in bioavailable estro-
gens, create the environment for endometrial carcinogenesis.
Sex steroid hormones play a role in colorectal cancer, and may partly
account for the stronger association with obesity observed in men. In
women, higher exposure to estrogen and progesterone, whether through
pregnancy or the use of MHT, is associated with lower risk of colorectal
cancer. For instance, in the Women’s Health Initiative trial, combined
use of estrogen and progestin was associated with a 40% lower risk
of colorectal cancer (Chlebowski et  al., 2004). Although associations
with circulating levels of estradiol are inconsistent (Clendenen et  al.,
2009; Gunter et al., 2008; Lin et al., 2013), a higher ratio of estradiol
to testosterone in women not using MHT has been associated with
lower colorectal cancer risk after adjustment for BMI and C-​peptide
levels (Lin et al., 2013). One potential explanation is that the increase
in estrogens associated with obesity may partially offset the increased
risk from obesity-​related metabolic factors, such as hyperinsulinemia.
Adiposity in men is associated with lower levels of androgens (Kapoor
et al., 2005); higher circulating levels of testosterone are associated with
lower colorectal cancer (Lin et al., 2013). A higher ratio of estradiol to
testosterone was associated with higher risk in men, which may reflect
increasing aromatization and lower testosterone levels (Lin et al., 2013).
Inflammation
Chronic inflammation creates a tissue microenvironment that stimu-
lates cellular proliferation, suppresses apoptosis, and generates free
radicals that can damage DNA (see Chapter 25). While it is difficult to
measure local inflammation in population studies, there are numerous
clinical examples in which chronic local inflammation predisposes to
certain types of cancer (see Chapter 25). This section discusses several
examples in which tissue damage caused by the effects of obesity fos-
ters neoplastic growth and malignant transformation. It also discusses
systemic markers of inflammation that have been measured in epide-
miologic studies of cancer.
Examples of Local Inflammation
Esophageal Adenocarcinoma. Esophageal adenocarcinoma
typically occurs in the lower one-​third of the esophagus, and has a
greater propensity to occur in men than in women (see Chapter 30).
Incidence rates have increased in parallel with the increasing preva-
lence of obesity. This malignancy usually arises from mucosa that has
been damaged by chronic reflux of acid and bile from the stomach into
the lower esophagus. A recent extensive meta-​analysis demonstrated
the importance of central adiposity in increasing risk of esophageal
inflammation, metaplasia (Barrett’s esophagus), and neoplasia (Singh
et al., 2013). Obesity, particularly central obesity, is the strongest risk
factor for acid reflux through disruption of the normal physiology of
the gastroesophageal junction (Friedenberg et al., 2008). The relation-
ship between obesity and acid reflux likely largely explains the asso-
ciation between obesity and esophageal adenocarcinoma. The male
propensity for an abdominal pattern of adiposity may at least partly
account for the higher rates of esophageal adenocarcinoma in men
(Friedenberg et al., 2008; Singh et al., 2013).
Gallbladder Cancer. Gallbladder cancer is associated with
excess adiposity (Larsson and Wolk, 2007; Park et al., 2014; Tan et al.,
2015), and with related metabolic abnormalities such as type 2 diabe-
tes (Gu et al., 2015), lipid disorders, and elevated fasting blood glu-
cose (Borena et al., 2014; Rapp et al., 2006) (see Chapter 34). Obese
women are at particularly high risk of gallbladder cancer. The main
risk factor for gallbladder cancer is a history of gallstones (Randi et al.,
2006) (see Chapter 34). Obesity, hyperinsulinemia, and dyslipidemia
are related to a cluster of factors that predispose to gallstones, including
biliary supersaturation with cholesterol, inflammation, hypersecretion
of mucin, slow colonic motility, and increased intestinal cholesterol
absorption. Chronic inflammation from recurrent gallstones is the pre-
sumptive mediator of obesity-​related gallbladder cancer.
Liver Cancer.  Obesity has been suggested to be the second larg-
est contributor to the recent increase in the incidence of hepatocel-
lular carcinoma in developed countries, after hepatitis C infection
(Caldwell et al., 2004; Starley et al., 2010) (see Chapter 33). Obesity
plays an important role in the progression from non-​alcoholic fatty
liver disease to steatohepatitis to cirrhosis and hepatocellular carci-
noma (Caldwell et al., 2004; Cohen et al., 2011; Hassan et al., 2015).
As the most common form of chronic liver disease, non-​alcoholic
fatty liver disease affects about 30% of the US general population
and up to 90% of those who are morbidly obese (Torres and Harrison,
2008). The more aggressive form of non-​alcoholic fatty liver disease,
 36
Obesity and Body Composition 363
non-​alcoholic steatohepatitis, has a prevalence of 5%–​7%; in this sub-
group, up to 9% can progress to cirrhosis (Ong and Younossi, 2007).
An estimated 40%–​60% of patients with cirrhosis from non-​alcoholic
steatohepatitis develop major complications, including hepatocellu-
lar carcinoma over 5–​7 years of follow-​up (Adams et al., 2005; Hui
et al., 2003).
Systemic Markers of Inflammation
Epidemiologic studies can more easily measure systemic markers of
inflammation than inflammation at the tissue level. It is often unclear
whether the increase in a systemic marker derives from local inflam-
mation or from a more generalized inflammatory process, perhaps
involving the infiltration of immune cells into adipose tissue, espe-
cially visceral adipose. It is also uncertain whether a low-​grade gen-
eralized inflammatory state can predispose to cancers at remote sites.
One of the most widely used inflammatory biomarkers is CRP, which
is secreted from the liver and is an acute phase marker of inflamma-
tion. CRP is increased in obese individuals (Visser et al., 1999), but
also is increased by smoking, alcohol, physical inactivity, and various
inflammatory conditions (Chan et al., 2015). Recognizing the complex
determinants of CRP, some studies have examined pre-​diagnostic CRP
levels in blood in relation to risk of various cancers. In a meta-​analysis
of circulating CRP and incident breast cancer risk, a statistically sig-
nificant positive association was found; each doubling of the CRP
concentration was associated with a 7% increase in incident breast
cancer (Chan et al., 2015). In a meta-​analysis of colon cancer, circu-
lating CRP was modestly associated with increased risk, although a
closely related inflammatory marker, IL-​6, was not (Zhou et al., 2014).
The interpretation of these results is unclear; some studies observed
increased risk with higher levels of the inflammatory markers only in
the early years after blood samples were provided (Song et al., 2013a),
raising the possibility that the tumor itself may have affected the circu-
lating levels (i.e., reverse causation).
Because CRP and IL-​6 are affected by many factors besides excess
body weight, it is difficult to ascribe any observed association strictly
to obesity. This problem is illustrated in a large case-​control study of
prostate cancer nested in a prospective cohort. As expected, obese
men had substantially higher levels of CRP and IL-​6. However, IL-​
6 was associated with increased risk of prostate cancer only among
men with normal BMI (Stark et al., 2009). An inverse relationship was
observed between IL-​6 and prostate cancer among men with increased
BMI. This finding suggests that determinants of elevated inflammatory
markers unrelated to adiposity accounted for the increased risk. A pos-
sible explanation is that high IL-​6 or CRP among the leaner men may
be more indicative of inflammation within the prostate gland, which
directly influences risk, whereas high concentrations of inflammatory
markers among the heavier men reflected the greater amount of adi-
pose tissue. Similarly, in colon cancer, an association with IL-​6 was
observed only in leaner men, again suggesting that inflammation at
the tissue level, rather than systemic inflammation related to adiposity,
influences risk (Song et al., 2013a). Further, using a Mendelian ran-
domization approach, genetic determinants of elevated levels of CRP
were not associated with increased risk of cancer, possibly arguing
against a causal role of systemic inflammation for cancer risk (Allin
et al., 2010).
Although it is not clear that obesity-​associated systemic inflam-
mation would necessarily affect the risk of solid tumors, effects on
immune system cancers are also plausible. Obesity has been associ-
ated with increased risk of multiple myeloma, a malignancy of plasma
cells (Teras et al., 2014); IL-​6, a pro-​inflammatory cytokine, is a potent
growth factor for plasma cells and may contribute to the risk of mul-
tiple myeloma (Ziakas et al., 2013).
Mechanisms Associated with Early Life Adiposity
Excess body fat in childhood and/​or adolescence occurs during an
important developmental period, and may influence lifelong metabolic
and hormonal patterns, as well as behaviors. Early life obesity has
been suggested to influence basal insulin levels, and thus contribute to
increased lifetime exposure to insulin (Caprio et al., 1995), which may
contribute to subsequent risk of colon cancer.
Mechanisms by which childhood/​adolescent obesity may influence
breast cancer risk later in life could involve both the hormonal milieu
in early life and the establishment of set points that persist with age.
Although overweight and obese girls are likely to have earlier ages
at menarche compared to normal weight girls, they also are more
likely to have anovulatory menstrual cycles (Rich-​Edwards et  al.,
1994; Stoll, 1998) and irregular cycle patterns (Tehard et al., 2005).
Adiposity at young ages is associated with slower adolescent growth
(Berkey et al., 1999). Excess adiposity in childhood is inversely asso-
ciated with at least two breast cancer risk factors in adulthood: circu-
lating IGF-​1 levels (Poole et  al., 2011), and breast density (Samimi
et al., 2008; Sellers et al., 2007). Among 6520 women in the Nurses’
Health Study and Nurses’ Health Study II, those who were overweight
at young ages had 14% lower adult plasma IGF-​1 levels, compared
with leaner girls (Poole et al., 2011). The inverse associations observed
between childhood body fatness and breast density suggest that the
structure of breast tissue may be established as a result of early life
adiposity and then may persist throughout life (Samimi et al., 2008;
Sellers et al., 2007).
Microbiome
The explosion of research in host-​microbe interaction over recent
years supports a potential role of the gut microbiota in human health
and disease through regulation of host metabolism and immune func-
tion (Blumberg and Powrie, 2012; Brestoff and Artis, 2013; Guarner
and Malagelada, 2003; Kau et al., 2011; Sommer and Backhed, 2013;
Tremaroli and Backhed, 2012). Several lines of evidence indicate a
bidirectional association. While perturbations in the gut microbiota
may predispose individuals to obesity (Cox and Blaser, 2013), obe-
sity also can alter gut microbiota, potentially contributing to obesity-​
linked carcinogenesis. Maintenance of body weight strongly predicts
microbiota stability (Faith et al., 2013); obesity has been associated
with lower diversity and altered composition of gut microbiota, spe-
cifically a decrease in the phylum Bacteroidetes and an increase in
Firmicutes (Furet et  al., 2010; Le Chatelier et  al., 2013; Ley et  al.,
2005, 2006). An opposite change has been observed with weight
loss (Aron-​Wisnewsky et  al., 2012; Furet et  al., 2010; Kong et  al.,
2013; Ley et  al., 2006; Zhang et  al., 2009). Furthermore, growing
evidence implicates the altered microbial community and enrich-
ment of certain microbes in cancer development (e.g., Fusobacterium
nucleatum in colorectal cancer) (Castellarin et al., 2012; Kostic et al.,
2013). Microbes may amplify or mitigate carcinogenesis by affecting
genomic stability (Cuevas-​Ramos et  al., 2010; Guerra et  al., 2011;
Nougayrede et  al., 2006), altering the balance of host cell prolif-
eration and death (Rubinstein et  al., 2013; Sears, 2009), regulating
pro-​inflammatory or immunosuppressive responses (Hu et al., 2013;
Irrazabal et  al., 2014; Kostic et  al., 2013; Warren et  al., 2013), and
influencing host metabolism (Belcheva et al., 2014; Donohoe et al.,
2014; Singh et al., 2014). Therefore, it has been hypothesized that the
gut microbiota may affect multiple pathways by which obesity influ-
ences cancer risk (Ohtani et al., 2014). Indeed, studies in liver cancer
have suggested that obesity-​induced alteration of the gut microbiota
resulted in enhanced production of DNA-​damaging secondary bile
acid (e.g., deoxycholic acid) that promotes carcinogenesis through
cellular senescence-​related pathways (Ohtani et al., 2014; Yoshimoto
et al., 2013). Given the potential role of secondary bile acids, further
studies are needed to investigate whether metabolic change due to
microbial imbalance also mediates obesity-​related tumor promotion
in other organs.
Site-​Specific Mechanisms: Hypertension
in Renal Cell Cancer
Obesity is a risk factor for hypertension. Hypertension is associated
with higher risk of renal cell cancer in many studies (Chow et  al.,
2000, 2010; Sanfilippo et  al., 2014; Weikert et  al., 2008), and has
364
364 PART III:  THE CAUSES OF CANCER
been postulated as a mechanism linking obesity to renal cell cancer.
However, epidemiologic data lend little support to this hypothesis.
Although individuals who are both obese and hypertensive have a
higher risk of renal cell cancer than those who have only one of these
conditions, the increased risk of renal cell cancer associated with BMI
persists even after adjustment for diagnosis of hypertension or mea-
surement of blood pressure (Adams et  al., 2008; Chow et  al., 2000;
Sanfilippo et  al., 2014; Setiawan et  al., 2007). This indicates that
hypertension-​independent mechanisms may mediate renal cell cancer
development in obese individuals.
ESTIMATED ATTRIBUTABLE FRACTION
FOR  INCIDENCE AND SURVIVAL
Several studies have estimated the population attributable fraction
(PAF), which incorporates both the prevalence of the exposure and the
strength of the association between the exposure and disease. While
the effects of obesity are relatively modest for specific types of cancer
(Table 20–​1), the prevalence of overweight and obesity are high, espe-
cially in the United States and other high-​income countries. Therefore
the number of cancer cases attributable to overweight and obesity is
likely to be substantial.
The WCRF/​AICR has estimated the PAF for cancer sites designated
as definitely caused by obesity (WCRF/​AICR, 2010b). The estimates
for the United States range from 11% for gallbladder cancer to 34%
for pancreatic cancer in men, and from 3% for colorectal to 49% for
endometrial cancer in women. PAF estimates for the world were pub-
lished recently by the IARC (Arnold et al., 2015); the estimated frac-
tions in men ranged from 6% for rectal cancer to 33% for esophageal
adenocarcinoma; for women, they ranged from 4% for rectal cancer to
34% for endometrial cancer.
Combining PAF estimates for specific cancer sites into an overall
PAF for obesity and cancer, the IARC estimated that 481,000 (3.6%)
of all new cancers in 2012 in adults were attributable to high BMI
(Arnold et al., 2015). By sex, the PAF were 1.9% in men and 5.4%
in women. Further, one-​quarter of these cases in 2012 were attributed
to the global increase in BMI since 1982. If the population had main-
tained the prevalence of overweight and obesity in 1982, instead of
increasing to today’s prevalence, an estimated 118,000 cases of cancer
could have been avoided. The magnitude of the PAF also varies by
human developmental indices (HDIs), since obesity is more common
in countries with higher HDIs. For example, the IARC estimates that
5.4% of all incident cancers could be attributed to obesity in countries
with very high HDI, 4.8% in those with high HDI, 1.6% in moderate
HDI countries, and 1.0% in those with low HDI.
In contrast to the estimates for obesity alone, the WCRF/​AICR
Continuous Update Project estimates the PAF for the combined effects
of diet, physical activity, and body mass (WCRF/​AICR, 2009). The
estimates range from 19% to 26% in low-​to high-​income countries,
respectively. While this approach would exaggerate the PAF due to
body mass alone, these factors inherently overlap, since weight gain
reflects both diet and activity level. For example, the association
between colorectal cancer and a dietary pattern that stimulates insulin
secretion appears to be highly dependent on BMI and physical activity
level (Fung et al., 2012). Thus, at least for some cancers, the effects
of obesity cannot be isolated from those related to diet and physical
inactivity.
The published PAFs (besides those from the WCRF/​ AICR
Continuous Update Project) for cancer are likely to be substantial
underestimates of the true impact of excess adiposity on cancer risk for
numerous reasons. First, despite the categorical terms such as “over-
weight” and “obesity,” adiposity is a continuous variable. Thus, selec-
tion of the cutpoint is arbitrary. For example, a cutpoint of 25 kg/​m2 is
typically used because it is the lower bound of overweight, and may
be considered a potential target for population-​level interventions. Yet,
the association may be linear even below 25 kg/​m2. Moreover, most
studies have relied on a single measure of adiposity, whereas BMI and
other measures of adiposity may vary over time. The potential impor-
tance of the cutpoint and of obtaining repeated measures of BMI are
illustrated in the Health Professionals Follow-​up Study, where the PAF
for colon cancer in men was 14% based on a single measure of BMI
and a cutpoint of 25, but increased to 30% when the BMI cutpoint was
reduced to 22.5 kg/​m2 and was based on an average of multiple mea-
sures of BMI (Thygesen et al., 2008).
Other methodologic factors also influence the estimates of PAF.
Although BMI is widely used for PAF estimates because of its avail-
ability, it is not an ideal measure of adiposity, as previously discussed.
More direct measures of visceral or central adiposity, such as VAT,
might be expected to provide stronger associations of the relative
risks and higher estimates of the PAF. For example, VAT based on CT
scan was strongly associated with risk of colorectal adenoma, even
adjusting for BMI (Keum et  al., 2015). In study populations where
the majority of participants had BMI levels below 25 kg/​m2, VAT was
strongly and linearly associated with the risk of colorectal adenoma
(Keum et al., 2015). To date, there are limited data by which to esti-
mate PAF using measures other than the traditional cutpoints for BMI.
Relying on a single measure of BMI during adulthood conflates
exposures that occur at different times of life. For example, a study of
breast cancer based on adult BMI cannot separate early life adiposity
(which decreases breast cancer risk) from adult weight gain (which
increases risk). On a per kilogram increment basis, adult weight gain is
a much stronger risk factor for breast cancer than is adult BMI (Keum
et al., 2015). Thus, the use of a single measure of BMI may not accu-
rately reflect the relevant measure of adiposity at different time points.
The presence of effect modifiers may also differ between populations
and may change over time, further constraining the estimates of PAF.
For example, as described earlier, MHT may modify the effect of obe-
sity on breast cancer, just as smoking modifies the relation of adiposity
to smoking-​related cancers. The prevalence and timing of these modi-
fying factors in the population will affect the strength of the association
and the estimated PAF. For example, as the fraction of perimenopausal
women who use MHT in the United States decreases, the estimated
PAF for obesity and breast cancer would be expected to increase.
A particularly important modifier to consider is smoking. As dis-
cussed earlier, the complex relationship between smoking and adi-
posity makes it difficult to interpret the effects of adiposity. In the
Cancer Prevention Study II, a prospective mortality study begun by
the American Cancer Society in 1982, the PAF of total cancer mortal-
ity in the United States due to high BMI was 4.2% in men and 14.3%
in women in the entire population, but these estimates increased to
14.2% and 19.8%, respectively, in the population limited to healthy
never-​smokers (Calle et  al., 2003). The inclusion of smokers quali-
tatively changes the association observed among never smokers,
either because of reverse causation (as hypothesized for lung cancer)
or intractable confounding (see earlier disucssion). Regardless of
the reason, given the strong effect modification, the implications are
that the overall PAF in a population is arbitrary because it depends
largely on the proportion of smokers in the population, and would not
apply to either the subgroup of smokers or to non-​smokers (Song and
Giovannucci, 2016).
In summary, while the PAF is a widely used measure for commu-
nicating the impact of obesity on cancer, the calculation of PAF is
not straightforward, and the exact value can be influenced by many
factors. Nevertheless, the high prevalence of obesity and its consistent
associations with multiple types of cancer indicate that the disease bur-
den is high for cancer, as for other major diseases.
EXCESS ADIPOSITY AND CANCER SURVIVAL
The association between obesity and survival of patients with cancer
is a relatively recent area of research, and one that is methodologi-
cally difficult for several reasons. If adiposity is measured before
diagnosis, one cannot separate an effect on cancer incidence from an
effect on disease progression. However, if adiposity is measured after
diagnosis, it becomes impossible to exclude the possibility that weight
loss resulted from reverse causation. Weight loss is a common and
generally unfavorable prognostic indicator in patients with advanced
or metastatic cancer. Particularly for cancers that tend to have short
 365
Obesity and Body Composition 365
survival time (e.g., pancreatic cancer), the effects of local progression
or metastatic disease may cause weight loss some time before diag-
nosis. Therefore, a measure of body mass at the time of diagnosis or
shortly thereafter is likely to be misleading. Further, low body weight
may reflect loss of lean body mass prior to diagnosis.
The relationship of obesity to survival from breast cancer has been
more extensively studied than its relationship to survival of other can-
cers, because of the large number of cases and generally long survival.
A recent meta-​analysis summarized the results of 82 studies, encom-
passing 213,075 breast cancer survivors and 41,477 deaths (23,182
from breast cancer). Increased adiposity was associated with poorer
overall and site-​specific survival for both pre-​and postmenopausal
breast cancer, regardless of when BMI was ascertained (Chan et al.,
2014). Relative to normal weight women, the summary RRs for all-​
cause mortality were as follows: 1.41, 95% CI: 1.29, 1.53 for obese
(BMI >30.0); 1.07, 95% CI:  1.02, 1.12 for overweight (BMI 25.0–​
<30.0); and 1.10, 95% CI:  0.92, 1.31 for underweight (BMI <18.5)
women. For breast cancer mortality, the associations were observed
regardless of menopausal status, but were non-​significantly stronger
for premenopausal (RRs for obesity: 1.75; 95% CI: 1.26, 2.41) than for
postmenopausal breast cancer (RR = 1.34; 95% CI: 1.18, 1.53). Breast
cancer mortality was increased when BMI was measured before diag-
nosis (14% increase per 5 kg/​m2 increment), <12 months after diagno-
sis (14%), and ≥12 months after diagnosis (29%). For total mortality,
the corresponding increases in risk were 17%, 11%, and 8%. The asso-
ciation between obesity with breast cancer outcome did not appear to
differ by hormone receptor status of the tumor (Niraula et al., 2012).
Obesity has generally not been associated with prostate cancer
incidence, but may be associated with poor survival. A meta-​analysis
based on 17 studies (Zhang X et al., 2015b), which included 3,569,926
men, found no association between obesity and prostate cancer inci-
dence (RR = 1.00; 95% CI: 0.95, 1.06), but a significant association
with prostate cancers categorized as aggressive (RR  =  1.14; 95%
CI: 1.04, 1.25) and with prostate cancer mortality (RR = 1.24; 95%
CI: 1.15, 2.33). These results were confirmed in another meta-​analysis
of six post-​diagnosis survival studies, including 18,203 patients with
932 prostate cancer deaths, where a 5 kg/​m2 increase in BMI was asso-
ciated with 20% higher prostate cancer-​specific mortality (RR = 1.20;
95% CI: 0.99, 1.46) (Cao and Ma, 2011). In 16 studies that followed
26,479 prostate cancer patients after primary treatment, a 5  kg/​m2
increase in BMI was significantly associated with 21% increased risk
of biochemical recurrence (RR = 1.21; 95% CI: 1.11, 1.31).
Four recent meta-​analyses have examined BMI in relation to colorec-
tal cancer survival, with similar results (Lee et al., 2015; Parkin et al.,
2014; Schlesinger et al., 2014; Wu et al., 2014). Being underweight
before diagnosis was associated with an approximately 60% higher
all-​cause death rate compared to being normal weight; whereas being
obese was associated with a 20%–​30% higher death rate. For post-​
diagnostic BMI, obesity generally was not associated with increased
risk of death, except for a suggested association with BMI ≥35 kg/​m2.
As observed for pre-​diagnostic underweight, being underweight after
diagnosis was associated with higher overall mortality.
At least five studies have examined pre-​diagnostic BMI in relation
to mortality from pancreatic cancer (Majumder et al., 2015). When all
were combined, each 1 kg/​m2 increase in BMI was associated with a
statistically significant 10% increase in mortality. Given that pancre-
atic cancer has an extraordinarily high mortality rate, it is not feasible
to study post-​diagnostic BMI in relation to outcome.
The international Ovarian Cancer Association Consortium related
BMI levels shortly before diagnosis to survival among women with
invasive ovarian cancer (Nagle et al., 2015). The consortium included
original data from 21 studies, 12,390 women with ovarian carci-
noma, and 6715 total deaths documented during follow-​up. Women
who had a BMI of 30–​34.9 had a 10% increase in the all-​cause death
rate; those with BMI ≥35 had a 12% increase. In a meta-​analysis
of 17 cohort studies (Bae et  al., 2014), obesity in early adulthood
(HR = 1.67; 95% CI: 1.29, 2.16) and obesity 5 years before ovarian
cancer diagnosis (HR  =  1.35; 95% CI:  1.03, 1.76) were associated
with increased patient mortality. In another meta-​analysis (Protani
et al., 2012), obesity was associated with poorer survival in women
with ovarian cancer. A suggestive association was found for studies
that assessed BMI before, at the time of diagnosis or post-​diagnosis,
or at commencement of chemotherapy. However, these were not sta-
tistically significant, and there was considerable heterogeneity across
studies.
One study collected clinical and pathologic data from 1543 patients
who underwent nephrectomy for renal cell cancer (Choi et  al., 2013).
In contrast to most cancers, higher BMI measured after diagnosis was
associated with improved survival. In the multivariable analysis, there
was lower overall mortality (HR = 0.45; 95% CI: 0.29, 0.68) and cancer-​
specific mortality (HR = 0.47; 95% CI: 0.29, 0.77) in obese (defined as
BMI ≥25) patients than in normal weight patients (BMI 18.5–<23). The
authors also conducted a meta-​analysis that corroborated these results.
While it is possible that renal cell cancers that develop in an obesogenic
environment may be molecularly more indolent than other renal cell can-
cers (Hakimi et al., 2013), reverse causation is a likely explanation.
For esophageal cancer, higher body weight has tended to be associ-
ated with better survival. This appears to be the case for either pre-​
diagnostic or post-​diagnostic BMI, and with squamous cell carcinoma
or adenocarcinoma of the esophagus (Fahey et al., 2015; Hong et al.,
2013; Zhang SS et al., 2013), but reverse causation cannot be ruled out.
Although excess adiposity has clearly been associated with
increased risk of numerous cancers, the influence of adiposity on
cancer survival has been less clear. The problem of reverse causation
from the cancer of interest or comorbidities is extremely difficult to
resolve. Some researchers have suggested the notion of an “obesity
paradox,” whereby those who develop cancer and remain overweight
or obese have a better prognosis than those with lower weight. This so-​
called paradox is seen especially with cancers of the digestive tract and
kidneys. The issue of reverse causation cannot be resolved, however,
without a better understanding of the natural history of weight loss
caused by either these cancers or comorbidities associated with them.
Furthermore, some evidence indicates that lean body mass is a critical
factor for survival, and this is not measured well by BMI (Prado et al.,
2015). After a diagnosis of cancer, future studies need to account for
body composition more precisely and not rely simply on BMI, which
does not discriminate between lean tissue and adipose.
Impact of Excess Adiposity on Treatment Efficacy
Obesity has been associated with poorer outcomes; the reasons for
this are numerous. Individuals who are obese are more likely to have
comorbid conditions and complications (McTiernan et al., 2010), mak-
ing treatment less effective and more difficult to manage. These comor-
bidities including surgical wound complications, lymphedema, and
possible congestive heart failure (McTiernan et al., 2010). Additionally,
obese cancer patients may be at risk for obesity-​related morbidities
including type 2 diabetes, hypertension, cardiovascular disease, osteo-
arthritis, and pulmonary disease (Demark-​ Wahnefried et  al., 2012;
McTiernan et al., 2010). In some cases, obesity may be associated with
a higher likelihood of unfavorable tumor characteristics (Griggs and
Sabel, 2008), making the cancer more virulent and difficult to treat.
Obesity is also a factor in suboptimal dosing of chemotherapy,
which decreases the effectiveness of the treatment and contributes
to poorer survival rates. Chemotherapy dosing for adults with can-
cer has traditionally been based on a patient’s estimated body surface
area (BSA) (Freireich et  al., 1966), but in practice many clinicians
use ideal body weight, rather than actual body weight, to calculate
the BSA, or use a cap such as 2.0 m2 (Griggs et  al., 2012). Studies
of clinical practice patterns show that up to 40% of obese patients
receive suboptimal doses that are not based on actual body weight
(Field et  al., 2008; Griggs and Sabel, 2008; Griggs et  al., 2005;
Lyman, 2009; Lyman et al., 2003, 2004; Shayne et al., 2007). While
this practice likely reflects clinicians’ concerns about over-​dosing
and chemotherapy-​related toxicity, there is no evidence to suggest
that toxicity is increased in obese patients receiving doses based on
actual weight (Griggs et al., 2012). Under-​dosing of chemotherapy has
been well documented in breast cancer patients who are overweight or
36
366 PART III:  THE CAUSES OF CANCER
obese (Colleoni et al., 2005; Demark-​Wahnefried et al., 2012; Griggs
et al., 2007; Griggs and Sabel, 2008; Madamas et al., 2001), which in
turn leads to increased recurrence and mortality (Griggs et al., 2012;
Lyman et al., 2004). Although data are more limited for other cancers,
the evidence in breast cancer and the observed dose–​response rela-
tionship for most chemotherapy agents led the American Society of
Clinical Oncology (ASCO), in 2012, to establish clinical guidelines
for dosing obese cancer patients (Griggs et al., 2012). The ASCO panel
concluded that full weight-​based chemotherapy doses should be used
to treat obese patients, although more research is necessary to better
understand chemotherapy pharmacokinetics in obese patients.
INTERPRETATION OF TEMPORAL TRENDS
The secular trends of increasing prevalence of obesity have contrib-
uted to temporal trends in the incidence of some types of cancer. For
example, kidney cancer incidence has increased in many developed
countries over the same time period that obesity prevalence has risen
(e.g., in the United States from 1975 to 2007, age-​standardized rates
doubled for women from 3.6 to 7.4 cases per 100,000, and nearly dou-
bled for men from 8.0 to 14.5 cases per 100,000) (Ferlay et al., 2014).
Over this same time period, the trend in the incidence of pancreatic
cancer actually reversed, from a statistically significant decrease in
incidence with the decrease in tobacco smoking from 1975 to 2000,
to a significant increase thereafter (Ryerson et al., 2016). Esophageal
adenocarcinoma incidence also has risen, with timing similar to the
rise in obesity prevalence. Given the strong association between adi-
posity and adenocarcinoma, the rising prevalence of obesity clearly
has contributed to the increase in incidence, although other factors also
may have contributed (see Chapter 30).
For other cancers that have clear links to obesity, such as endome-
trial and postmenopausal breast cancer, the incidence of disease over
time is affected by obesity, but the picture is further complicated by
secular changes in MHT use. The relationship of the obesity epidemic
with colorectal cancer incidence over time is similarly complicated by
coincident increases in colonoscopy screening rates.
Although the impact of the obesity epidemic is seen in the incidence
of some cancers, given the relative recency of the obesity epidemic
and long latency of cancer, it is likely that the full effects of obesity on
cancer risk have not become apparent. A similar finding was observed
in the association between smoking and lung cancer risk, where early
studies did not capture the full effects of smoking from adolescence
through adulthood (Thun et al., 2013). Thus, while obesity is clearly
associated with cancer risk, the impact of obesity across the life course,
accumulating to decades of excess weight in many individuals, likely
has not yet reached its peak in the population.
OPPORTUNITIES FOR PREVENTION
The evidence of the harmful effect of adiposity on cancer risk and
mortality is robust, and the biologic mechanisms underlying these
associations are numerous. The critical question now is how best to
reduce the number of cases of cancer that arise in the population as
a result of adiposity. Along with increased risks of cardiovascular,
endocrine, pulmonary, renal, gastrointestinal, and musculoskeletal
diseases, the association with cancer provides further impetus for
intervention to reduce the incidence and prevalence of obesity in the
population. Given that extensive evidence from the literature has docu-
mented the difficulty for people to lose weight and keep weight off, the
most important public health message is likely to be to avoid gaining
weight across the life course. However, this message is not applicable
to the millions of people worldwide who are currently overweight and
obese, and the millions of overweight and obese children today who
are likely to become overweight and obese adults. In these individuals,
there should be attempts to prevent further weight gain (e.g., going
from overweight to obese), more research in ways to reduce BMI,
and efforts to find ways to ameliorate risk due to excess adiposity (for
example, diet, physical activity, drugs). Despite the inverse association
between childhood adiposity and subsequent breast cancer risk, the
harms of childhood obesity and the high likelihood of childhood
becoming adulthood obesity far outweigh the inverse association with
one type of cancer. Therefore, encouraging a prevention focus, for all
ages, on improvements in diet and physical activity is necessary to
strive toward better energy balance (see Chapter 62.2 for more details).
FUTURE RESEARCH DIRECTIONS
While the associations between obesity and several cancers are clear,
there are still many areas where further research is necessary to
improve our understanding of the etiologic relationships and disease
burden. First, it is clear that obesity across the life course is impor-
tant, starting with childhood body size and following the trajectory
of weight gain over adulthood. However, understanding the complete
picture of cancer risk associated with a life course of excess weight
is essential given the large numbers of overweight children who are
growing into overweight adults. There is an urgent need for strategies
to prevent this trajectory. More research is necessary on the underly-
ing biologic effects of childhood obesity, particularly to understand
why childhood obesity is protective against breast cancer, in hopes of
identifying an intervention without the health hazards of obesity for
girls who are lean.
Second, evidence is emerging that distribution of body fat (e.g., the
more metabolically active visceral fat), not just total amount of fat, is
important in the etiology of some cancers. However, to better under-
stand the role of visceral fat and its independence from BMI in cancer
etiology, we need better tools to assess this in epidemiology studies,
without relying on expensive MRI or relatively crude waist circumfer-
ence measures. The availability of a simple tool to assess visceral fat
could allow more accurate assessment of individual risk without the
need for expensive testing. Further, a better assessment of lean mass
versus adipose tissue would allow for enhanced understanding of the
role of body mass at the time of and following a cancer diagnosis.
Further research into tumor molecular markers specifically related
to energy balance may contribute insights into the role of obesity and
energy balance in carcinogenesis. We propose that fatty acid syn-
thase (FASN) may be a candidate biomarker, because in tumor cells,
most fatty acids are synthesized de novo by FASN. FASN has been
suggested to act as a “metabolic oncogene,” conferring a selective
growth advantage to meet the excessive bioenergetic and structural
demands of proliferating neoplastic cells (Menendez and Lupu, 2007).
Experimentally, FASN activity appears to promote tumor cell prolif-
eration and survival and to allow neoplastic cells to attain autonomy
from the regulation of host metabolic status. In one analysis based
on the Nurses’ Health Study, women who were overweight or obese
were at higher risk of FASN-​negative tumors but not at increased risk
of FASN-​positive tumors relative to normal-​weight women (Kuchiba
et  al., 2012). The authors hypothesized that FASN-​ inactive cells
are dependent on excess energy balance for malignant progression,
whereas FASN-​active cells may progress to cancer independent of
energy balance status. In addition to incidence, tumor FASN status
may also have an influence on prognosis. For both colorectal (Ogino
et  al., 2008)  and prostate cancer (Nguyen et  al., 2010), obesity was
an adverse prognostic factor in individuals whose tumors expressed
FASN. Other tumor-​related metabolic factors may be important in
determining how obesity will influence the development and progres-
sion of specific cancers. Further tumor tissue-​based studies should
increase our understanding of the underlying mechanisms between
adiposity and cancer.
Finally, while it is clear that weight gain should be avoided, the
direct association between weight loss and long-​term cancer risk
deserves further study, given the relatively sparse data on weight loss
to date. In addition, new ideas to reduce this highly prevalent expo-
sure in the population are desperately needed, and may require policy
changes similar to those used to address tobacco control. At a mini-
mum, efforts should be undertaken to increase access to affordable
healthy foods and to enhance opportunities for physical activity for
the population.
 367

Obesity and Body Composition 367

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 37
21 Physical Activity, Sedentary Behaviors, and Risk of Cancer
STEVEN C. MOORE, CHARLES E. MATTHEWS, SARAH KEADLE,
ALPA V. PATEL, AND I-​MIN LEE
OVERVIEW
Current physical activity guidelines recommend that adults perform
at least 150 minutes per week of moderate-​intensity physical activ-
ity (e.g., brisk walking), or 75 minutes per week of vigorous-​intensity
activity (e.g., jogging), or an equivalent combination of these. In the
United States and worldwide, many adults fail to meet these recom-
mended activity levels, with deleterious consequences for health,
including increased risk of some cancers.
In this chapter, we review the epidemiologic evidence for links
between physical activity and cancer, emphasizing published meta-​
analyses and the results of a recent large consortium-​based study. We
find the evidence to be convincing that physical activity reduces risk
of colon and female breast cancers, and probable that it reduces risk
of kidney and endometrial cancers. Moreover, physical activity has
been associated with lower risk of cancers of the bladder, liver, gastric
cardia, head and neck, esophagus (adenocarcinoma), and myeloma,
myeloid leukemia, and non-​Hodgkin lymphoma. Mechanistic studies
indicate that an inadequate level of physical activity can increase levels
of known cancer risk factors such as sex steroid hormones, insulin, and
inflammatory proteins. Physical activity likely has no substantial effect
on risk of cancers of the ovary or lymphocytic leukemia.
We also review evidence that sedentary behaviors (i.e., inactivity
while seated or reclining) may independently increase cancer risk.
Sedentary behaviors are most consistently associated with colon,
endometrial, breast, and ovarian cancers; for other cancer sites, the
current data are inadequate to form conclusions. We also discuss how
physical activity can play a role in the treatment, rehabilitation, and
survivorship from cancer.
Finally, we discuss future research directions, specifically the need
for studies that characterize the dose–​response relationships between
physical activity and cancer, that use new technologies to improve
measurement of physical activity, and that evaluate sedentary behav-
iors in relation to cancer risk.
DEFINITIONS AND CORE CONCEPTS
Physical activity is classically defined as “any bodily movement
produced by skeletal muscles that results in energy expenditure”
(Caspersen et  al., 1985). It includes both “exercise,” defined as
planned, structured, and repetitive activities done to improve health or
fitness (Physical Activity Guidelines Advisory Committee, 2008), and
non-​exercise activities. A  variety of physical and social contexts or
“domains” are used to categorize physical activity; these include activ-
ities related to occupation, the household, education, transportation,
and leisure time. The term “leisure-​time physical activity” reflects a
broad class of activities that involve both exercise and recreational
pursuits. In practice, the terms “leisure time” and “recreational” are
sometimes used interchangeably, and recreational physical activity
may include exercise. Sedentary behaviors are behaviors done during
waking hours that involve sitting or reclining and/​or a low level of
energy expenditure (Lynch et al., 2010).
Physical activity and sedentary behaviors are characterized accord-
ing to the type, frequency, duration, and intensity of activity. Type
refers to the specific kind of exercise, such as aerobic (e.g., walking
or running) or muscle-​ strengthening activities like weight lifting.
Frequency refers to the number of times the activity occurs, usually
in days per week. Duration refers to the time expended, usually in
hours per week. Intensity refers to the average energy cost of the activ-
ity; it is typically quantified using metabolic equivalents (METs).
The MET expresses an individual’s energy expenditure in terms of
multiples of energy expenditure at rest. An MET of 1 equals energy
expenditure during quiet sitting; an MET of less than 3 corresponds
to energy expenditure during light-​intensity activities such as washing
dishes; an MET of 3.0–​5.9 corresponds to energy expenditure during
walking or other moderate intensity activities; and an MET of 6.0+
corresponds to energy expenditure during vigorous-​intensity activities
such as running. The MET values of at least 600 types of activities
have been measured in controlled laboratory settings and compiled in
the Compendium of Physical Activities (https://​sites.google.com/​site/​
compendiumofphysicalactivities).
The volume or total amount of activity for a given individual rep-
resents cumulative energy expended during a specified time period,
often per week. This is calculated by multiplying the intensity of each
activity (in METs) by its duration (in hrs/​wk), and then summing
across all activities to obtain an overall MET-​hrs/​wk.
EXPOSURE MEASUREMENT
Habitual patterns of behavior can be estimated from records, such
as job classifications, or self-​reported information obtained by inter-
view or self-​administered questionnaires. Epidemiologic studies also
increasingly incorporate personal devices such as accelerometers to
track movement, or other objective measures of cardiorespiratory fit-
ness and muscular strength. Since there are as yet relatively few stud-
ies of cancer outcomes that have used these methods, this chapter
focuses primarily on studies of self-​reported or occupational indicators
of physical activity in relation to cancer.
Questionnaires
Nearly 100 different surveys/​ questionnaires have been developed
and validated to assess physical activity behaviors over the short (1–​
30  days) and long term (1–​10  years, lifetime) (Pereira et  al., 1997;
Sallis and Saelens, 2000; van Poppel et al., 2010). These questionnaires
can be either self-​administered or completed using trained interviewers.
The time period of interest can be limited to the past year, or can cover
the entire life course, beginning in childhood and adolescence.
Interviewer-​ administered questionnaires are commonly used in
case-​control studies where staff can make direct contact with partici-
pants or their next of kin. The interviews can take from 10 minutes
to 1 hour, depending on the length and complexity of the instrument.
They typically collect more detailed information than can be obtained
with self-​administered questionnaires. Interviewers help to ensure that
respondents understand the questions and that the responses are logi-
cal (Sallis, 1997).
Self-​administered questionnaires are widely used in prospective
cohort studies, where collecting data by personal interview is cost
377
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378 PART III:  THE CAUSES OF CANCER
prohibitive. Self-​administered questionnaires tend to be simpler and
more streamlined than interviewer-​ administered instruments; they
generally assess the amount of time spent per week in only a few
activity domains (e.g., leisure-​time, occupation), plus one or two addi-
tional questions to assess common daily activities (e.g., household
chores, sitting time). Self-​administered instruments tend to focus on
the domain(s) that are reported most reliably and that pertain to spe-
cific hypotheses, such as the effects of leisure-​time physical activity
on cancer risk.
A limitation of both interviewer-​ based and self-​ administered
questionnaires is that it is difficult for people to recall behaviors in
past years (Matthews, 2002). The extent to which this contributes to
measurement error continues to be debated, however (Neilson et al.,
2008)  and likely varies by the type of activity. Leisure-​time and/​or
vigorous activities are known to be more reliably reported than other
aspects of daily life (Sallis and Saelens, 2000; van Poppel et  al.,
2010), possibly because they represent discrete and structured enti-
ties (Matthews et al., 2012b). In contrast, lower-​intensity daily activi-
ties (e.g., non-​exercise activity), often conducted in short bouts, are
reported less reliably (Matthews et al., 2012b). In prospective studies,
errors in measuring physical activity that occurred many years before
the onset of disease are likely to be non-​differential with respect to dis-
ease. Non-​differential misclassification of exposure typically attenu-
ates associations (Ferrari et al., 2007; Matthews et al., 2012b), thereby
underestimating relationships that are causal. Similar considerations
apply to the assessment of sedentary behaviors. Structured sedentary
behaviors, such as television viewing, appear to be reported more reli-
ably than sporadic, unstructured behaviors (Healy et al., 2011).
Job Classifications/​Occupational Physical Activity
Job titles provide some information about the amount of physical
activity or sedentary behavior while at work. For example, epidemi-
ologists have compared the cancer risk among people with more sed-
entary jobs (e.g., office and clerical workers) with workers whose jobs
require physical activity (e.g., laborers, delivery workers) (Garabrant
et al., 1984; Moradi et al., 1998). Employment records are especially
useful because they provide objective evidence about the jobs held
and the duration of each job. Limitations of job titles are that they do
not specify the actual behavior(s) involved, the variations in activity
among individuals with the same title, and changes in employment
over time.
GUIDELINES FOR PHYSICAL ACTIVITY
In 2008, the US government released “Guidelines for Physical Activity
for Americans” (US Department of Health and Human Services).
These guidelines recommended the amount and intensity of aerobic
and muscle-​strengthening activities considered optimal to maintain
health in adults. For aerobic activity, adults were advised to engage
in at least 150 minutes per week of moderate-​intensity physical activ-
ity (e.g., brisk walking), or 75 minutes per week of vigorous-​intensity
activity (e.g., jogging), or some combination thereof that expends an
equivalent amount of energy. For muscle-​strengthening activities, the
guidelines recommend muscle-​strengthening activities that involve all
major muscle groups on 2 or more days a week. Similar guidelines
have been adopted by other countries worldwide for general health
recommendations (World Health Organization, 2010), and specifically
for cancer prevention (World Cancer Research Fund and American
Institute for Cancer Research 2007).
SURVEYS OF PHYSICAL ACTIVITY
Several health surveys monitor physical activity in the United States.
These include the Behavioral Risk Factor Surveillance System
(BRFSS), a telephone survey conducted by random-​ digit dialing
(Behavioral Risk Factor Surveillance System); the National Health
Interview Survey (NHIS), which uses personal interviews (National
Health Interview Survey); and the National Health and Nutrition
Examination Survey (NHANES), which conducts both personal
interviews and physical examinations (National Health and Nutrition
Examination Survey). All three surveys collect self-​reported informa-
tion on physical activity. In addition, NHANES uses accelerometers to
measure movement over 7 days (Troiano et al., 2008).
Different physical activity questionnaires obtain different informa-
tion. Because of this, estimates of the proportion of US adults who meet
the recommended activity levels differ, especially when compared to
accelerometry measurements (Carlson et al., 2009). According to the
BRFSS survey in 2011, 51.6% of US adults met the aerobic activity
guideline, 29.3% met the muscle-​strengthening guideline, and 20.6%
met both parts (Centers for Disease and Prevention, 2013). Similar
prevalence estimates were reported in the 2013 NHIS, in which 49.4%,
23.9%, and 20.4% of respondents, respectively, met the guidelines
for aerobic activity, muscle strengthening, or both (National Center
for Health Statistics, 2015). According to self-​reported data in the
NHANES 2005–​2006 collection cycle, 62.0% of respondents met the
aerobic activity guideline (Tucker et al., 2011). However, only 9.6% of
participants met this guideline according to accelerometry measure-
ments limited to activities that lasted at least 10 minutes, as speci-
fied by the guidelines. This percentage increased to 44.6% when all
measurements were included, without the restriction to ≥ 10-​minute
duration (Tucker et al., 2011).
Several factors likely contribute to the large discrepancy in the
proportion meeting the aerobic activity guideline (62.0% versus
9.6%) when comparing self-​reported data (62.0%) to accelerometry
measurements (9.6%). First, accelerometers only record continuous
movement and discount all periods of rest. For example, in a 2-​hour
tennis game, the accelerometer will register less than 2 hours of con-
tinuous movement, because of breaks during the game. In contrast,
individuals may report the game as 2 full hours of activity. Second, the
algorithms used to process raw accelerometer information (i.e., activ-
ity counts) into minutes of moderate-​to-​vigorous-​intensity activity
can influence prevalence estimates. When a different algorithm—​one
designed to capture a broader range of daily activities—​was applied
to the NHANES data, it resulted in prevalence estimates that were
more consistent with the estimates based on self-​report (Matthews
et al., 2005; Watson et al., 2014). Comparable data do not exist for
muscle-​strengthening activities since the accelerometer cannot mea-
sure these activities.
While estimates of the proportion of people meeting the physical
activity guidelines may vary, the descriptive data consistently indicate
that Americans are sedentary during at least half of their waking day.
In the 2003–​2004 data collection cycle of NHANES, time expended
in sedentary behaviors was measured objectively by accelerometry
(Matthews et al., 2008). Among the more than 6000 participants with
at least one 10-​hour day of monitoring, 54.9% of the monitored time
was sedentary. Most people in the United States spent the majority of
their time on behaviors that expend very little energy.
Internationally, many other countries have also collected self-​
reported information on physical activity. Self-​reported data collected
for the WHO global health observatory data repository show that
31.1% of the adult population worldwide in 2008 did not meet the
guideline for aerobic activity (i.e., 68.9% did) (Hallal et  al., 2012).
The percentage failing to meet the guideline ranged from 17.0% in
Southeast Asia to approximately 43% in the Americas and the eastern
Mediterranean region.
MECHANISMS OF CARCINOGENESIS
Physical activity is a physiologically complex behavior that involves
numerous highly coordinated biological responses. An acute bout of
physical activity increases oxygen consumption by up to 15-​fold
compared with the resting state, accelerates ATP turnover in skel-
etal muscle, increases secretion of glucose into the bloodstream and
uptake of glucose into muscles, and modulates the levels and activ-
ity of multiple signaling factors such as insulin, growth factors, and
hormones (Hawley et  al., 2014). Because physical activity results
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Physical Activity, Sedentary Behaviors, and Risk of Cancer 379
in a variety of interrelated biological effects that are still not com-
pletely understood (Hawley et  al., 2014), research on the mecha-
nisms by which physical activity may affect cancer risk continues
to evolve. Research to date has focused primarily on the effects of
physical activity on sex steroid hormones, insulin and insulin-​like
growth factors, inflammation, and weight change (Friedenreich
et al., 2010; McTiernan, 2008).
Sex Steroid Hormones
Sex steroid hormones have powerful proliferative and mutagenic
effects. Excessive levels of estrogens, in particular, increase risk of
breast and endometrial cancers (Chlebowski et al., 2003; Weiderpass
et al., 1999; Yager and Davidson, 2006). A meta-​analysis of random-
ized exercise intervention studies of 3–​12 months duration (Ennour-​
Idrissi et al., 2015) showed that exercise reduces concentrations of
total estrogens (21 studies), free estradiol (5 studies), free testos-
terone (9 studies), androstenedione (7 studies), and DHEA sulfate
(8 studies), and increases concentrations of sex hormone–​binding
globulin (14 studies). The effect of exercise on total estrogens,
while statistically significant, was relatively weak and appeared
to be mediated through exercise-​induced changes in body weight,
rather than through exercise itself. In contrast, its effects on free
estradiol (not bound to proteins) and sex hormone–​binding globu-
lin are greater than its effect on total estrogens, and are indepen-
dent of changes in body weight. The effects of physical activity on
sex hormones have been documented in randomized clinical trials.
These, combined with definitive evidence that sex hormones influ-
ence carcinogenesis, provide strong, albeit indirect, evidence that
sex hormones mediate at least part of the effect of physical activity
on hormonally related cancers.
Insulin and Other Growth Factors Related
to Insulin Resistance
Insulin is a known mitogen (Ish-​Shalom et al., 1997; Mu et al., 2012);
administration of exogenous insulin promotes breast tumor growth in
animal models (Shafie and Hilf, 1981). Chronic hyperinsulinemia is
also associated with reduced hepatic secretion of sex hormone–​binding
globulin (Pugeat et al., 1991), which increases levels of bioavailable
steroidal sex hormones. In observational studies, higher levels of insu-
lin have been associated with increased risk of breast, endometrial,
pancreatic, and colorectal cancers (Godsland, 2010; Gunter et  al.,
2008, 2009; Kaaks and Lukanova, 2001; Stolzenberg-​Solomon et al.,
2005). In two randomized clinical trials of physical activity, assign-
ment to the exercise group for 12  months reduced circulating levels
of insulin by 13% and 16% in postmenopausal women (Frank et al.,
2005; Friedenreich et al., 2011). The ability of exercise to reduce insu-
lin levels may partly explain why physical activity is associated with
lower risk of cancers thought to be insulin-​related. However, it is dif-
ficult to separate the effects mediated by insulin from other factors
closely related to insulin.
Insulin-​like growth factor (IGF)-​ 1 is a hormone with high
sequence similarity to insulin, but with even stronger mitogenic
effects (Zapf et  al., 1984). Molecular epidemiological studies
have confirmed an association between high circulating levels of
IGF-​1 and modest increases in risk of cancers of the breast, pros-
tate, and colorectum (Endogenous Hormones and Breast Cancer
Collaborative Group, 2010). However, randomized clinical trials of
exercise suggest that exercise does not affect the circulating levels
of IGF-​1 (McTiernan et al., 2005). Therefore IGF-​1 seems unlikely
to mediate the inverse relationship between physical activity and
risk of these cancers.
Inflammation
Chronic inflammation increases the risk of multiple types of cancer
(Chapter  25). Inflammation creates a tissue microenvironment with
elevated levels of DNA-​damaging reactive oxygen species (Coussens
and Werb, 2002) and chemokines that stimulate cellular proliferation
and promote the survival of genetically damaged cells (Mantovani
et al., 2008). In epidemiologic studies, increased levels of circulating
pro-​inflammatory factors, such as C-​reactive protein (CRP), interleu-
kin 6 (IL6), tumor necrosis factor ɑ (TNFɑ), and decreased levels of
anti-​inflammatory factors like adiponectin have been associated with
increased cancer risk (Gunter et al., 2015; Ho et al., 2012; Nimptsch
et al., 2015; Ollberding et al., 2013; Toriola et al., 2013; Wang et al.,
2011). It is unclear, however, whether regular physical activity modi-
fies the effects of local and/​or systemic inflammation. In randomized
clinical trials, assignment to exercise for 12 months has had inconsis-
tent effects on levels of C-​reactive protein, with some studies report-
ing an inverse association (Campbell et  al., 2009), but others not
(Campbell et al., 2008; Kelley and Kelley, 2006). Randomized exer-
cise trials among postmenopausal women also had little effect on adi-
ponectin concentrations (Abbenhardt et al., 2013; Friedenreich et al.,
2011). Overall, while inflammation may ultimately prove to mediate
some the effects linking low physical activity to cancer risk, the cur-
rent evidence is mixed.
Prevention of Weight Gain
Excess body weight increases the risk of more than a dozen different
types of cancer (World Cancer Research Fund and American Institute
for Cancer Research, 2007) (Chapter 20). Several of the mechanisms
thought to mediate the effects of excess body fat on cancer risk are
also affected by physical inactivity. For example, whereas excess
adiposity increases the peripheral aromatization of testosterone and
androstenedione in fat tissue and is a major source of estrogen in
postmenopausal women (Judd et al., 1982; Key et al., 2015), physi-
cal activity has been shown to reduce the concentrations of free
estradiol, free testosterone, and other sex hormones in randomized
clinical trials. This hormonal effect is thought to contribute to the
increased risk of endometrial and postmenopausal breast cancer in
obese women, and to the reductions in risk of these cancers in physi-
cally active women (Brown and Hankinson, 2015; Key et al., 2003).
Excess adiposity and physical activity also have opposing effects on
hyperinsulinemia and perhaps inflammation (Calle and Kaaks, 2004;
Kahn and Flier, 2000).
A meta-​analysis of 16 randomized exercise intervention studies,
including a total of 1737 participants, has shown that exercise, usu-
ally for a period of 3–​12 months, results in an average body weight
loss of 1.8 kg (Ennour-​Idrissi et al., 2015), a modest but discernible
difference in weight. In longer-​term studies, young adults (age 18–​
30 years) who maintain a high level of activity over 20 years gain less
body weight compared to their less active counterparts. Active men
gained 2.6 fewer kilograms and women gained 6.1 fewer kilograms
(Hankinson et al., 2010). In a study of middle-​aged women (mean age
54.2 years), a high level of physical activity was associated with 0.12
fewer kilograms gained per 3 years (Lee et al., 2010). In sum, excess
body weight contributes to increased cancer risk, and physical activ-
ity at the levels typically performed in the general population helps to
reduce weight gain.
Other Mechanisms
The recent advent of new “omics”-​based technologies, such as pro-
teomics and metabolomics, has broadened the opportunities to study
the endocrine functions of skeletal muscle. Myokines are cytokines
or proteoglycan peptides that are produced and released by muscle
cells in response to muscular contraction. Different types of myo-
kines have different effects on fat metabolism. For example, irisin
stimulates development of brown fat, and brain-​derived neurotrophic
factor (BDNF) helps to modulate fatty acid oxidation (Pedersen and
Febbraio, 2012). Prolonged physical activity may also increase β-​
oxidation of fatty acids within the mitochondria by increasing lipolysis
and fatty acid oxidation (Hawley et al., 2014). It is presently unclear
whether or how these effects may relate to cancer.
380

380 PART III:  THE CAUSES OF CANCER

PHYSICAL ACTIVITY AND RISK
OF DEVELOPING CANCER
Our review of physical activity in relation to cancer risk is based on
the findings of the most recent and comprehensive meta-​analyses
of the topic (Table 21–​1) and on a pooled analysis of 12 large pro-
spective cohorts participating in the National Cancer Institute Cohort
Consortium (Moore et  al., 2016). The number of cases in both
approaches, references for the meta-​analyses, and degree of overlap
between the meta-​and pooled analyses are shown in Table 21–​1.
Description of the Studies
All of the meta-​analyses listed in Table 21–​1 used a similar approach
to measure the risk ratios associated with physical activity and site-​
specific cancers. In each, the highest level of physical activity cor-
responds to the top quintile, quartile, or tertile of activity in the
populations studied, and the lowest level corresponds to the bottom
quintile, quartile, or tertile. Consequently, the relative risks from
the meta-​analyses can be interpreted as approximately the contrast
between the top and bottom quartile of physical activity in both the
prospective and retrospective studies.
With one exception (Zhong et  al., 2014), the meta-​analyses com-
bined all of the domains of physical activity, although data on
leisure-​time physical activity predominate. Occupational activity was
specified in some studies. Several of the meta-​analyses published rel-
ative risk estimates for specific domains; we present these findings
where appropriate.
The 2016 pooled analysis included 1.44 million participants, aged
19–​98  years (median 59  years). Subjects were drawn from 12 pro-
spective cohorts in the United States and Europe, and followed for a
median of 11 years. Overall, 186,932 incident cancers were diagnosed
during follow-​up.
The pooled analysis compared cancer risk in the 90th to the 10th
percentile of leisure-​time physical activity and found that greater
activity was associated with lower cancer risk for 13 of the 26 sites
or subsites examined. The overall summary figure for the analysis is
shown in Figure 21–​1, but the results are discussed in the chapter in the
context of each specific type of cancer.
Strengths of the 2016 pooled analysis are that it relied entirely on
data from prospective studies, eliminated several sources of hetero-
geneity, and increased the number of cases identified prospectively
for some types of cancer. The latter factor was particularly impor-
tant for uncommon and rare types of cancer. For example, the 2016
pooled analysis nearly doubled the number of cases in the literature
for esophageal adenocarcinoma (N  =  899 vs. 454)  and liver cancer
(1384 vs. 628). The pooled analysis eliminated heterogeneity related
to study type (e.g., case-​control vs. prospective cohort), physical activ-
ity domain (leisure-​time vs. occupational activity), and the categories
being contrasted (e.g. tertiles vs. quintiles).
Results from the Meta-​and Pooled Analyses
Table 21–​2 shows the multivariable relative risk (RR) estimates and
95% confidence intervals (CIs) for high versus low levels of physical
activity by cancer type as reported by the meta-​and pooled analy-
ses. The results from the pooled analysis are presented graphically in
Figure 21–​1. The similarity of findings from the meta-​analyses and
the 2016 pooled analysis strengthens confidence that these results are
reproducible.
Summary of Evidence
Based on these data, we characterized the evidence for a causal rela-
tionship between physical activity and reduced risk of various types of
cancer into one of six levels: convincing, probable, limited–​suggestive,
uncertain–​may be confounded, inconsistent, and substantial effect
unlikely. The criteria used to define these evidence levels are shown in
Table 21–​3. For three of the levels (convincing, probable, and limited–​
suggestive), the criteria were adapted from those used by the World
Cancer Research Fund (WCRF) and the American Institute for Cancer
Research (AICR) in their review entitled “Food, Nutrition, Physical
Activity, and the Prevention of Cancer: A Global Perspective” (World
Cancer Research Fund and American Institute for Cancer Research,

Table 21–​1. Case Numbers in Meta-​analyses that Examine Physical Activity and Cancer Associations and in a 2016 Pooled Analysis1

Cases in Meta-​ Cases Overlapping

Analysis, Prospective + Cases in Meta-​Analysis, Cases in Pooled Between Meta-​analysis and
Cancer Reference Case-​Control Prospective Studies Analysis Pooled Analysis

Colon Wolin et al., 2009 Not specified Not specified 14,160 6,612
Breast Wu et al., 2013 63,786 63,786 35,178 21,891
Kidney Behrens and Leitzmann, 2013 10,756 6104 4548 1,238
Endometrial Schmid et al., 2015 19,558 10,740 5346 3,309
Bladder Keimling et al., 2014 27,784 25,174 9073 1,831
Liver Behrens et al., 20132 628 628 1384 628
Esophageal Behrens et al., 2014 965 454 899 454
adenocarcinoma
Gastric cardia Behrens et al., 2014 844 436 790 313
Myeloma Jochem et al., 2014 1362 1362 2161 814
Myeloid leukemia N/​A 0 0 1692 0
Non-​Hodgkin lymphoma Jochem et al., 2014 9447 5243 6953 3,506
Head and neck Leitzmann et al., 20082 1249 1249 3985 1,249
Lung Brenner et al., 2016 20,169 14,306 19,133 8,605
Malignant melanoma N/​A 0 0 12,438 0
Pancreas Behrens et al., 2015 10,501 8091 4186 1,877
Prostate Liu et al., 2011 88,294 74,942 46,890 20,691
Rectum Robsahm et al., 2013 8698 8698 5531 2,463
Brain Niedermaier et al., 2015 2538 1194 2110 257
Thyroid Schmid et al., 2013 2250 1329 1829 770
Ovary Zhong et al., 2014 9459 2467 2880 801
Lymphocytic leukemia N/​A 0 0 2160 0

1
Moore et al. (2016). Association of leisure-​time physical activity with risk of 26 types of cancer in 1.44 million adults. JAMA Intern Med, 176(6), 816–​825.
2
Case numbers are based on the largest prospective cohort study, as no meta-​analyses or reviews have been published.
 381

Physical Activity, Sedentary Behaviors, and Risk of Cancer 381

Cancer # of Studies Cases HR (95% Cl) Ptrend Pheterogeneity
Esophageal adenocarcinoma 5 899 0.58 (0.37–0.89) 0.01 0.01

Gallbladder 6 382 0.72 (0.51–1.01) 0.06 0.29

Liver 10 1,384 0.73 (0.55–0.98) 0.04 0.02

Lung 12 19,133 0.74 (0.71–0.77) < 0.001 0.47

Kidney 11 4,548 0.77 (0.70–0.85) < 0.001 0.40

Small intestine 7 503 0.78 (0.60–1.00) 0.05 0.85

Gastric cardia 6 790 0.78 (0.64–0.95) 0.02 0.99

Endometrial 9 5,346 0.79 (0.68–0.92) 0.003 < 0.01

Esophageal squamous 6 442 0.80 (0.61–1.06) 0.12 0.78

Myeloid leukemia 10 1,692 0.80 (0.70–0.92) 0.002 0.78

Myeloma 9 2,161 0.83 (0.72–0.95) 0.008 0.36

Colon 12 14,160 0.84 (0.77–0.91) < 0.001 0.01

Head and neck 11 3,985 0.85 (0.78–0.93) < 0.001 0.45

Rectum 12 5,531 0.87 (0.80–0.95) 0.001 0.38

Bladder 12 9,073 0.87 (0.82–0.92) < 0.001 0.84

Breast 10 35,178 0.90 (0.87–0.93) < 0.001 0.30

Non-Hodgkin lymphoma 11 6,853 0.91 (0.83–1.00) 0.05 0.18

Thyroid 11 1,829 0.92 (0.81–1.06) 0.26 0.48

Gastric non-cardia 7 1,428 0.93 (0.73–1.19) 0.56 0.09

Soft tissue 10 851 0.94 (0.67–1.31) 0.70 0.03

Pancreas 10 4,186 0.95 (0.83–1.08) 0.40 0.14

Lymphocytic leukemia 10 2,160 0.98 (0.87–1.11) 0.73 0.99

Ovary 9 2,880 1.01 (0.91–1.13) 0.81 0.98

Brain 10 2,110 1.06 (0.93–1.20) 0.41 0.43

Prostate 7 46,890 1.05 (1.03–1.08) < 0.001 0.90

Malignant melanoma 12 12,438 1.27 (1.16–1.40) < 0.001 0.02

0.3 0.6 1 0.5

Hazard Ratio (90th vs 10th percentile of physical activity)

Figure 21–​1.  Summary multivariable hazard ratios (HR) and 95% confidence intervals (CI) for a higher (90th percentile) versus lower (10th percentile)
level of leisure-​time physical activity by cancer type in a pooled analysis of 12 prospective studies (Moore et al., 2016).

2007). Important considerations included the number of cases in pro- Colon Cancer

spective studies, the biological plausibility of the association (demon-
strated for many cancers in mechanisms section above), evidence for
a dose–​response relationship, and the likelihood of residual confound-
ing. Our findings are summarized in Table 21–​3.
Under these criteria, there was convincing evidence that physical
activity reduces the risk of colon and female breast cancers, and there
was probable evidence that activity protects against the development of
kidney and endometrial cancers. There was some evidence that physi-
cal activity may be inversely related to cancers of the bladder, liver,
gastric cardia, and head and neck, as well as esophageal adenocar-
cinoma, myeloma, myeloid leukemia, and non-​Hodgkin lymphoma.
The evidence was “uncertain–​may be confounded” for lung cancer
and melanoma because of concerns that observed associations were
influenced by residual confounding by smoking (lung cancer) and
sun exposure (melanoma). The evidence was inconsistent for cancers
of the pancreas, prostate, rectum, brain, and thyroid; for these sites,
unexplained heterogeneity in the associations was detected across the
studies. Finally, for ovarian cancer, and lymphocytic leukemia, evi-
dence indicates that a substantial effect of physical activity on risk is
unlikely.
We review the findings for each cancer in the following, presented
in order of the strength of the total evidence for a physical activity and
risk association.
Cancers of the large bowel were the most commonly studied can-
cers in early epidemiologic research on physical activity and cancer
(Chapter  23, Lee and Oguma, 2006). The inverse relationship with
physical activity was consistently stronger for colon than for rectum
cancer; we therefore discuss rectal cancer separately below, as part of
“other cancers.”
The meta-​analysis by Wolin and colleagues (2009) included cases
from 52 publications based on 28 cohort and 24 case-​control studies
conducted in the United States, Europe, and Asia. The total number of
cases was not specified. Overall, the most active people had 24% lower
risk of colon cancer than those who were least active (meta-​RR = 0.76;
95% CI: 0.72, 0.81) (see Figure 21–​2). The findings were similar for
men (RR = 0.76; 95% CI: 0.71, 0.82) and women (RR = 0.79; 95%
CI: 0.71, 0.88).
The inverse association was stronger in the meta-​analysis of case-​
control (RR  =  0.69; 95% CI:  0.65, 0.74) than that of cohort studies
(RR  =  0.83; 95% CI:  0.78, 0.88), most likely reflecting recall bias
among participants in case-​control studies. Investigators also exam-
ined domain-​specific physical activity in the meta-​analysis with signif-
icant risk reductions observed for both occupational (RR = 0.78; 95%
CI:  0.74, 0.83) and leisure-​time physical activity (RR  =  0.77; 95%
CI: 0.72, 0.82).
382

382 PART III:  THE CAUSES OF CANCER

Table 21–​2. Multivariable Relative Risks (RRs) and 95% Confidence Intervals (CIs)
for High Versus Low Levels of Physical Activity by Cancer Type According to Recent
Meta-​analysis and Moore et al.

RR (95% CI) HR (95% CI)

Cancer Meta-​analysis1 Moore et al.2

Colon 0.76 (0.72, 0.81) 0.84 (0.77, 0.91)

Breast 0.87 (0.83, 0.92) 0.90 (0.87, 0.93)
Kidney 0.88 (0.79, 0.97) 0.77 (0.70, 0.85)
Endometrial 0.80 (0.75, 0.85) 0.79 (0.68, 0.92)
Bladder 0.85 (0.74, 0.98) 0.87 (0.82, 0.92)
Liver3 0.64 (0.49, 0.84) 0.73 (0.55, 0.98)
Esophageal adenocarcinoma 0.79 (0.66, 0.94) 0.58 (0.37, 0.89)
Gastric cardia 0.83 (0.69, 0.99) 0.78 (0.64, 0.95)
Myeloma 0.86 (0.68, 1.09) 0.83 (0.72, 0.95)
Myeloid leukemia Not available 0.80 (0.70, 0.92)
Non-​Hodgkin lymphoma 0.91 (0.82, 1.00) 0.91 (0.83, 1.00)
Head and neck3 0.89 (0.74, 1.06) 0.85 (0.78, 0.93)
Lung 0.76 (0.69, 0.85) 0.74 (0.71, 0.77)
Malignant melanoma Not available 1.27 (1.16, 1.40)
Pancreas 0.93 (0.88, 0.98) 0.95 (0.83, 1.08)
Prostate 0.90 (0.84, 0.95) 1.05 (1.03, 1.08)
Rectum 0.98 (0.88, 1.08) 0.87 (0.80, 0.95)
Brain 0.86 (0.76, 0.97) 1.06 (0.93, 1.20)
Thyroid 1.06 (0.79, 1.42) 0.92 (0.81, 1.06)
Ovary 0.92 (0.84, 1.00) 1.01 (0.91, 1.13)
Lymphocytic leukemia Not available 0.98 (0.87, 1.11)

1
Results incorporate multiple study designs (i.e., case-​control studies and prospective studies) and
multiple types of physical activity, including occupational and leisure-​time (recreational) physical
activity. References are provided in Table 21–​1.
2
Results based on only prospective studies and leisure-​time physical activity.
3
RR derived from the largest prospective cohort study in the literature as no meta-​analyses or reviews
have been published.

The meta-​analysis by Wolin et al. (2009) was unable to examine
the dose–​response relationship in the combined studies because the
methods used to measure physical activity varied. The research-
ers did mention that most of the analyses of cohort studies tested
formally for a dose–​response relation, yet fewer than half reported
a statistically significant inverse trend. Of the 10 case-​control
studies that also tested for a trend across activity levels, four
reported a significant inverse trend in at least one subgroup. In the
Nurses’ Health Study (Wolin et al., 2007), a 23% risk reduction—​
comparable to the overall meta-​analysis results—​was observed
among women expending 21.5 MET-​hours/​week of leisure-​time
physical activity (equivalent to 5–​6 hours/​week of brisk walking),
compared to those expending < 2 MET-​hours/​week (approximately
0.5 hours/​week).
The relative risk estimates reported by the individual studies were
adjusted for multiple potential confounders that varied across studies.
The majority of studies included obesity as a potential confounder. The
findings suggested that the inverse relationship between physical activ-
ity and colon cancer risk was independent of its effects on body weight.
A meta-​analysis by Boyle et  al. (2012) investigated whether the
reduction in colon cancer risk associated with physical activity differed
for proximal and distal cancers. Cancers that arise in these two subsites
differ with regard to their morphologic, molecular, and genetic charac-
teristics. Among the 12 cohort and case-​control studies included, risk

Table 21–​3. Summary of Evidence on Physical Activity and its Association with Risk of Cancer

Evidence Level Criteria for Evidence Level Cancers at Evidence Level

Convincing > 10,000 cases in prospective studies Colon, Female breast
Evidence for a dose–​response relationship
Biologically plausible
Low possibility of confounding
Probable > 5000 cases in prospective studies Kidney, Endometrium
Evidence for a dose–​response relationship
Biologically plausible
Some possibility of confounding
Limited–​suggestive > 500 cases in prospective studies Bladder, Liver, Esophageal adenocarcinoma,
Evidence for a relationship Gastric cardia, Myeloma, Myeloid leukemia,
Biologically plausible Non-​Hodgkin lymphoma, Head and neck
Some possibility of confounding
Uncertain–​may be confounded Evidence for a relationship Lung, Melanoma (increased risk)
Results seem likely to be confounded
Sensitivity analyses do not rule out confounding
Inconsistent Results vary by study type or over time Pancreas, Prostate, Rectum, Brain, Thyroid
Reasons for variability are unclear
Substantial effect unlikely > 2000 cases in prospective studies Ovary, Lymphocytic leukemia
Aggregate RR of 0.95 to 1.05
 38
Physical Activity, Sedentary Behaviors, and Risk of Cancer 383
Category # of Studies
Overall 52
Cohort 28
Case-control 24
Men 30
Women 30
Occupational 32
LTPA 26
0 1
Relative risk (95% Cl)
High vs. low physical activity
Figure 21–​2.  Colon cancer and its association with physical activity.
of proximal colon cancer was 27% lower among the most active peo-
ple compared to the least active (random effects summary RR = 0.73;
95% CI: 0.66, 0.81). This reduction in risk was indistinguishable from
the 26% lower risk of distal colon cancer (RR = 0.74; 95% CI: 0.68,
0.80). As with the other analyses described earlier, the findings were
similar in men and in women, and the inverse relationship was stronger
in case-​control than cohort studies.
The results of the pooled analysis in 2016 strongly support the find-
ings of Wolin et  al. (2009) with respect to the overall reduction in
risk. The relative risk and 95% confidence interval estimates for high
versus low levels of leisure-​time activity were 0.84 (95% CI:  0.77,
0.91) for colon cancer. This is nearly identical to the hazard ratio of
0.83 observed in the meta-​analysis of prospective studies by Wolin
et al. (2009).
In summary, based on the available evidence, there is convinc-
ing support for a causal relationship between physical activity and
reduced risk of developing colon cancer. This conclusion is consist-
ent with those of several expert panels (IARC Handbooks of Cancer
Prevention, 2002; Kushi et al., 2012; World Cancer Research Fund and
American Institute for Cancer Research, 2007).
Female Breast Cancer
The only meta-​analysis that formally quantified the association between
physical activity and breast cancer risk was by Wu et  al. (2013). It
included 63,786 breast cancer cases drawn from 31 prospective cohorts
in North America, Europe, and Asia. Overall, the most active women
had a 13% lower risk of developing breast cancer than the least active
women (RR = 0.87; 95% CI: 0.83, 0.92; see Figure 21–​3). Associations
were similar for recreational activity (RR = 0.87; 95% CI: 0.83, 0.91;
25 studies) and occupational activity (RR = 0.84; 95% CI: 0.73, 0.96;
7 studies). The analysis of recreational activity used restricted cubic
spline models to show that the dose–​response association was approxi-
mately linear (P for non-​linearity = 0.45); each additional increment of
10 MET-​hours/​week correlated with a 3% lower risk of breast cancer.
The associations were stronger for vigorous-​intensity physical activity
(RR = 0.85; 95% CI: 0.80, 0.90; 21 studies) than for moderate-​intensity
activity (RR = 0.95; 95% CI: 0.90, 0.99; 16 studies).
Wu et  al. (2013) also examined whether the inverse associa-
tion between breast cancer and physical activity was modified by
RR (95% Cl)
0.76 (0.72, 0.81)
0.83 (0.78, 0.88)
0.69 (0.65, 0.74)
0.76 (0.71, 0.82)
0.79 (0.71, 0.88)
0.78 (0.74, 0.83)
0.77 (0.72, 0.82)
2
menopausal status, body mass index, or period of life during which
activity occurred. The point estimates were lower for women with
premenopausal breast cancer (RR  =  0.77; 95% CI:  0.69, 0.86)
than postmenopausal disease (RR = 0.87; 95% CI: 0.82, 0.92), and
in those with a BMI < 25  kg/​m2 (RR  =  0.72; 95% CI:  0.65, 0.90)
than in women who were overweight or obese (BMI ≥ 25  kg/​m2)
(RR  =  0.93; 95% CI:  0.87, 0.98). Finally, the pooled RR estimate
associated with physical activity was slightly lower for women age
≥ 50 years (RR = 0.83; 95% CI: 0.76, 0.91) than for women age <
25 years (RR = 0.90; 95% CI: 0.81, 1.02). However, no formal tests
of heterogeneity were reported, and the 95% CI overlapped in most
subgroup analyses.
Associations also varied according to estrogen receptor (ER) and
progesterone receptor (PR) positivity, with lower point estimates for
ER–​/​PR–​cancers (RR = 0.77; 95% CI: 0.65, 0.90) (8 studies) than for
ER+/​PR+ cancers (RR  =  0.93; 95% CI:  0.87, 0.98) (7 studies). The
significance of this is uncertain, given the limited number of studies in
these analyses and the lack of a mechanistic basis for the finding.
Relative risk estimates in studies were appropriately adjusted for
potential confounders, including body mass index (BMI), menopau-
sal status and hormone therapy, reproductive history, and family his-
tory. Where available, the authors also presented relative risks from
analyses adjusted only for age and found substantively similar results
(RR  =  0.85; 95% CI:  0.79, 0.90), indicating that adjustment for the
available confounders had little overall effect on the results.
Friedenrich et al. (2011) systematically reviewed the association of
physical activity with breast cancer risk in 75 cohort and case control
studies conducted worldwide. In this review, women who were the
most physically active had, on average, 25% lower risk of developing
breast cancer as compared with the least active women. These inverse
relationships were slightly stronger in the case control studies (RR 0.7)
than in the cohort studies (RR 0.8). Overall, the results were generally
consistent with those of Wu et al. (2013).
The 2016 pooled analysis reported a relative risk estimate of 0.90
(95% CI: 0.87, 0.93) comparing breast cancer risk among women with
the highest versus lowest level of leisure-​time activity. This is similar
to the hazard ratio of 0.87 reported from the meta-​analysis by Wu et al.
(2013).
In summary, the evidence is convincing that higher levels of physi-
cal activity are associated with lower risk of breast cancer. Additional
data on the benefits of vigorous-​intensity versus moderate-​intensity
384

384 PART III:  THE CAUSES OF CANCER

Category # of Studies RR (95% Cl)

Overall 31 0.87 (0.83, 0.92)

Premenopausal 6 0.77 (0.69, 0.86)

Postmenopausal 17 0.87 (0.82, 0.92)

ER-/PR- 7 0.77 (0.65, 0.90)

ER+/PR+ 8 0.93 (0.87, 0.98)

Occupational 7 0.84 (0.73, 0.96)

LTPA 25 0.87 (0.83, 0.91)

0 1 2
Relative risk (95% Cl)
High vs. low physical activity

Figure 21–​3.  Female breast cancer and its association with physical activity.

activities, and on how associations vary according to ER/​PR and other
breast cancer subtypes, would help to refine understanding of this
relationship.
Kidney Cancer
Behrens and Leitzmann (2013) identified a total of 19 studies (11
cohort, 8 case control) from North America, Europe, and Asia that
examined the association between physical activity and renal cell
carcinoma, which accounts for approximately 90% of all kidney
cancers. The analysis was based on 10,756 cases. Overall, physi-
cal activity was inversely associated with risk of renal cell cancer
(RR = 0.88; 95% CI: 0.79, 0.97). Results were similar for the pro-
spective studies (RR = 0.87; 95% CI: 0.79, 0.97) and case-​control
studies (RR  =  0.89; 95% CI:  0.74, 1.06). The point estimate was
somewhat lower (RR = 0.78; 95% CI: 0.66, 0.92) in studies judged
to be of higher quality according to a predetermined rubric than
in the overall analysis. The dose–​response relationship was not
assessed. The strength of association was similar for recreational
and occupational physical activity, and did not appear to vary
according to the age when the activity occurred. Adjustments for
smoking, BMI, hypertension, and diabetes had little effect on the
association.
In the 2016 pooled analysis, leisure-​ time physical activity was
inversely associated with kidney cancer (RR  =  0.77; 95% CI:  0.70,
0.85). This association was stronger than that observed by Behrens
and Leitzmann (2013) when comparing high versus low levels of over-
all activity (RR = 0.88; 95% CI: 0.79, 0.97), and recreational activity
(RR = 0.88; 95% CI: 0.77, 1.00). The findings from the 2016 pooled
analysis strengthen the evidence of an inverse association between
physical activity and kidney cancer.
Endometrial Cancer
A meta-​analysis by Schmid et  al. (2015) identified 18 cohort stud-
ies, 1 case-​cohort study, and 14 case-​control studies that examined
the association between physical activity and endometrial cancer risk.
Collectively, these studies included 19,558 endometrial cancer cases.
The risk of endometrial cancer risk was 20% lower for women in the
highest compared to the lowest category of physical activity, as shown
by the summary estimate of relative risk (RR = 0.80; 95% CI: 0.75,
0.85) in Figure 21–​4.
Exposure assessment in studies of endometrial cancer and physical
activity was based on self-​administered questionnaires (16 studies),
interview-​assisted questionnaires (10 studies), occupational job titles
(4 studies), or a combination of job titles and interview-​assisted ques-
tionnaires (3 studies).
Physical activity was inversely associated with endometrial cancer
risk across all domains of activity. In 22 studies of recreational physi-
cal activity there was a 16% reduction in the risk of endometrial cancer
(RR = 0.84; 95% CI: 0.78, 0.91) comparing the highest to the lowest
category of activity; in 19 studies of occupational activity there was a
19% reduction in risk (RR = 0.81; 95% CI: 0.75, 0.87), and in 7 studies
of household activity there was a 30% reduction in risk (RR = 0.70;
95% CI:  0.47, 1.02). Ten studies specifically examined walking and
reported an 18% reduction in risk (RR = 0.82; 95% CI: 0.69, 0.97).
No differences in risk were observed among studies with different
intensity of physical activity. Two studies included light activity and
reported a 35% risk reduction (RR = 0.65; 95% CI: 0.49, 0.86), eight
assessed moderate-​to-​vigorous physical activity and reported a 17%
reduction (RR = 0.83; 95% CI: 0.71, 0.96) and eight included vigorous
activity and reported a 20% reduction (RR = 0.80; 95% CI: 0.72, 0.90).
The dose–​ response relationship was examined separately in nine
studies that expressed activity in terms of MET-​hours per week. The
inverse association between the level of physical activity and risk of
endometrial cancer appeared to be non-​linear, with no further decrease
in risk observed at activity levels higher than 20 MET-​hours per week.
As with other end points, the inverse relationship with endometrial
cancer appeared to be stronger in the case-​control studies (RR = 0.72;
95% CI: 0.64, 0.80) than in the prospective cohort studies (RR = 0.84;
95% CI: 0.78, 0.91), suggesting some influence from reporting bias.
Most studies (N = 29) were conducted in North America, or Europe
(N = 29); three studies were from Asia and one from South America.
No significant differences were observed in the associations among
geographic regions, based on the limited number of studies currently
available in middle and low-​income countries. There was no evidence
that the association differed by study size or quality.
 385

Physical Activity, Sedentary Behaviors, and Risk of Cancer 385

Category # of Studies RR (95% Cl)
Overall 33 0.80 (0.75, 0.85)

Cohort 19 0.84 (0.78, 0.91)

Case-control 14 0.72 (0.64, 0.80)

Premenopausal 4 0.74 (0.49, 1.13)

Postmenopausal 7 0.81 (0.67, 0.97)

Occupational 19 0.81 (0.75, 0.87)

LTPA 22 0.84 (0.78, 0.91)

Adjusted for adiposity 24 0.79 (0.73, 0.85)

Not adjusted for adiposity 9 0.83 (0.72, 0.97)

0 1 2
Relative risk (95% Cl)
High vs. low physical activity

Figure 21–​4.  Endometrial cancer and its association with physical activity.

One potential confounder in the analysis of endometrial cancer is
unopposed estrogen therapy for menopausal symptoms. Adjustment
for menopausal hormone therapy did not change the association
between physical activity and endometrial cancer. There was no evi-
dence of effect modification by parity, use of oral contraceptives,
menopausal status, or the time period of physical activity (i.e., adoles-
cence, midlife, or older age).
Increased body weight is strongly associated with the risk of endo-
metrial cancer. Most of the studies (24 of 33)  in the meta-​analysis of
physical activity controlled for BMI as a potential confounder, but nine
studies did not, including some that considered BMI a potential mediator
that should not be adjusted for. In the meta-​analysis, there was no differ-
ence in the summary estimate between studies that controlled for BMI
(RR = 0.79; 95% CI: 0.73, 0.85) and those that did not (RR 0.83; 95%
CI: 0.72, 0.97).
In the 2016 pooled analysis, the relative risks and 95% confidence
intervals for a high versus low level of leisure-​time activity were 0.79
(95% CI:  0.68, 0.92) for endometrial cancer, similar to the meta-​
analysis estimate. However, in contrast to the meta-​analysis, the pooled
study found that adjustment for BMI essentially eliminated the inverse
association between physical activity and endometrial cancer (relative
risk of 0.98). When compared with previous studies, the pooled anal-
ysis used a more thorough approach in adjusting for BMI, including
each of the subcategories of obesity (30.0–​34.9, 35.0–​39.9, 40+ kg/​m2)
separately. Finer adjustment may explain the greater attenuation in the
2016 pooled analysis. Replication is needed to resolve this difference
in results.
In summary, higher levels of physical activity are associated with
an approximately 20% reduction in the risk of endometrial cancer. It
is presently unclear, however, whether this association is confounded
and/​or mediated by BMI.
Bladder Cancer
A meta-​analysis by Keimling et  al. (2014) identified 15 studies
(11 cohort, 4 case control) from North America, Europe, and Asia
that examined the association between physical activity and blad-
der cancer risk. The analysis, based on 27,784 cases, found an
inverse association between physical activity and bladder cancer risk
(RR = 0.85; 95% CI: 0.74, 0.98). The findings were not significantly
different between the prospective studies (RR = 0.89; 95% CI: 0.80,
1.00) and the case-​control studies (RR = 0.71; 95% CI: 0.43, 1.16)
(Pheterogeneity  =  0.11). Statistical modeling suggested a linear dose–​
response relationship. There was no evidence of heterogeneity by
gender or BMI, nor was there obvious confounding by BMI or smok-
ing. Associations did not differ for recreational versus occupational
activity.
The 2016 pooled analysis found an inverse relationship between
bladder cancer risk and leisure-​time physical activity (RR = 0.87; 95%
CI: 0.82, 0.92), with a point estimate similar to that observed in the
meta-​analysis (Keimling et al., 2014). However, when stratifying on
smoking, the association was stronger in former than in never smokers,
raising the possibility of residual confounding. Thus, despite the large
number of cases in the published studies, the level of evidence was
considered limited (suggestive).
Liver Cancer and Gallbladder Cancer
The association between physical activity and risk of liver cancer and
gallbladder cancer has been studied only recently. No meta-​analyses
have been conducted. The largest published study is based on the
National Institutes of Health (NIH)-​AARP Diet and Health Study, a
prospective cohort of more than 500,000 men and women residing in
North America (Behrens et al., 2013). A total of 628 cases of liver can-
cer and 123 cases of gallbladder cancer were identified in the cohort
over 10 years of follow-​up. Physical activity, defined by the number of
days per week that subjects performed vigorous physical activity con-
tinuously for at least 20 minutes, was inversely associated with liver
cancer (RR  =  0.64; 95% CI:  0.49, 0.84). The association with gall-
bladder cancer was similar but not statistically significant (RR = 0.63;
95% CI: 0.33, 1.21). The dose–​response relationship between physical
activity and liver cancer was approximately linear, with no apparent
effect modification by age, gender, BMI, diabetes, alcohol intake, or
coffee consumption.
The 2016 pooled analysis, which included the NIH-​AARP cohort,
also found an inverse association between leisure-​time physical activ-
ity and risk of liver cancer (RR = 0.73; 95% CI: 0.55, 0.98). The num-
ber of cases in the pooled study (N  =  1384) more than doubled the
number in the AARP study (N = 628) (Behrens et al., 2013). The over-
all evidence for causality was considered to be “limited–​suggestive.”
386

386 PART III:  THE CAUSES OF CANCER

Gastroesophageal Cancers
Behrens et al. (2014) identified 24 studies (9 cohorts, 15 case control)
from North America, Europe, Asia, and the Middle East that examined
associations between physical activity and subtypes of gastroesopha-
geal cancer. The analyses included 965 cases of esophageal adenocar-
cinoma, 844 cases of gastric cardia cancer, 1444 cases of esophageal
squamous cell carcinoma, and 1571 cases of non-​cardia stomach can-
cers. Physical activity was inversely associated with risk of esophageal
adenocarcinoma (RR = 0.79; 95% CI: 0.66, 0.94) and gastric cardia
cancer (RR = 0.83; 95% CI: 0.69, 0.99), but not esophageal squamous
cell carcinoma (RR = 0.94; 95% CI: 0.41, 2.16). In an analysis that
combined all subtypes of gastroesophageal cancer, the point estimate
for physical activity was lower in the case control studies (RR = 0.77;
95% CI: 0.67, 0.89) than in the prospective studies (RR = 0.89; 95%
CI: 0.78, 1.01). The dose–​response relationship was non-​linear, with
diminishing benefits at high levels of physical activity. The inverse
association was somewhat stronger in women than in men, and more
strongly associated with early-​life physical activity than that occurring
later in life. There was no apparent confounding by BMI, smoking, or
alcohol use.
In the 2016 pooled analysis, leisure-​ time physical activity was
inversely associated with risk of esophageal adenocarcinoma (RR = 0.58;
95% CI: 0.38, 0.89) and cancer of the gastric cardia (RR = 0.78; 95%
CI:  0.64, 0.95). These results were similar to, but somewhat stronger
than, those of the Behrens et al. (2014) meta-​analysis. The analysis was
based on 899 cases of esophageal adenocarcinoma and 790 cases of gas-
tric cardia cancer. The evidence for these two cancer endpoints was con-
sidered to be “limited–​suggestive.” Evidence for other gastroesophageal
endpoints was too sparse to draw conclusions.
Hematologic Cancers
A meta-​analysis by Jochem et al. (2014) included 23 studies (15 cohort,
8 case control) from North America, Europe, and Asia that examined
the relationship between physical activity and risk of hematologic
malignancies. The analysis was based on 1362 cases of myeloma, 1736
cases of leukemia (limited data available on subtypes), and 9447 cases
of non-​Hodgkin lymphoma. No statistically significant association
was observed between physical activity and all hematologic cancers
combined. The RR estimates comparing high versus low physical activ-
ity were 0.86 (95% CI: 0.68, 1.09) for multiple myeloma, 0.97 (95%
CI: 0.84, 1.13) for leukemia, and 0.91 (95% CI: 0.82, 1.00) for non-​
Hodgkin lymphoma. Results were generally similar between cohort
and case-​control studies, and for recreational and occupational activity.
In the 2016 pooled analysis, leisure-​ time physical activity was
inversely associated with risk of myeloma (RR = 0.83; 95% CI: 0.72,
0.95), and myeloid leukemia (RR  =  0.80; 95% CI:  0.70, 0.92), and
there was a borderline significant association for non-​Hodgkin lym-
phoma (RR = 0.91; 95% CI: 0.83, 1.00). No association was observed
with lymphocytic leukemia. The point estimates for these hematologic
cancers were similar but statistically more precise than those in the
meta-​analysis by Jochem et al. (2014).
Based on these analyses, the evidence for a causal relationship
with myeloid leukemia, myeloma, and non-Hodgkin lymphoma was
considered to be “limited–​suggestive.” Although the evidence for
non-​Hodgkin lymphoma was based on more than 10,000 cases in
the prospective studies, the association reached only borderline sig-
nificance (p = 0.05) in both the meta-​analysis and the 2016 pooled
analysis. For lymphocytic leukemia, the null findings indicate that a
substantial effect is unlikely.
Head and Neck Cancer
No meta-​ analyses have examined physical activity in relation to
head and neck cancer risk. In the NIH-​AARP Diet and Health Study
(Leitzmann et al., 2008), during up to 8 years of follow-​up, 1249 cases
of head and neck cancer were diagnosed. In age-​and gender-​adjusted
analyses, physical activity was inversely associated with head and neck
cancer risk (RR  =  0.62; 95% CI:  0.52, 0.74) comparing the top and
bottom quintiles. The association became statistically non-​significant
(RR  =  0.89; 95% CI:  0.74, 1.06), however, after multivariate adjust-
ment for smoking, alcohol consumption, and other factors. The authors
stated that the association in age-​and gender-​adjusted analyses likely
reflected some degree of residual confounding by smoking status in
particular.
In the pooled analysis, the risk of head and neck cancers was
inversely associated with leisure-​time physical activity (RR  =  0.85;
95% CI:  0.78, 0.93). This association was statistically significant
even after adjusting for smoking status, and was similar for never

Category # of Studies RR (95% Cl)

Overall 27 0.76 (0.69, 0.85)

Cohort 21 0.79 (0.70, 0.89)

Case-control 6 0.64 (0.55, 0.74)

Men 17 0.82 (0.74, 0.90)

Women 10 0.83 (0.69, 0.99)

Never smokers 4 0.96 (0.78, 1.18)

Current smokers 2 0.66 (0.49, 0.89)

Adenocarcinoma 6 0.80 (0.72, 0.88)

Squamous 6 0.80 (0.71, 0.90)
Small cell 6 0.79 (0.66, 0.94)

0 1 2
Relative risk (95% Cl)
High vs. low physical activity

Figure 21–​5.  Lung cancer and its association with physical activity.

 387
Physical Activity, Sedentary Behaviors, and Risk of Cancer 387
(RR = 0.83; 95% CI: 0.68, 1.02), former (RR = 0.90; 95% CI: 0.79,
1.04), and current smokers (RR  =  0.85; 95% CI:  0.65, 1.10). These
results do not support residual confounding by smoking. The evidence
was designated “limited–​suggestive.”
Lung Cancer
Brenner et  al. (2016) conducted a meta-​analysis of 27 studies (21
cohort, 6 case control) from North America, Europe, and Asia on the
association of recreational physical activity with risk of lung cancer.
In total, the meta-​analyses included 20,169 cases. A significant 24%
lower risk of being diagnosed with lung cancer was noted (RR = 0.76;
95% CI:  0.69, 0.85), comparing adults with higher versus lower
levels of physical activity (see Figure 21–​5). A  subset of studies in
the meta-​analysis stratified the analysis by smoking status. Physical
inactivity was inversely associated with lung cancer in two studies
of current smokers (RR = 0.66; 95% CI: 0.49, 0.89) but not in four
studies that restricted the analysis to never smokers (RR = 0.96; 95%
CI: 0.78, 1.18).
In the 2016 pooled analysis, higher levels of leisure-​time physical
activity were associated with lower risk of lung cancer in the overall
population (RR  =  0.74, 95% CI:  0.71, 0.77), but not in an analysis
restricted to never smokers (RR = 1.03; 95% CI: 0.89, 1.20). The null
findings in never smokers underscore concern about residual con-
founding by smoking in the overall analysis.
In summary, higher levels of physical activity are consistently asso-
ciated with 25% lower risk of developing lung cancer in prospective
studies. However, this association is susceptible to confounding by
smoking, which is associated with both physical inactivity and a large
(approximately 25-​fold) increase in lung cancer risk. The inverse asso-
ciation has not been observed in studies of never smokers. Unless it
can be shown that physical activity decreases lung cancer risk in never
smokers, or changes the natural history of lung cancer in smokers, the
likelihood of confounding cannot be excluded. The overall level of
evidence for a causal association between physical activity and lung
cancer risk was designated “uncertain–​may be confounded.”
Malignant Melanoma
No prior meta-​analyses or prospective cohort studies have examined
the association between physical activity and risk of melanoma. Only
one case-​control study with 386 cases had previously examined this
association (Shors et al., 2001); this study reported that people with
a high versus low level of physical activity had a 30% lower risk of
melanoma.
In contrast, the 2016 pooled analysis, based on 12,348 cases, found
that leisure-​time physical activity was associated with increased risk of
melanoma (RR = 1.27; 95% CI: 1.16, 1.40). Not only was the pooled
analysis much larger than the single previous case-​control study, but
separate analyses of 8 of the 12 cohorts found at least a 20% higher
risk among those who were physically active.
No biological mechanisms have been proposed to explain how
physical activity might increase the risk of melanoma. An alternative
hypothesis is that physically active individuals spend more time out-
doors and have greater exposure to the sun. Physical activity is fre-
quently done outdoors in light clothing, increasing the risk of sunburn
(Holman et al., 2014). The overall level of evidence for a causal rela-
tionship between physical activity and melanoma risk is “uncertain–​
may be confounded.”
Pancreatic Cancer
As reviewed by Behrens et al. (2015), a total of 30 studies (22 cohort,
8 case control) from North America, Europe and Asia have examined
the association between physical activity and risk of incident pancre-
atic cancer. Taken together, these studies included 10,501 cases. The
results differ markedly between prospective studies and case-​control
studies and so are presented separately. The prospective studies,
which comprise most of the data on this issue, suggest that phys-
ically active participants have a 7% lower risk of pancreatic cancer
(RR  =  0.93; 95% CI:  0.88, 0.98) than inactive participants. Results
from case-​control studies show a larger reduction; risk was 22% lower
(RR = 0.78; 95% CI: 0.66, 0.94) among the most active versus least
active participants. A dose–​response analysis suggests that the asso-
ciation departs somewhat from linearity, reaching a plateau at high
activity levels. The association had no evident heterogeneity by gen-
der, smoking, or BMI, and no difference in results for recreational as
opposed to occupational activity. The strength of the association did
not appear to vary in relation to the timing of physical activity over
the life span, though it was suggested that consistent physical activity
over time may be more important than recent physical activity or phys-
ical activity during any given past period of life. Level of adjustment
for different confounders also had little effect. Overall, these results
indicate that the link between physical activity and lower risk of pan-
creatic cancer—​if a true association exists—​is comparatively weak.
This represents a downgrading of the evidence since prior reviews
(Schottenfeld and Fraumeni, 2006; World Cancer Research Fund and
American Institute for Cancer Research, 2007), largely owing to the
weak associations observed in more recent cohort studies.
In the 2016 pooled analysis, leisure-​time physical activity was not
significantly associated with the risk of pancreatic cancer (RR = 0.95;
95% CI:  0.83, 1.08), although the point estimate was similar to
that from the prospective studies in the Behrens et  al. (2015) meta-​
analysis (RR = 0.93). These findings differ markedly from the results
of case-​control studies (RR = 0.78). Consequently, the evidence level
for an association between physical activity and pancreatic cancer is
“inconsistent.”
Prostate Cancer
A total of 43 studies (19 cohort, 24 case control) from North America
and Europe have examined the association between physical activity
and prostate cancer (see Figure 21–​6), as summarized by Liu et  al.
(2011). The studies included a total of 88,294 cases. This meta-​analysis
found that a high level of total physical activity (leisure-​time physical
activity and occupational activity together) was inversely associated
with prostate cancer risk (RR = 0.90; 95% CI: 0.84, 0.95). The asso-
ciation was weaker in prospective studies (RR = 0.94; 95% CI: 0.90,
0.98) than in case-​control studies (RR  =  0.86; 95% CI:  0.75, 0.97),
however. Additionally, the associations were not consistent across
domains of physical activity, with weaker associations for leisure-​time
physical activity (RR  =  0.95; 95% CI:  0.89, 1.00) than for occupa-
tional physical activity (RR = 0.81; 95% CI: 0.73, 0.91). The reasons
for the heterogeneity of associations across study designs and domains
of physical activity are not well understood. Some evidence suggests
that men who engage in a high level of leisure-​time physical activity
are more frequently screened for prostate cancer, either by PSA or dig-
ital rectal exam, than men who engage in little leisure-​time physical
activity (Moore et al., 2008). This may lead to higher detection rates
among active men, and the resulting bias may obscure inverse associa-
tions that would have otherwise been present. The extent of detection
bias could plausibly be different for leisure-​time physical activity than
for occupational physical activity, leading to heterogeneity by type of
activity.
Fewer than half of the studies reported whether there was a sig-
nificant trend in prostate cancer risk with increasing physical activ-
ity levels. Taken together with the disparate physical activity types
and measurements, it was not possible to determine whether a dose–​
response association exists.
Associations were stronger in studies where the mean age of men
was less than 65 years than in studies where the mean age was higher,
perhaps reflecting the greater range in activity levels among younger
men. Whether this difference by age subgroup was statistically sig-
nificant was not formally tested in the meta-​analysis, leaving open the
possibility of a chance finding. Associations were also much stronger
in studies with longer follow-​up time (i.e., greater than 10 years) than
in studies with less follow-​up time, perhaps reflecting that a relatively
38
388 PART III:  THE CAUSES OF CANCER
Category # of Studies
Overall 43
Cohort 19
Case-control 24
Localized cases 14
Advanced cases 14
Occupational 27
LTPA 34
0 1
Relative risk (95% Cl)
High vs. low physical activity
Figure 21–​6.  Prostate cancer and its association with physical activity.
long period of physical activity may be required to decrease prostate
cancer risk.
In analyses of prostate cancer subtypes, physical activity was asso-
ciated with approximately the same decrease in risk for both localized
and advanced subtypes. The studies in the analysis included a wide
range of potential confounders. These confounders appeared to have
little effect on the association, as results did not vary between models
that were more fully adjusted and those that were minimally adjusted.
In contrast to previous studies, the 2016 pooled analysis showed
that higher levels of leisure-​time physical activity were associated with
increased, rather than decreased, risk of prostate cancer (RR = 1.06;
95% CI: 1.03, 1.08). Inconsistency in the results for prostate cancer is
unsurprising given the concerns about detection bias and the hetero-
geneity of associations across study designs and domains of physical
activity noted above in the Liu et al. (2011) meta-​analysis.
In summary, while physical activity was associated with a mod-
estly lower risk of prostate cancer, especially in case-​control studies,
this was not confirmed by the pooled analysis of prospective studies.
Consequently, the evidence that physical activity protects against pros-
tate cancer risk is considered “inconsistent” rather than “probable” or
“convincing.”
Rectal Cancer
A meta-​ analysis by Robsahm et  al. (2013) compiled findings for
11 cohort studies (case-​control studies were excluded) from North
America, Europe, Asia, and Australia that examined physical activity
in relation to rectal cancer risk. There were 8698 rectal cancer cases
overall. In the meta-​analysis, the authors found that the relative risk
of rectal cancer comparing most active with least active participants
in cohort studies was 0.98 (95% CI = 0.88, 1.08). No association was
observed between physical activity and risk of developing rectal cancer.
In the 2016 pooled analysis, leisure-​ time physical activity was
inversely associated with risk of rectal cancer (RR  =  0.87; 95%
CI:  0.80, 0.95). This finding contradicts the null association previ-
ously reported by Robsahm et al. (2013), leaving considerable uncer-
tainty about the true relationship. We consider the current evidence
for an association between physical activity and rectal cancer to be
“inconsistent.”
RR (95% Cl)
0.90 (0.84, 0.95)
0.94 (0.90, 0.98)
0.86 (0.75, 0.97)
0.96 (0.87, 1.05)
0.94 (0.80, 1.10)
0.81 (0.73, 0.91)
0.95 (0.89, 1.00)
2
Brain Cancer
As reviewed by Niedermaier et  al. (2015), a total of six studies (4
cohort, 2 case control) from North America, Europe, and Australia
(have examined physical activity in relation to risk of glioma (a het-
erogeneous cancer that comprises approximately 80% of all brain can-
cers). There were a total of 3057 glioma cases. The authors found that
high versus low physical activity levels were inversely associated with
risk of glioma (RR = 0.86; 95% CI: 0.76, 0.97). Preliminary evidence
indicates that the magnitude of the association may vary according to
the timing of physical activity during the life span, with physical activ-
ity during adolescence associated with greater reductions in risk than
activity later in life (Moore et al., 2009).
The 2016 pooled analysis found no association between leisure-​
time physical activity and brain cancer risk (RR = 1.06; 95% CI: 0.93,
1.20). This contradicts the prior finding of an inverse association for
gliomas (Niedermaier et  al., 2015), leading us to conclude that the
overall evidence for an association is “inconsistent.”
Thyroid Cancer
As reviewed by Schmid et al. (2013), a total of eight studies (5 cohort,
3 case control) from North America, Europe, and Asia have examined
the association between physical activity and risk of thyroid cancer. In
total, their meta-​analysis included 2250 cases of thyroid cancer. The
authors found that high versus low levels of physical activity had no
association with thyroid cancer risk (RR = 1.06; 95% CI: 0.79, 1.42).
In prospective studies, those with high versus low levels of physical
activity had increased risk of thyroid cancer (RR = 1.28; 95% CI: 1.01,
1.63), whereas in case-​control studies, they had a statistically non-​
significant decrease in risk (RR = 0.70; 95% CI: 0.48, 1.03). In the 2016
pooled analysis, no association was observed between thyroid cancer
and leisure-​time physical activity (RR = 0.92; 95% CI: 0.81, 1.06). The
evidence for this association is considered to be inconsistent.
Ovarian Cancer
Zhong et al. (2014) identified a total of 19 studies (9 cohort, 10 case
control) from North America, Europe, Asia, and Australia on the
 389
Physical Activity, Sedentary Behaviors, and Risk of Cancer 389
association between non-​occupational (mostly recreational) physical
activity and ovarian cancer risk. There were 9459 cases in the analysis.
Overall, there was a borderline inverse association between physical
activity and ovarian cancer risk (RR = 0.92; 95% CI: 0.84, 1.00). In pro-
spective studies, no association was observed between physical activity
and ovarian cancer risk (RR = 1.03; 95% CI: 0.87, 1.20), in contrast to
the findings of case-​control studies (RR = 0.86; 95% CI: 0.80, 0.93).
In the 2016 pooled analysis, leisure-​time physical activity was not
associated with ovarian cancer risk (RR = 1.01; 95% CI: 0.91, 1.13).
Given that results from cohort studies are afforded greater weight than
case-​control studies due to their lower potential for recall and selec-
tion biases, the balance of evidence indicates that physical activity is
unlikely to have a substantial effect on ovarian cancer risk.
All Other Cancers
Other cancers that have been examined with regard to an association
with physical activity include esophageal squamous cell carcinoma
(Behrens et al., 2014), gallbladder cancer (Behrens et al., 2013), can-
cers of the small intestine (Cross et al., 2013), and soft tissue (Moore
et  al., 2016). Data on these cancers are too sparse to draw conclu-
sions about whether physical activity is associated with decreases or
increases in risk.
SEDENTARY BEHAVIORS AND RISK
OF DEVELOPING CANCER
Sedentary behavior (i.e., sitting) has features that differ from general
physical inactivity, and has been independently associated with vari-
ous risk factors for chronic disease such as weight gain, high choles-
terol, and high fasting insulin levels, as well as other biomarkers (Ford
et al., 2005; Fung et al., 2000; Healy et al., 2008; Jakes et al., 2003).
Sitting time has also been associated with premature mortality, cardio-
vascular disease, type 2 diabetes mellitus, and obesity (Biswas et al.,
2014). Few studies have examined associations between sitting time
and cancer with mixed results.
A recent meta-​analysis, including 21 prospective cohorts and 22
case-​control studies, examined sitting time in relation to site-​specific
cancer risk (Schmid and Leitzmann, 2014). Evidence was limited for
most individual cancer sites, however. Only a few studies examined
any given site, often in relation to different domains of sitting time
(e.g., occupational, television, leisure-​time, or total). Approximately
half of those studies examined occupational sitting time. Overall, the
meta-​analysis found that sitting time was positively associated with
colon and endometrial cancer risk.
Following this meta-​ analysis, a recent study comprehensively
examined leisure time spent sitting in relation to total and site-​specific
cancer incidence and found that women who reported sitting for more
than 6 hours/​day versus fewer than 3 hours/​day during their leisure
time had a 10% higher risk of all cancers combined (Patel et al., 2015).
The overall association in women was driven by site-​specific asso-
ciations with invasive breast cancer (RR = 1.10; 95% CI: 1.00, 1.21),
ovarian cancer (RR = 1.43; 95% CI: 1.10, 1.87), and multiple myeloma
(RR = 1.65; 95% CI: 1.07, 2.54). Leisure-​time sitting was not associ-
ated with cancer risk in men overall, although among obese men there
was an 11% higher risk associated with high levels of sitting time.
Most previous studies reporting a positive association with colon
cancer specifically examined television time (Howard et  al., 2008;
Steindorf et  al., 2000)  or occupational sitting (Boyle et  al., 2010;
George et al., 2010; Gerhardsson et al., 1986; Weiderpass et al., 2003),
and only one study (Howard et al., 2008) reported an association with
total sitting time. Associations appear to be strongest with television
watching, but it is not clear whether this may reflect the greater preci-
sion of measuring television time versus overall sitting, or effect modi-
fication by unhealthy behaviors, such as excess snacking, that may
correlate with television watching. While some previous studies have
reported positive associations with endometrial cancer, these asso-
ciations are attenuated by adjustment for BMI (Friberg et  al., 2006;
Gierach et  al., 2009; Patel et  al., 2015). Collectively, these findings
suggest that the association between sitting time and endometrial can-
cer incidence may be confounded or mediated by BMI.
Seven other studies have examined leisure-​time sitting in relation to
cancer mortality (Dunstan et al., 2010; Katzmarzyk et al., 2009; Kim
et al., 2013; Matthews et al., 2012a, 2014; Patel et al., 2010; Wijndaele
et  al., 2010). Of these, three reported statistically significant positive
associations between sitting time and cancer mortality in women (Kim
et al., 2013; Matthews et al., 2012a; Patel et al., 2010), whereas only
two reported positive associations in men (Kim et al., 2013; Matthews
et al., 2012a).
Evidence linking sitting time to other individual cancer sites is lim-
ited, although some associations have been reported. Two prospective
studies reported modestly higher risk of invasive breast cancer asso-
ciated with total sitting (George et  al., 2010)  or leisure-​time sitting
(Patel et al., 2015). One prospective cohort (Patel et al., 2015) and one
case-​control study (Zhang et al., 2004) reported a higher risk between
leisure-​time sitting and ovarian cancer, whereas two studies of occupa-
tional sitting (Dosemeci et al., 1993; Lee et al., 2013) and one of total
sitting time (Xiao et  al., 2013)  were null. A  statistically significant
association has been reported with multiple myeloma and borderline
associations with head and neck and gallbladder cancer in men and
women; associations with esophageal cancer in women and pancreatic
cancer in men have also been reported (Patel et al., 2015). In contrast,
two prospective cohort studies have reported an inverse association
with total prostate cancer, although there was no dose–​response rela-
tionship, and the results were attenuated when restricted to advanced
disease (Lynch et  al., 2014; Patel et  al., 2015). In general, physical
activities of a moderate to vigorous intensity, BMI, and age have not
been shown to modify associations of sitting time with cancer risk.
In summary, there is some, but not sufficient evidence to support
a positive association between sitting time and some types of cancer,
including colon, endometrium, breast, and ovary. The exact amount
or domain of sitting time that may be associated with increased risk
remains unclear; whether associations are modified by exercise or
body weight requires further investigation. The role of body weight on
the causal pathway for some cancers, such as endometrial cancer, also
warrants further exploration.
PHYSICAL ACTIVITY, SEDENTARY BEHAVIORS,
AND CANCER SURVIVORSHIP
Currently, there are approximately 14.5  million individuals in the
United States living after a diagnosis of cancer. While cancer treat-
ments have improved, traditional therapies have significant toxicity,
and targeted therapies are expensive.
In the late 1980s researchers began to investigate whether exer-
cise training during active treatment could mitigate the side effects
of treatment and help to preserve physical function (MacVicar et al.,
1989). This research has accelerated in the last decade. Courneya and
Friedenreich (2007) have elegantly described where and how physical
activity fits within the cancer control framework (Figure 21–​7). Here
we briefly describe the evidence regarding the benefits of physical
activity following a diagnosis of cancer. Points of intervention include
pre-​treatment, treatment, and survivorship (Figure 21–​7).
Exercise prior to surgery, chemotherapy, or radiation is prescribed
as “prehab” to enhance physical fitness and coping prior to initiating
cancer treatment. Cancer rehabilitation and health promotion programs
also use exercise during and after treatment to reduce fatigue, enhance
function, and improve the quality of life (Schmitz et al., 2010). There
is ample evidence that exercise can be safe during this period. The
American College of Sports Medicine has developed exercise guide-
lines to enhance the safety and effectiveness of exercise (Schmitz
et al., 2010) during and after cancer treatment. The American Cancer
Society has published recommendations for physical activity (Rock
et al., 2012), and practical information for cancer survivors (Demark-​
Wahnefried et al., 2015).
In the last decade, researchers have begun to investigate whether
physical activity before or after diagnosis can improve survival and
390
390 PART III:  THE CAUSES OF CANCER
DIAGNOSIS
CANCER CONTROL CATEGORIES
Prevention Detection Treatment Treatment
Preparation/ Effectiveness/
Coping Coping
Prescreening Screening Pretreatment Treatment
PREDIAGNOSIS
CANCER-RELATED TIME PERIODS
Figure 21–​7.  Physical activity and cancer control framework.
reduce cancer recurrence. Recently, Schmid and Leitzmann (2014)
reviewed 16 survivorship studies of breast and colorectal cancer
encompassing 49,095 participants and 8129 total deaths. They exam-
ined physical activity performed before and after diagnosis in relation
to cause-​specific mortality rates. Physical activity before diagnosis
was associated with significantly lower death rates from breast cancer
(HR = 0.77; 95% CI: 0.66, 0.90), and colorectal cancer (HR = 0.75;
95% CI: 0.62, 0.91). For post-​diagnosis activity, meeting currently rec-
ommended amounts of moderate to vigorous physical activity during
the post-​diagnosis period was associated with 24% lower mortality for
breast cancer survivors, and 28% lower risk for those previously diag-
nosed with colorectal cancer. For cancer-​specific death, post-​diagnosis
physical activity was associated with a 28% lower risk for breast can-
cer mortality (HR = 0.72; 95% CI: 0.60, 0.85), as well as a 39% lower
risk for colorectal cancer mortality (HR = 0.61; 95% CI: 0.40, 0.92).
There is much less evidence for prostate cancer, although in some
studies physical activity is associated with a lower risk of dying from
prostate cancer, and recent studies have suggested that physical activ-
ity post-​diagnosis can improve survival among men diagnosed with
prostate cancer (Bonn et al., 2014); still, much more work is needed.
This emerging body of evidence suggests significant mortality bene-
fits from physical activity for cancer survivors; however, some caveats
must be considered. Many of the observational studies reporting these
results were not originally designed to address this question, and there
is often limited information about surgical procedures and outcomes,
or detailed treatment information throughout the course of chemother-
apy and radiation treatments, or information about compliance with
long-​term hormonal treatment (e.g., aromatase inhibitors), all of which
can have an impact on survival and may influence physical activity lev-
els of study participants. Thus, the potential for residual confounding
and/​or reverse causation calls for caution in interpreting these results.
In summary, the number of individuals who will live for many
years after their cancer diagnosis has increased dramatically in recent
decades, and physical activity has emerged as an important poten-
tial component of our cancer control framework during the active
treatment period and in the post-​treatment rehabilitation and health-​
promotion phases of cancer survivorship.
OPPORTUNITIES FOR PREVENTION
Opportunities to prevent cancer by increasing physical activity lev-
els and decreasing sedentary behaviors are discussed in detail in
Chapter 62.2 of this volume.
FUTURE RESEARCH
The relationship of physical activity with cancer risk is an active area
of research, with many aspects of this relationship being investigated
Recovery/ Disease Prevention/ Palliation Survival
Rehabilitation Health Promotion
Survivorship End of Life
POSTDIAGNOSIS
simultaneously. We highlight two research areas of particular importance
for improving our understanding of physical activity and cancer in the
future.
Ascertaining the Type, Intensity, and Amount
of Physical Activity Needed to Reduce Cancer Risk
and Establishing the Role of Sedentary Behaviors
in Cancer Incidence
Studies of physical activity and cancer risk have typically quanti-
fied the relative risk for high versus low levels of physical activity.
However, to develop clear recommendations with respect to cancer
risk, it is also important to define the type, intensity, and amount of
physical activity required for each level of benefit. For example, is
there a particular kind of physical activity (e.g. aerobic vs. strength-​
oriented) that is especially beneficial with respect to reducing cancer
risk? Are the benefits comparable for light versus moderate versus vig-
orous intensity activity?
Especially important are efforts to define the dose–​response relation-
ships between sedentary behavior, physical activity, and cancer risk. The
relationship of physical activity with health and longevity is typically
characterized as curvilinear, with the greatest benefits resulting from the
transition from inactivity to the recommended minimum activity levels
(Arem et al., 2015; Moore et al., 2012). As activity levels increase, the
benefits are thought to diminish, ultimately reaching a plateau at activity
levels two to three times that of the US recommended minimum levels.
For cancer incidence, however, the dose–​response association may dif-
fer; preliminary evidence suggests that benefits may accrue in a more
linear relationship with activity levels (Moore et al., 2016). If replicated,
this would have important implications for the framing of physical activ-
ity recommendations in cancer prevention and control efforts.
Most of the existing studies of sedentary behaviors and cancer risk
have focused on relatively few types of cancer. Future studies should
examine a broader range of cancer sites. In addition, not all studies
explicitly account for the potential for sedentary behaviors to displace
physical activity, especially light-​intensity physical activity. Future
studies should evaluate the separate effects of sedentary behavior and
physical inactivity, while accounting for potential displacement of
active behaviors. The effects of prolonged sitting, independent of total
sitting time, deserve further study.
Application of Novel Technologies to Improve
Measurement of Physical Activity
To date, most of the research on sedentary behavior, physical activity,
and cancer has used self-​reported rather than objective measurement.
Recall of activity levels over months or years in the past is difficult, in
the absence of contextual cues. Misclassification of exposure due to
 391
Physical Activity, Sedentary Behaviors, and Risk of Cancer 391
errors in recall can attenuate relative risk estimates in epidemiologic
studies. Newer technological approaches aim to minimize such error
by using Internet-​based 24-​hour recalls, or accelerometry to measure
movement objectively.
Over the last 5  years, several automated Internet-​based 24-​hour
recalls of physical activity behavior (Gomersall et al., 2011; Matthews
et  al., 2012b) have been validated with respect to measuring sitting
time, including different activity intensities and the location and pur-
pose of the activity (Gomersall et al., 2011; Hunt et al., 2013; Keadle
et al., 2014; Mace et al., 2014; Matthews et al., 2013). These recalls
have been shown to have less reporting error than many questionnaires
(Gomersall et al., 2011; Matthews et al., 2013), and can be adminis-
tered multiple times per year in order to assess habitual or usual sitting
and physical activity levels (Matthews et al., 2012b). To date, 24-​hour
physical activity recalls have not been employed in large-​scale popu-
lation studies due to logistical concerns. However, as epidemiologic
studies move toward collecting participant data using mobile technolo-
gies, it will become increasingly feasible to integrate 24-​hour recalls
into ongoing protocols for population-​based studies.
Accelerometers are wearable motion sensors that measure accelera-
tions in up to three different directions multiple times per second. These
data are then integrated into estimates of overall energy expenditure
per day or week, time in distinct activity intensity categories (e.g., sed-
entary, moderate), and/​or time seated versus standing. Accelerometers
have several advantages over self-​report, including that they minimize
recall and social desirability biases. Accelerometers perform well for
estimating time in sedentary and light-​intensity activities, which is par-
ticularly difficult to measure from self-​reported data. They also place
no cognitive demands on participants, thus making the technology
attractive for studies in children. However, accelerometers are expen-
sive, their application to large-​scale studies can be logistically com-
plicated, and they yield complex data that are challenging to process
(Lee and Shiroma, 2014). Despite these challenges, at least two studies
with 10,000 or more participants with prospective follow-​up for dis-
ease outcomes are currently underway (Howard et al., 2015; Lee and
Shiroma, 2014). In addition to research-​based accelerometers, com-
mercial monitors to assess activity, such as the Fitbit and Apple Watch,
are now widely available in consumer markets and are used by millions
of people. Data from such commercial monitors could potentially be
used to conduct large-​scale epidemiologic studies at a relatively low
cost, provided that their reliability and validity can be confirmed.
CONCLUSION
In the last 5 years, the publication of numerous prospective studies and
meta-​analyses, as well the large consortium-​based analysis, have shed
considerable light on the relationship between physical activity and
cancer risk. In addition to the associations for colon, postmenopausal
breast, and endometrial cancers previously identified, physical activity
has now been associated with lower risk of multiple types of cancer,
including, for example, gastroesophageal and hematologic malignan-
cies. The extensive breadth of findings highlights a key role for phys-
ical activity in population-​level cancer prevention and control efforts.
Although much has been learned in recent years about physical
activity and cancer risk, many questions remain. Newly identified
associations should be confirmed, and the type, intensity, and amount
of physical activity needed to reduce cancer risk should be clearly
defined. Newer technological methods should be implemented in can-
cer etiology studies. Finally, whether sedentary behaviors indepen-
dently contribute to cancer risk should be thoroughly investigated in
large prospective studies and consortia-​based studies.
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 395
22 Hormones and Cancer
ROBERT N. HOOVER, AMANDA BLACK, AND REBECCA TROISI
OVERVIEW
Hormones are highly biologically active endogenous compounds that
control the growth, development, physiology, and homeostasis of
numerous organ systems. Because of this, they have long been thought
likely to play key roles in both normal and abnormal (malignant)
growth. They are also noteworthy for being produced away from the
tissues that they control, and are thus secreted into circulating blood to
reach their target organs. This combination of potent, targeted agents
of growth and development that can be measured in available biologic
fluids has made them particularly susceptible and relevant to epide-
miologic investigation. In addition, as pharmacologic science has pro-
gressed, medications containing hormones and hormone antagonists
have come into widespread use, providing further opportunities for
epidemiologic insights into hormonal carcinogenesis. Based on the
development of increasingly more accurate assays to measure sex hor-
mones and their metabolites, this has been the most productive subject
matter area to date, with major advances in understanding the hormonal
etiology of breast and gynecologic malignancies. It has also taught us
the challenges and complexities of these studies, such as our continu-
ing failure to uncover a role for androgens in prostate cancer etiology.
One major lesson learned is that because of the biological importance
of hormones, there are multiple mechanisms to regulate them and their
effects. These include some things that can be measured and accounted
for, such as circulating binding proteins that inhibit the hormone’s
ability to bind to the tissues it regulates. However, there are also potent
effects of other regulatory mechanisms that are not easily accounted
for in epidemiologic studies. Perhaps the most important of these are
hormone receptors to which virtually all hormones bind in order to
initiate their actions. A  variety of homeostatic mechanisms control
the activation and availability of these receptors, including increasing
activation in the presence of declining hormone levels, and decreas-
ing activation with rising levels. With the major and rapid advances
in molecular biology and molecular epidemiology, we are seeing a
surge of new opportunities and creative new investigations across the
entire range of human hormones, and anticipate major advances in our
understanding of human hormonal carcinogenesis in the near future.
To take full advantage of these opportunities, we will also need to learn
how to account for the relevant regulatory mechanisms that evolution
has developed to control the effects of these potent biologic agents.
INTRODUCTION
Hormones are chemical signals secreted into the bloodstream that
act on distant tissues, usually in a regulatory fashion (Melmed et al.,
2016). In humans, hormones have important roles in growth, develop-
ment, homeostasis, and maintenance of normal physiology. As such, it
would seem that they might also have a central role, for better or worse,
in the process and regulation of abnormal growth and development, as
in malignancies. Despite this, with one notable exception, hormones
have garnered little interest in cancer epidemiology. The exception is
the area of sex hormones, which for decades has been a major focus
of investigations of cancers of the reproductive system. Currently, we
may be seeing the beginnings of a broader epidemiologic interest in
hormonal carcinogenesis in the context of the recent revolution in
molecular science, opening possibilities for molecular epidemiology
to shed light on the role of metabolic pathways in cancer—​pathways
that often involve hormonal control. The recognition of the potentially
central roles that two such hormones—​insulin and IGF-​1—​may play
in multiple malignancies is one example of this trend (Renehan et al.,
2004). Indeed, the very existence of this chapter is further evidence of
an expanded interest beyond sex hormones. The first two editions of
this text had no such chapter, and the third edition had one, restricted
to “Exogenous Hormones.”
The current chapter is not intended to be a compilation of the state
of our current knowledge of which hormones are, or might be, related
to specific cancers or of cancers of hormone-​producing glands, as these
will be summarized, along with the supporting data, in the relevant
chapters on site-​specific cancers. Instead, we will discuss some of the
history of the attempts to identify and understand hormonal carcino-
genesis via epidemiologic investigations, and what we might learn from
these efforts. We will begin with the sex hormones, since as noted, they
remain by far the most extensively investigated hormones in relation to
cancer risk. Following this will be a brief discussion of other hormones
that have come under exploration more recently, and likely represent
the vanguard of a more concerted effort in the near future to exploit the
opportunities provided by the various “-​omics” and other new molecular
epidemiologic tools now being developed. Finally, we will also discuss
how lessons learned thus far might guide us in designing new investiga-
tions in this era of interdisciplinary studies and rapid expansion of our
understanding of the underlying biology of cancer. It is our hope that
when the time for the fifth edition of this text arrives, the authorship of
this chapter will need to be extensively expanded in order to cover the
new knowledge brought about by using these new tools to study hor-
mones responsible for controlling so much of human physiology.
SEX HORMONES
Estrogen, progesterone, and androgens (particularly testosterone) are
hormones that have specific roles in reproduction and sexual develop-
ment, and have thus been labeled as sex hormones. Studies of their
effects on cancer risks have consequently been focused on reproduc-
tive organs—​specifically, the roles of these hormones in breast, endo-
metrial, and ovarian cancers in women, and in prostate and testicular
cancers in men. While appropriate, this focus is also somewhat myo-
pic since all of these hormones are biologically active in more organs
than simply the reproductive ones, as evidenced by the presence of
estrogen receptors in the central nervous, cardiovascular, respira-
tory, gastrointestinal, urinary, and other organ systems (Levin, 2015;
Millas and Liquidato, 2009). The observation of a possible protective
effect of menopausal estrogen therapy on colon cancer risk (Chan and
Giovannucci, 2010), and the recent appreciation that the risk of breast
cancer associated with circulating levels of testosterone likely may not
be wholly explained by its role as a substrate for estrogen synthesis
indicate the need for broader and more biologically based assessments.
Breast Cancer
As noted in the introduction, the history of our past attempts at using epi-
demiologic approaches to understand hormonal carcinogenesis can teach
us valuable lessons about productive ways to pursue these goals in the
future. Perhaps the most instructive example is the study of breast cancer,
395
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396 PART III:  THE CAUSES OF CANCER
which has a long history, filled with innovative methods and creative
insights, as well as missed opportunities and flawed interpretations. In
1700, Bernardino Ramazzini noted that “… cancerous tumors are very
often generated in the woman’s breast, and tumors of this sort are found
in nuns more often than in other women. Now these are not caused by
suppression of the menses but rather, in my opinion, by their celibate
life” (Ramazzini, 1700). It was over 100  years later that Rigoni-​Stern
quantified this observation by noting that the proportional mortality rates
for breast cancer in Verona, Italy, and its surrounding area were six times
higher in nuns compared to women in the general population (Rigoni-​
Stern, 1842). One of the first to link breast cancer risk to ovarian function
was Beatson, who in 1896 posed the question, “Is cancer of the mamma
due to some ovarian irritation, as from some defective steps in the cycle
of ovarian changes; and, if so, would the cell proliferation be brought to a
standstill … were the ovaries to be removed” (Beatson, 1896).
The concept of chemical “messengers” in the body had been recog-
nized in the mid-​nineteenth century (Bernard, 1949), and persons with
certain disorders were being treated with extracts of various endocrine
organs by late in the century (Borell, 1976). However, laboratory enthu-
siasm to pursue studies of these compounds did not really take hold until
the early 1900s, when Ernest Starling coined the term “hormone”: “These
chemical messengers, however, or hormones (from the Greek word
óρμáω, I  excite or arouse), as we might call them, have to be carried
from the organ where they are produced to the organ which they affect
by means of the blood stream and the continually recurring physiological
needs of the organism must determine their repeated production and cir-
culation through the body” (Henderson, 2005). Even with this stimulus,
it was not until 1929 that the estrogen molecule was identified and char-
acterized (Tata, 2005). However, this was quickly followed by laboratory
animal experiments linking estrogen exposure to increased breast cancer
risk (Kordon, 2008). While this led to a substantial and sustained labora-
tory commitment to understanding the role of estrogens in breast and
other cancers, epidemiologic advances had to wait for the maturation of
the newly developing field of chronic disease epidemiology.
Hormonally Linked Risk Factors
In the 1950s and 1960s, Brian MacMahon (MacMahon et al., 1970),
Abraham Lilienfeld (Lilienfeld, 1956), Ernst Wynder (Wynder et al.,
1960), and several other pioneers in this field turned their attention to
breast cancer and discovered multiple important risk factors, includ-
ing many associated with reproduction—​ nulliparity, parity within
the parous, age at menarche, age at first birth, lactation, and age at
menopause. About the same time, obesity among postmenopausal
women was also identified (Kelsey, 1979). Given the hormone-​related
Duration of use and
time since last use Cases/Controls
Never-user 12467/23568
Last use < 5 years before diagnosis
Duration < 1 year 368/860
Duration 1–4 years 891/2037
Duration 5–9 years 588/1279
Duration 10–14 years 304/633
Duration ≥ 15 years 294/514
Last use ≥ 5 years before diagnosis
Duration < 1 year 437/890
Duration 1–4 years 566/1256
Duration 5–9 years 151/374
Duration ≥ 10 years 93/233
Figure 22–​1.  Relative risk (RR) of breast cancer for duration of use within categories of time since last use of HRT. *Source: Collaborative Group on
Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705
women with breast cancer and 108 411 women without breast cancer. Lancet 1997;350:1047–1059.
nature of these risk factors, and the compelling findings from animal
studies (Mceuen, 1939; Nandi et  al., 1995), estrogens were indicted
as the most likely responsible carcinogen. Geographic pathologists
also contributed, identifying major international differences in breast
cancer risk, most notably between East Asian and Western countries
(Haenszel and Kurihara, 1968), differences that progressively disap-
peared over two to three generations of migrants from low-​to high-​
risk countries (Ziegler et al., 1993). These geographic differences and
changes with migration were also attributed to hormonal differences,
specifically circulating estrogen levels that were thought to be driven
by major differences in dietary fat consumption (Lea, 1966).
The belief that hormones, and specifically estrogens, explain these
risk factors was so strong that little was done to test these hypotheses.
Rather, they were combined to support a unifying hypothesis that vir-
tually all established breast cancer risk factors were consistent with an
explanation of cumulative lifetime estrogen exposure being the cause
of breast cancer (Henderson and Feigelson, 2000; Marshall, 1993).
Over time, many observations have been made that seem inconsistent
with this hypothesis, and we will return to this point later.
Exogenous Hormones
Surprisingly understudied by the mid-​1970s were estrogen drugs. The
first synthetic estrogens were produced in 1938 (Dodds et al., 1938),
and shortly thereafter were administered to women to treat various
disorders of pregnancy, menopausal symptoms, and other conditions.
Assessments of the long-​term consequences of these therapies were
few, and most were methodologically flawed. Indeed, a publication in
1971 (Defares, 1971)  summarized four small follow-​up studies that
included 1130 women treated with estrogen drugs for menopause, and
noted that 74 cases of cancer would have been expected, but only 2
were observed, concluding that exogenous estrogens were profoundly
protective for all cancer. Beginning in 1976 (Hoover et al., 1976), and
over the course of the next 15 years, a series of epidemiologic stud-
ies of estrogen therapy (ET) for menopause was conducted. Most,
but not all, demonstrated a positive association of breast cancer with
duration of ET use. A combined analysis of studies conducted by the
early 1990s found an overall association with breast cancer that was
particularly consistent and strong among those studies rated as hav-
ing high-​quality methods (Steinberg et al., 1991). Larger studies and
pooled analyses added to and refined our understanding of the role of
exogenous estrogen in carcinogenesis. Particularly noteworthy was the
finding that stopping ET resulted in a rapid and marked decline in risk
(Beral and Million Women Study Collaborators, 2003; Collaborative
Group on Hormonal Factors in Breast Cancer, 1997). In fact, as
RR (FSE)* RR and 99% FCl*
1.00 (0.021)
0.99 (0.085)
1.08 (0.060)
1.31 (0.079)
1.24 (0.108)
1.56 (0.128)
1.12 (0.079)
1.12 (0.068)
0.90 (0.115)
0.95 (0.145)
0 0.5 1.0 1.5 2.0
 397
Hormones and Cancer 397
depicted in Figure 22–​1 within only a few years of stopping, long-​term
users had risks equivalent to those who never used ET (Figure 22–​1).
The addition of progestins to ET (EPT) was also a learning experi-
ence. A year before the 1976 publication linking ET to breast cancer
risk, two studies (Ziel and Finkle, 1975; Smith et al., 1975) found a
very strong increased risk of endometrial cancer with use of ET. The
combination of strong associations with two common cancers appear-
ing over a short time period led to a decline in ET prescriptions. Given
that progestins were known to differentiate the endometrium, stopping
estrogen-​driven proliferation, formulations combining both an estro-
gen and a progestin were introduced and became increasingly popu-
lar. Suggestions were made that in addition to lowering the risk of
endometrial cancer related to ET, combined formulations would likely
also ameliorate any increase in breast cancer (Gambrell, 1984), even
though it had been established that progesterone had different biologic
activity in the breast versus the endometrial epithelium (Key and Pike,
1988). In 1989, data from a Swedish cohort (Bergkvist et  al., 1989;
Persson et  al., 1999)  suggested that while endometrial cancer risk
was substantially lower among the EPT users versus ET users, breast
cancer was not, and might actually be higher among EPT users. This
finding of increased breast cancer risk was subsequently replicated in
larger data sets (Schairer et al., 2000), indicating significant heteroge-
neity in risk between EPT and ET use.
In the mid-​1990s, the Women’s Health Initiative (Rossouw et  al.,
1995), a randomized clinical trial of hormone therapy in menopau-
sal women, was initiated. The main goal of the trial was to determine
whether the suggestion from observational studies that hormone ther-
apy in menopausal women might provide protection from cardiovascu-
lar disease was correct, and if so, whether the benefit outweighed the
risks of treatment, particularly the increase in breast cancer. Women
with an intact uterus were randomized to EPT or placebo, and women
who had undergone hysterectomy were randomized to ET or placebo.
The EPT trial was stopped when women had been on the medications
for an average of 5.2 years. The primary reason for stopping was an
excess risk of cardiovascular disease, rather than an anticipated defi-
cit, among those taking the active drugs (Manson et al., 2003; Writing
Group for WHI, 2002). At the time of stopping, a significant increase in
breast cancer with increasing duration of EPT use, similar to that seen
in the observational studies, was observed. Since stopping, the EPT
group has experienced a marked reduction in excess breast cancer risk
(Chlebowski et al., 2009), also similar to the findings in the observa-
tional studies. The ET trial was also stopped early, primarily because of
an excess risk of strokes in the exposed group. For the women in the ET
group, however, there was no evidence of increased breast cancer risk
(Anderson et al., 2012). In fact, at the time of stopping, this group had
a non-​significant deficit of 20%; early in the post-​intervention period,
this deficit remained and became statistically significant (Manson et al.,
2013). Indeed, this association had a rather unusual pattern, as depicted
in Figure 22–​2 with the deficit appearing almost immediately after trial
No. (%) of Events
CEE Placebo
Invasive breast cancer
Intervention 104 (0.28) 135 (0.35)
Postintervention 47 (0.26) 64 (0.75)
Overall 151 (0.27) 199 (0.35)
Figure 22–​2.  Cumulative hazard of breast cancer associated with Conjugated Equine Estrogen (CEE), overall and post-​intervention. The hazard ratios
(HRs) are derived from proportional hazards models stratified by prior disease (for outcomes in which women were eligible for enrollment with and
without the prevalent condition), age, and dietary modification randomization group. The P values for differences between the intervention and post-​
intervention phases were calculated from models for the overall mean follow-​up period that also included a time-​dependent term for trial phase. For the
intervention and overall phases, time to event equals 0 on date of randomization. For the post-​intervention phase, time to event equals 0 on February
29, 2004. Source: JAMA 2011;305(13):1305–1314.
initiation, and remaining at about the same level during the trial and
also for several years after cessation of treatment (Figure 22–​2).
Based on the results of observational studies described in the pre-
ceding, this finding of apparent protection in the ET group was unex-
pected. On closer inspection, the reduced risk appeared to be driven by
subjects in the trial who began use 5 or more years after their meno-
pause, whereas those who began their use closer in time to menopause
had risks similar to the placebo group (Prentice, 2009). It has been
noted that this pattern of reduced risk could be consistent with the
observation that among women with breast cancer, treatments result-
ing in long-​term estrogen deprivation can cause “the eventual devel-
opment and evolution of anti-​hormonal resistant cell populations that
emerge with a vulnerability, as estrogen is no longer a survival signal,
but is an apoptotic trigger” (Lewis-​Wambi and Jordan, 2009; Obiorah
et al., 2014). In a very large cohort study that had enough women to
assess those who had not begun use of ET until 5 years or more after
menopause, these women were not at a reduced risk of breast cancer,
but also were not at increased risk, while those who began use within
5  years of menopause were at a significantly increased risk (Beral
et al., 2011).
There are also a number of other, more mundane reasons that the
trial may not be able to optimally address the observational findings.
One relates to dose–​response. In the ET trial, the average follow-​up
time at stopping was 6.8 years (Anderson et al., 2004). In several of
the larger observational studies, the excess risk does not appear until at
least 5 to 8 years of exposure, and rises with further use (Collaborative
Group on Hormonal Factors, 1997; Schairer et  al., 2000). Also, as
noted earlier, most of the observational studies have found evidence of
a strong interaction of estrogen use and breast cancer risk with body
mass index (BMI), with the risks being higher in, and frequently lim-
ited to, those with a BMI under 25 (Collaborative Group on Hormonal
Factors, 1997; Schairer et al., 2000). With only 1110 women with a
BMI under 25 in the ET arm of the WHI, and an expectation of no, or
a very low level of, excess risk at 6 years of follow-​up, there is likely
little statistical power to adequately address this question.
Endogenous Hormones
With the plethora of seemingly hormone-​related risk factors for breast
cancer, and with the prime explanatory candidate hypothesized to be
estrogen, one would think that an early response would have been an
assessment of circulating levels of estrogen. This did not happen for
some time, likely due to concern over the quality of assays availa-
ble, and particularly with the paucity of prospective cohort studies
with biospecimen collections. For whatever reason, it was not until
30  years after the elucidation of many hormonally related risk fac-
tors, and 20  years after the first assessments of exogenous estrogen
exposure, that reasonable studies of prospectively collected endoge-
nous estrogens began to appear. Most of the initial studies, although
relatively small, did show evidence of a positive association between
HR P value Favors Favors
(95% Cl) for Difference CEE Placebo
0.79 (0.61–1.02)
0.75 (0.51–1.09) .76
0.77 (0.62–0.95)
0.50 0.67 1.00 1.50 2.00
HR (95% Cl)
398
398 PART III:  THE CAUSES OF CANCER
estradiol and estrone levels and elevated breast cancer risk in post-
menopausal women that became convincing in larger studies and
pooled analyses (Key et  al., 2002). More recently, circulating estro-
gens in premenopausal women have been linked to increased breast
cancer risk (Endogenous Hormones and Breast Cancer Collaborative
Group et al., 2013), although at lower levels of risk than for postmeno-
pausal women—​somewhat surprising given the much higher absolute
estrogen concentrations in premenopausal women. There is also some
evidence that the magnitude of this risk may differ by time in the men-
strual cycle when estrogen was measured (Fortner et al., 2013). Thus
far, these observations on premenopausal estrogen levels have come
from assessing all breast cancers following hormone measurement.
Very recently, one study was able to assess the association of premen-
opausal estrogen levels separately for breast cancers occurring before
and after menopause (Fortner et al., 2013). A doubling of premeno-
pausal estradiol resulted in a 10% increase in risk for breast cancers
occurring in premenopausal women, but a 40% reduced risk for those
occurring in postmenopausal women. It is clear that what is needed is
much more focus on studies of the effects of premenopausal hormonal
profiles in order to understand the underlying biology.
Before there were even prospective epidemiologic studies of cir-
culating estrogens, both epidemiologists and laboratory investigators
were interested in a potential role for estrogen metabolism, and thus
metabolites in carcinogenesis. The most prominent early hypothesis
from epidemiologists was the estrogen-​fraction hypothesis (Cole and
MacMahon, 1969). Noting that estriol, a metabolite of the estrogens
estrone and estradiol, was a much “weaker” estrogen than its parents,
it speculated that women with larger ratios of estriol to estradiol and
estrone would be at lower breast cancer risk. Since there were no pro-
spective studies in which to test such a hypothesis, they tried to assess
its credibility by comparing measurements in populations with vary-
ing breast cancer risks, including women living in high-​and low-​risk
countries, and among women by their parity, ages at first birth, at men-
arche, and menopause, and other risk factors (MacMahon et al., 1970).
While some of these comparisons were consistent with the hypothesis,
some were not, and there were some differences between pre-​and
postmenopausal studies. In addition, as one of the originators of the
hypothesis commented, “… as knowledge of the biology of the estro-
gen fractions developed, the idea that the estrogen fractions compete
for binding sites became less attractive” (MacMahon, 2006).
At about the same time as the estrogen fraction hypothesis emerged,
laboratory investigators, after decades of work on potential mechanisms
of carcinogenesis, had also turned their attention to estrogen metabo-
lism. It was noted that the parent estrogens were rapidly metabolized,
with the initial step being hydroxylation at the 16, 2, or 4 position of the
steroid ring, followed by a cascade of metabolites down each of these
pathways. It was found that the 16-​hydroxy metabolites had an affinity
for the estrogen receptor and thus were strong mitogens stimulating cell
proliferation. On the other hand, metabolites down the 2 and 4 pathways
(known as the catechol estrogens) were not strong mitogens, but could
be oxidized to form quinones that interact directly with DNA to form
a variety of adducts that could enhance mutational events (Yager and
Davidson, 2006). This was particularly true for the 4-​OH pathway. As a
result, two distinct hypotheses arose for how estrogen could cause breast
cancer and maybe other malignancies as well—​a mitogenic hypothesis
and a mutagenic hypothesis (Yager and Davidson, 2006). Each of these
hypotheses developed a constituency within the laboratory community,
leading to several decades of experiments and spirited debates on which
hypothesis was correct, or at least more important than the other. Until
recently, for the most part, the epidemiology community had not been
involved in assessing these hypotheses. Indeed, for about a decade,
many epidemiologists were largely unaware of the relevant laboratory
work. Even after becoming aware of it, there was very little investi-
gation in human populations because there were no reliable assays to
measure the relevant metabolites in humans. Eventually, two of the
metabolites within these pathways were measured (2-​hydroxyestrone
and 16-​alpha-​hydroxyestrone), with inconsistent results with respect to
risk (Cauley et al., 2003; Muti et al., 2000; Ursin et al., 1999). Several
years later, a comprehensive method to assess a range of metabolites
across these pathways was finally developed (Xu et al., 2007). As noted
in Chapter  45 of this volume, the first studies to use this method to
comprehensively evaluate these pathways in prospective cohort studies
of breast cancer (Dallal et al., 2014; Falk et al., 2013; Fuhrman et al.,
2012; Moore et al., 2016) found a strong relationship of decreasing risk
of postmenopausal breast cancer with an increasing proportion of estro-
gen being metabolized down the 2-​OH pathway. This supported the
mitogenic hypothesis for estrogen-​induced breast cancer. The fact that
low breast cancer–​risk populations in Asia have relatively high ratios of
2-​OH to 16-​OH metabolites that decline in Asian migrants to the West
(Falk et al., 2005; Moore et al., 2016), along with more favorable ratios
being associated with increased levels of exercise (Dallal et al., 2016;
Matthews et al., 2004), suggest that this risk factor may be modifiable.
Unifying Hypothesis?
As previously noted, very early in the pursuit of the epidemiology
of breast cancer, risk factors seemed to indict hormones, specifically
estrogens, leading to the unifying hypothesis that cumulative lifetime
exposure to estrogen explained the disease. Unfortunately, this was so
widely accepted that it seemed to discourage any analytic attempts to
robustly test the hypothesis. Over many decades, a number of well-​
replicated observations have challenged this assumption.
• Obesity, associated with increased levels of estrogen, is a postmeno-
pausal breast cancer risk factor, but only near the time of diagnosis,
and not when it only existed, even for long periods, at some time in
the past (Ziegler, 1997).
• Long-​term use of exogenous estrogen therapy by postmenopausal
women increases risk, but only among current or very recent users,
with even very long-​ term users who have stopped for several
years having the same risk as never users (Collaborative Group on
Hormonal Factors in Breast Cancer, 1997).
• The anticipated additional increased risk associated with exogenous
hormones is not apparent in obese women who take these drugs
(Collaborative Group on Hormonal Factors in Breast Cancer, 1997).
• Circulating estrogens in premenopausal women (when estrogen lev-
els are at their highest) are associated with only modest increases
in breast cancer risk (Endogenous Hormones and Breast Cancer
Collaborative Group et al., 2013) compared to effects in postmeno-
pausal women (Key et al., 2002).
• With respect to the international differences in risk, the actual dif-
ferences in circulating estrogens between low-​and high-​risk popula-
tions do not appear to explain much of the observed differences in
breast cancer rates (Hoover, 2012). Moreover, in new data from a
previously unstudied Asian population (Mongolians), we see very
low rates of breast cancer, but higher estrogen levels than those in
the West (Troisi et al., 2014).
• Doubt has even been raised about the risk factor that was thought
to most clearly show a long-​ term estrogen dose effect—​ age at
menarche—​where seemingly a few years more of menstrual cycling
would end up contributing to risk many years later. Breast can-
cer incidence in Bangladesh is five times lower than in the United
Kingdom, and South Asians in Britain have a rate double that in
South Asia, a pattern that has also been observed with East Asian
populations studied in the past (Houghton et al., 2014). However, in
a recent study of Bangladeshi migrants, the age at menarche was the
same for girls living in Bangladesh as for those who had migrated to
Britain, and both were the same as for British girls (Houghton et al.,
2014). What was different was the pubertal transition (Figure 22–​3).
As depicted in Figure 22–​3 the interval from adrenarche (when the
adrenal cortex secretes increased levels of androgens) to thelarche
(the onset of breast development) decreased, and that from thelar-
che to menarche increased with increasing Western acculturation.
This is just one study, and conclusions may change with further
investigations, but it has stimulated investigators to speculate about
whether the historic age at menarche observation might not operate
by increasing lifetime estrogen exposure, but through early molec-
ular events impacting cancer susceptibility. This is the direction
that much of the search for the underlying mechanism of the effect
of another risk factor, age at first birth, has been taking recently.
Initially, the focus was on possible hormonal changes associated
 39
White British 1.6 3.9
British-Bangladeshi 2.2 2.5
Bangladeshi 3.5
Years between milestones
Adrenarche to Thelarche Thelarche to Menarche
Figure 22–​3.  Juvenile and pubertal tempo.
with this risk factor (MacMahon et al., 1970), but most recent efforts
have turned to studies of significant molecular changes within the
breast (Sivaraman and Medina, 2002).
While the described findings are not consistent with a cumulative
lifetime exposure hypothesis for estrogen carcinogenesis, they do pro-
vide impressive support for estrogen acting relatively late in breast
carcinogenesis, likely as a tumor promoter. In addition, some of these
findings—​lack of additive effects of obesity and menopausal hormone
therapy, smaller effects for pre-​versus postmenopausal circulating
estrogen—​could be viewed as reflecting a potential (upper) threshold
for estrogen’s influence. This would be consistent with estrogen acting
mainly via receptors, with saturation of available receptors at some level
of concentration. But if we have learned anything from the last 60 years
of breast cancer research, perhaps we simply should be working to more
fully characterize and understand the known risk factors, rather than
attempting to develop comprehensive explanatory hypotheses.
Breast Cancer Subtypes
It should be noted that the discussions of hormones and breast cancer in
this chapter have focused on the development of our knowledge of its
etiology over many decades, and therefore we have described studies
of overall breast cancer. More recently, molecular markers in tumors
have been used to form subgroups that have distinct therapeutic, and
likely etiologic, implications. The first and most widely used catego-
rization distinguishes between tumors that express estrogen receptors
and those that do not. As might be expected, most etiologic studies
that address both types find that the estrogen-​related risk factors tend
to be much stronger in, and sometimes limited to, the estrogen receptor
positive (ER+) malignancies (Press et al., 2011; discussed comprehen-
sively in the reproductive factors section of Chapter 45 in this volume).
Studies of recent time trends in incidence have noted a steady decline
in incidence of ER–​tumors and an increase in ER+ tumors, trends
that are predicted to continue at least through 2030 (Anderson et al.,
2011; Rosenberg et al, 2015). Discerning the reasons for these patterns
would seem to be a high priority.
Until recently, the classification of subtypes for therapeutic pur-
poses has used classical immunochemistry (e.g., estrogen, progester-
one, and HER2 receptors) in combination with clinical and pathologic
variables. The recent introduction of high-​throughput gene-​expression
analyses has introduced a whole new and complex method for predict-
ing tumor response to treatments (Blows et al., 2010; Dai et al., 2015).
How many prognostic categories this will result in and how relevant
any of this will be to etiology are unknown, but worth keeping track of.
Future Prospects
Some of the seemingly conflicting evidence for hormonal effects in
breast cancer risk could be clues to a deeper understanding of hor-
monal carcinogenesis, but for the most part has not been aggressively
pursued with this in mind. A good example of this is the striking risk
Hormones and Cancer 399
factor differences for pre-​versus postmenopausal disease. Circulating
estrogen levels, a well-​ established risk factor for postmenopausal
breast cancer, is likely associated, but to a much smaller degree, with
premenopausal disease. Likewise, obesity is associated with increased
risk of postmenopausal breast cancer, but actually appears to be pro-
tective for premenopausal disease (Hunter and Willett, 1993). In fact,
the expectation that pre-​and postmenopausal breast cancers should
have a common epidemiology and share the same risk factors could be
the problem. Certainly all aspects of reproductive biology and lacta-
tion have been driven by powerful evolutionary pressures over millen-
nia, while postmenopausal hormonal physiology was likely not subject
1.8
to such pressures. Thus, perhaps one should actually expect there to be
consequential differences between pre-​and postmenopausal hormonal
epidemiology, and exploiting these differences may give us clues to
etiology. For example, normal postmenopausal breast lobules contain
4–​5 times the number of cells expressing estrogen receptors than those
present in premenopausal lobules (Bernstein and Press, 1998). This
likely at least partially reflects the frequently observed phenomenon
of an increase in activation of receptors in response to a decline in
the presence of their ligands (De Meyts and Rousseau, 1980). If this
relatively simple explanation is responsible for the shift in ER status
of tumors with age, some focus on a more comprehensive understand-
ing of the epidemiology of ER expression might be useful. Another
emerging possibility is one that has a more general implication as
well. That is, as our knowledge of hormones and their actions expand,
we are seeing the breadth of hormones that contribute and interact
in regulation of specific organs and their functions. One of the more
recent of these to be appreciated for the breast is the interrelationship
between estrogens and their receptors and the insulin/​IGF system of
hormones and their receptors. Recent prospective studies have shown
stronger associations of circulating levels of IGF-​1 with postmeno-
pausal breast cancer risk in the presence of elevated androgens or
estrogens (Tworoger et al., 2011). In addition, there is impressive lab-
oratory evidence of “cross-​talk” between these two hormonal systems,
suggesting that assessment of interactions between these two systems
in human risk might be fruitful (De Marco et al., 2015). However, to
do this comprehensively will likely require not only measurement of
the hormones, but also their receptors, for which practical methods of
measurement in large epidemiologic studies will need to be developed.
Receptors are not the only likely significant modifiers of estroge-
nicity. Sex hormone binding globulin (SHBG) binds these hormones,
particularly androgens and estrogens, and can thus modify their impact
on multiple biologic actions (Thaler et al., 2015). Fortunately, SHBG
can be measured reasonably well in serum and can be evaluated for its
impact on the effects of hormones. Indeed, as our colleagues in basic
science pursue advances in molecular biology, it has become clear that
steroid hormones can be bound by numerous proteins in the cell mem-
brane (Caldwell et al., 2016). As is frequently the case, it will be up to
epidemiologists to determine which aspects of this continuing elucida-
tion of the complexity of biologic processes need to be accommodated
in order to come to meaningful conclusions relevant to disease risk and
prevention opportunities at the population level.
While exploring new possibilities for hormones that might play a
role in breast cancer etiology, we need to also include other sex hor-
mones that seem obvious, but have not yet been thoroughly investi-
gated. The most notable of these are progesterone, testosterone and
prolactin. Given that the proliferative action of progesterone in breast
duct tissue has been known for decades (Graham and Clarke, 1997),
and its carcinogenic action as a component of menopausal hormone
therapy has been known for some time (Schairer et al., 2000), remark-
ably little has been done to assess its role at physiologic levels in
breast cancer etiology (Endogenous Hormones and Breast Cancer
Collaborative Group, 2013; Fortner et al., 2013; Kaaks et al., 2014).
With respect to testosterone, while not pursued as extensively as
estrogen, prospective studies have fairly consistently found circulating
levels to be positively associated with both pre-​(Kaaks et al., 2014) and
postmenopausal breast cancer (Key et al., 2002). Until very recently,
the association in postmenopausal women has frequently been writ-
ten off as only reflecting testosterone’s role as the molecular source
for the synthesis of estrogen in peripheral fat. However, this seems
40
400 PART III:  THE CAUSES OF CANCER
Table 22–​1. The Effect on Basal Serum Prolactin Levels of Pregnancy,
Parity, and the Elapsed Time after the Last Delivery
Serum Prolactin ng/​ml
Variable No. (mean = SE) P Value*
Pregnancy
Nulliparous 19 8.85 ß 1.39
Parous 29 4.77 ß 0.43 < 0.01
No. of
pregnancies
1 10 5.18 ß 0.47
2 14 4.61 ß 0.48
3 5 4.40 ß 0.35 NS
Time since last
delivery (mo)
12–​36 10 4.15 ß 0.42
37–​78 10 4.87 ß 0.53
79–​150 9 4.83 ß 0.25 NS
NS = not significant.
less likely to explain its association with premenopausal breast cancer,
where circulating estrogen levels primarily reflect ovarian production.
For postmenopausal disease, in studies that include both estrogen and
testosterone in their models, both hormones remain associated, but at
reduced levels (Key et al., 2002). Clarifying the role and mechanism(s)
of action of testosterone’s effect on breast cancer risk would seem to
be a high priority for both epidemiology and laboratory investigators.
Prolactin, with its major role in normal breast physiology, has also
long been thought of as a candidate hormone for impact on breast can-
cer risk. This enthusiasm was enhanced when it was determined that
normal levels of circulating prolactin were reduced by about 50% fol-
lowing a first birth, and further reduced by smaller amounts with each
successive birth (Musey et al., 1987; Table 22–​1). This led to specula-
tion that this lowering might explain the age at first birth and parity risk
factors for breast cancer. Unfortunately, as noted in Chapter 45, studies
to date have not consistently linked circulating prolactin to breast can-
cer risk (Tikk et al., 2014). Some of this inconsistency may relate to
measurement issues. There are in fact a number of different isoforms
of prolactin, with substantial differences in size and shape. From a
teleological perspective, this would seem to imply that these prolactin
variants might have different biologic roles. Some have attempted to
identify “bioactive” forms of prolactin using various immunoassays.
The most recent effort found some evidence of increased risk with
a bioactivity assay in a subgroup of postmenopausal women whose
blood was sampled relatively close in time to breast cancer diagnosis
(Tworoger et al., 2015). A more definitive resolution of the role of pro-
lactin will probably require a comprehensive, agnostic assessment of
all of its isoforms, a technology not yet available.
Summary
While the saga of attempts to identify hormonal risk factors for breast
cancer, and the underlying hormones and mechanisms involved in car-
cinogenesis, has spanned centuries, revealing associations that have
markedly increased our understanding of some of the elements of
breast cancer etiology, as yet only a few provide practical opportuni-
ties for prevention. On the other hand, much remains unknown, despite
many provocative observations. This is itself a commentary on the level
of knowledge that we need in order to translate findings in hormonal
carcinogenesis, as well as in other metabolic processes, into practi-
cal prevention. In much of chemical carcinogenesis, it is sufficient to
identify the carcinogen and design ways of decreasing exposure to it.
Since hormones are essential for life and generally are regulated in
a fairly tight manner, for the most part we need to understand their
underlying mechanisms in human populations in order to determine
if and how we can use this information for prevention. We have been
able to recommend no or minimal use of menopausal hormone ther-
apy, have emphasized the need to reduce obesity, and have developed
certain hormone-​targeted chemoprevention interventions for women
whose risk/​benefit ratio supports such treatment. The last example
is unfortunately also an example of how, even when we understand
enough about a specific aspect of hormonal carcinogenesis to develop
a preventive intervention, the pervasive level of biologic activities of
hormones can discourage meaningful uptake of such an intervention.
Clinical trials of tamoxifen and raloxifene, medications that can block
estrogen receptors, have documented reductions in breast cancer risk
of 40%–​50% (Fisher et al., 1998; Vogel et al., 2006). They also have
documented consequential adverse biologic effects. Statistical model-
ing of benefit/​risk ratios have identified groups of women for whom
benefits outweigh risks (Gail, 2012), and such prevention efforts have
been widely promoted for these groups. These efforts have been widely
rejected by the women involved, who have made quite different per-
sonal risk/​benefit judgments (Hoerger et al., 2016; Smith et al., 2016).
Because the hormonal component for breast cancer is so pro-
found, there has been hope that with a deeper understanding of the
relevant underlying normal and abnormal hormonal mechanisms, we
might learn how to use this knowledge for more effective preventive
strategies.
Prostate Cancer
Given the role of testosterone, or androgens generally, in the growth,
function, and maintenance of the prostate gland, as well as how prom-
inently androgens are associated with tumor activity once the disease
develops, it has been surprising and mystifying to clinicians, epide-
miologists, and laboratory scientists alike that circulating levels of
these hormones have not been consistently related to prostate cancer
risk (Roddam et al., 2008). Attention has turned to the possibility that
other hormones such as estrogen, or the balance of estrogen and tes-
tosterone, may be important. In men, most testosterone is converted to
dihydrotestosterone (DHT) by 5a reductase, but may also be enzymat-
ically converted to estrogens by aromatase (CYP19). While it has been
hypothesized that higher levels of intraprostatic DHT may be associated
with increased prostate cancer risk (Platz and Giovannucci, 2004), it is
also possible that if 5a reductase activity is inhibited, excess testoster-
one may instead be metabolized to estradiol. The bulk of the evidence
shows no association of estradiol concentrations and prostate cancer
risk, and findings for the association of the estradiol:testosterone ratio
and prostate cancer risk have been mixed. A recent study of aggressive
prostate cancer in the PLCO cohort study simultaneously assessed the
effects of testosterone and the estradiol:testosterone ratio and found
a marked attenuation of an association with testosterone, but min-
imal effect on the inverse association for the estradiol:testosterone
ratio (Black et al., 2014). Estrogen’s metabolites have drawn attention
recently in prostate cancer epidemiology, as they have in breast can-
cer epidemiology, because of improvements in assay methodologies
used to measure them. A recent meta-​analysis (Roddam et al., 2008)
showed an increased risk of prostate cancer with higher urinary 16a-​
hydroxyestrone and a protective effect of excretion of urine with a
higher 2:16a-​hydroxyestrone ratio, neither of which was observed in
a recent study of aggressive disease (Black et al., 2014). In contrast,
the latter study reported a positive association between serum 2:16a-​
hydroxyestrone ratio and aggressive prostate cancer (Black et al.,
2014). The inverse association for estradiol:testosterone ratio, together
with the increasing risk with an increasing proportion of estrogen
being metabolized down the 2-​OH pathway, may indicate a potential
role for estrogen metabolism in the development of aggressive pros-
tate cancer. In breast cancer model systems, 16a-​hydroxyestrone can
bind covalently to the ER and has been shown to induce abnormal
cell proliferation (Bradlow et al., 1985; Suto et al., 1993), whereas 2-​
hydroxyestrone has a weak binding capacity to the estrogen receptor
and has been associated with normal cell differentiation and apoptosis
(Gupta et al., 1998; Telang et al., 1997).
 401
Hormones and Cancer 401
In contrast, strong estrogenic effects (relative to androgen or antago-
nistic metabolites of estrogen) may give protection against aggressive
prostate cancer. Previous work to establish independent associations of
androgens and estrogens with prostate cancer risk may have resulted
in inconclusive findings because these hormones interact as part of
a complex pathway. Future work should focus on mechanistic stud-
ies in prostate cancer, which are currently lacking. Given the track
record for studies of this malignancy—​of positive findings that are not
replicable—​these recent findings clearly require replication before any
further pursuit.
The accumulation of increasing numbers of studies focused on
various hypotheses to explain the lack of any consistent association
between circulating androgens and prostate cancer risk has not yet led
to an answer. This has resulted in speculation that perhaps circulating
levels of testosterone may not reflect its concentration in the prostate.
As previously noted, testosterone is one of the hormones for which
paracrine and autocrine production is particularly noteworthy. While
the textbook examples of this often focus on testosterone’s role in the
testes, paracrine production also occurs in the prostate. It would seem
to be a high priority, using modern measurement techniques, to assess
the levels of correlation between circulating and prostate tissue levels
of androgens and estrogens overall, and for their various metabolic
subtypes.
In addition, as was discussed for the estrogens, it is likely that
an adequate understanding of the role of androgens in prostate car-
cinogenesis is also going to require much more information about,
and measurement of, androgen receptors. In fact, the complexity of
receptor activity is enhanced in the prostate gland. Both epithelial
and stromal tissues have receptors that have differential expression
that can result in different growth factors expressed by the stroma.
These actions can mediate the effects of androgen on the epithelium,
potentially influencing malignant initiation. Similar interactions can
also affect the progression of an established malignancy, including the
induction of direct apoptotic effects, effectively moving androgens
from a cause to a potential treatment of prostate cancer (Berry et al.,
2008; Nieto et al., 2014; Stamatiou and Pierris, 2013).
Part of our difficulty in understanding the role, if any, of hormones
in prostate cancer risk may also lie in our ignorance of almost any risk
factors for prostate carcinogenesis. It is often pointed out that many
decades ago we knew of three well-​established risk factors—​age, race,
and family history—​and this describes our level of knowledge today
as well. For a long period of time, part of the enthusiasm for pursuing
a hormonal etiology was not only the central role of hormones in the
normal function of the prostate, but also the belief that prostate cancer
showed substantial international variation, similar to breast and other
hormonally related cancers. This belief was based on major interna-
tional differences in prostate cancer incidence and mortality, with low
rates in Asian and African men, higher rates in Asian migrants to the
United States, substantially higher rates in white men in the United
States, and the highest prostate cancer rates in the world in African-​
American men. Recent observations have called these conclusions into
question. With the improvement of cancer registration in Africa, esti-
mates of prostate cancer there have risen (Korir et al., 2015). Indeed, a
systematic prostate cancer screening study in Ghana produced prostate
cancer rates similar to those among African-​Americans (Hsing et al.,
2014). Coupled with these observations has been an increasing appre-
ciation of the major role of genetics in prostate cancer etiology. While
a family history of prostate cancer has been a well-​recognized risk fac-
tor, the magnitude of the role of genetics in this tumor was not appre-
ciated until recently. A seminal study within the Nordic Twin Cohort
reported in 2000 that the estimate of heritability for prostate cancer
was 42%, higher than for any other common cancer (Lichtenstein
et  al., 2000). A  more recent update of the study (Hjelmborg et  al.,
2014)  with increased numbers of cases and improved methods esti-
mated heritability at 58% (95% CI: 52, 63). Concurrently, over the past
10 years, with the new capability to agnostically interrogate the entire
genome for common genetic variants associated with cancer risk, the
number of such identified variants has risen from less than 6 to more
than 600—​and counting (Gusev et al., 2016). Initially surprising, but
in line with the heritability estimates, the cancer with the most such
variants identified has been prostate cancer. Currently, over 100 such
susceptibility loci have been identified, likely explaining a meaningful
proportion of the familial risk. These numbers are also likely to rise
further with ongoing genetic studies.
As for the vast majority of all the newly identified genetic variants
associated with cancer risks, we know little about the biologic path-
ways through which the variants related to prostate cancer risk oper-
ate. It will take some time for our laboratory colleagues to address
these questions. However, in the interim, we will have the ability to
investigate how this major role of genetics in prostate cancer etiology
controls, relates to, and/​or interacts with other potential risk factors in
prostate carcinogenesis. Certainly, investing in such efforts with can-
didate hormonal exposures may help to clarify the current enigmatic
state of our knowledge.
Our attempts to understand the hormonal etiology of prostate can-
cer provide a valuable counterpoint to the epidemiologic elucidation
of the role of estrogen and other hormones in breast and gynecologic
malignancies. Hormones are central to normal growth, development,
and homeostasis, and thus are also likely to be biologically involved
in pathologic alterations of these processes. In some instances, these
might be easily identified using epidemiologic tools at hand. In other
instances, we may need to have a much more detailed understanding of
the possible underlying biology involved in order to develop the tools
and methods required to assess effects in human populations. With the
recent marked advances in molecular science, and the development of
molecular epidemiologic methods, we are hopefully entering an era
where this will be possible.
ENDOCRINE DISRUPTORS
There is one area of hormonal carcinogenesis that has garnered
substantial attention in both scientific and lay communities—​ the
potential impact of endocrine-​disrupting agents in the environment
and the risk of various cancers (Soto and Sonnenschein, 2010). Of
particular concern are exposures to these agents in very early life,
when most hormone-​driven development of many organs is promi-
nent. To date, most of the concerns have come from laboratory animal
experiments (Fenton et al., 2012; Newbold et al., 1987), augmented
by various malformations and malignancies identified in wildlife
raised in water sources highly polluted with endocrine-​disrupting
chemicals (Bernanke and Köhler, 2009; Hamlin and Guillette, 2010).
Epidemiologically robust studies of cancer risks in humans following
high-​level exposure to suspect endocrine disruptors have been few
and limited, and have generally not found consistently compelling
evidence of risk (Soto and Sonnenschein, 2010; Teitelbauma et al.,
2015). The one notable exception has been in utero exposure to high
doses of the synthetic estrogen drug diethylstilbestrol (DES). The
first evidence of adverse effects of in utero exposure to DES was the
identification of a cluster of seven cases of the rare tumor clear-​cell
adenocarcinoma of the vagina in adolescent girls whose mothers had
used the drug in their pregnancies (Herbst et al. 1971; Ulfelder, 1980).
More systematic studies have estimated the attack rate of this tumor
in the exposed through age 39 to be about 1.6/​1000 women (Melnick
et al., 1987; Troisi et al., 2007). Other studies of this exposure have
also identified evidence of increased risk of pre-​malignant lesions of
the uterine cervix (Hatch et al., 2001) and adenocarcinomas of the
breast (Troisi et al., 2007). While these are important leads, it should
also be recognized that the overwhelming adverse impact on women
of this fetal exposure has been in anatomic and physiologic abnormal-
ities resulting in very high rates of infertility and abnormal conditions
and complications of pregnancy, as depicted in Figure 22–​4 (Hoover
et al., 2011). Both the neoplastic and adverse gynecologic outcomes
risks are higher among women whose mothers received higher doses
and/​or received them early in gestation, as evidenced by the increased
prevalence of vaginal epithelial changes in these women, an anatomic
marker of high-​dose and/​or early exposure. Overall it is estimated
that 27.5% of women in these high-​risk categories experienced one
or more serious adverse outcomes by age 55 years as a result of their
exposure (Hoover et al., 2011).
402

402 PART III:  THE CAUSES OF CANCER

Infertility§§

Spontaneous abortion†§§

Ectopic†§§

Second trimester loss†

Preterm birth†§§

Pre-eclampsia†

Stillbirth‡†

Neonatal deathत

Early menopause

ClN2+§
VEC +
VEC –
Breast cancer ≥ 40§

0.4 1 10 40
HR and 95% Cl (log-scale)

Figure 22–​4.  Health Outcomes According to Diethylstilbestrol (DES) Exposure Status and, in the DES-​Exposure Group, the Presence or Absence of
Vaginal Epithelial Changes (VEC) at a Young Age. Hazard ratios differed significantly between VEC-​positive and VEC-​negative subgroups of the DES-​
exposed group for infertility, spontaneous abortion, ectopic pregnancy, preterm delivery, and neonatal death (P < 0.01), as well as for grade 2 or higher cer-
vical intraepithelial neoplasia (CIN 2+ and invasive breast cancer at an age of 40 years or older (P < 0.05). Total numbers of women vary among outcomes,
primarily reflecting whether all, pregnant, or parous women were included in the analysis, but also owing to some missing responses to the questionnaires
ascertaining the outcome and, to a lesser extent, to specific questions. Data for spontaneous abortion, ectopic pregnancy, and loss of second-​trimester preg-
nancy were computed with age as the time metric and with adjustment for date of birth and cohort. Data for preterm delivery, pre-​eclampsia, stillbirth,
and neonatal death were restricted to pregnant women and were adjusted for number of pregnancies. † The analysis was restricted to gravid women and
adjusted for number of pregnancies. ‡ The analysis was restricted to parous women and adjusted for number of births. § p-​value < 0.05. §§ p-​value < 0.01.
Source: Hoover RN, Hyer M, Pfeiffer RM, et al. Adverse health outcomes in women exposed in utero to diethylstilbestrol. N Engl J Med 2011;365:1304–1314.

Many fewer males exposed in utero to DES have been systemati-
cally studied, limiting our ability to assess the scope of resulting adverse
effects. Overall, they have experienced more urogenital anomalies,
including cryptorchidism (Palmer et  al., 2009), than those unexposed
to DES. Relevant to this, they appear to have incurred about a two-​fold
increased risk of testicular cancer over the adolescent–​young-​adult peak
of this cancer (Strohsnitter et al., 2001). However, this observation fell
short of nominal statistical significance (RR 2.04; 95% CI = 0.82, 4.20).
Prenatal exposure to high doses of DES has become a key compo-
nent of laboratory research into the carcinogenicity of in utero and other
early-​life exposures to endocrine disruptors (Newbold, 1995). Some of
these studies have found evidence of trans-​generational effects (i.e., an
increase in malignancies in animals not exposed, but whose mothers
were exposed when they were in utero; Newbold et al., 2006). This has
been interpreted as consistent with the mechanism of action being epi-
genetic changes caused by the exposure (in this instance, changes in the
ova of the exposed mother). With respect to studies in humans, there has
been only one study of offspring of mothers exposed when they were
in utero (Titus et al., 2008). This cohort (n = 793) of primarily young
women has not identified any excess in potentially exposure-​related
outcomes, but there have been relatively few relevant outcomes overall,
and the sample size of the cohort is likely not large enough to address
the issues raised by the animal experiments.
EMERGING OPPORTUNITIES
In the following we briefly summarize research on some hormones
that have received less attention in epidemiologic studies but for which
there is increasing enthusiasm that such efforts are warranted.
Anti-​Müllerian Hormone
Anti-​Müllerian hormone (AMH), also called Müllerian inhibiting sub-
stance (MIS), is produced by the granulosa cells of the ovarian follicles
and serves as a biomarker of ovarian reserve. It is structurally related
to inhibin and activin and belongs to the transforming growth factor
β (TGF-​β) family. Available evidence indicates a positive association
between AMH concentrations and breast cancer, and no overall associ-
ations with ovarian and prostate cancer. Findings from two prospective
 403
Hormones and Cancer 403
studies (Dorgan et  al., 2009; Nichols et  al., 2015)  demonstrated an
increased risk of breast cancer with higher compared with lower or
undetectable premenopausal AMH concentrations. In both studies, the
risk was most pronounced among women who were older at diagno-
sis compared with those who were younger, and in one study, the risk
was limited to ER+ tumors (Nichols et al., 2015). AMH declines as
women approach menopause, so higher concentrations could indicate
an older age at menopause. However, adjusting for total and bioavaila-
ble estrogen and testosterone did not materially change the association
of AMH with breast cancer risk (Dorgan et al., 2009). In a study with
prospectively collected AMH concentrations, there was no association
with risk of invasive serous ovarian cancer overall, but results varied
by age at which AMH was measured: in women who were older com-
pared with younger, higher AMH was associated with a decreased risk,
whereas in women who were younger compared with older, higher
AMH was associated with an increased risk (Schock et  al., 2014).
AMH measured prior to diagnosis was not associated with prostate
cancer in the PLCO (Sklavos et al., 2014).
Insulin, Growth Hormone, and Insulin-​Like
Growth Factor
IGF-​1 is similar in chemical structure to insulin, as its name implies.
Insulin increases bioactive IGF-​ 1 through various mechanisms,
including regulation of growth hormone (GH). Additionally, insulin
reduces hepatic release of IGF binding protein-​1 (IGFBP-​1), which
binds with high-​affinity to IGF-​1, thereby reducing its bioactive form.
IGF-​1 effects on cellular proliferation, together with strong antipop-
totic activity, results in hyperproliferation, and thus IGF-​1 is an active
player in cancer angiogenesis and metastasis.
A systematic review and meta-​analysis of IGFs and IGFBPs and
cancer (Renehan et al., 2004) concluded that higher circulating total
concentrations of IGF-​1 were associated with prostate, colorectal, and
premenopausal breast cancer. Dose–​response associations were con-
firmed for prostate and premenopausal breast cancer but not for colon
cancer. Except for a possible inverse association of lung cancer with
higher concentrations of IGFBP-​3, there were no protective effects
with any of the other cancer sites.
A modest positive association of IGF-​1 concentrations and breast
cancer risk was demonstrated in a large, pooled analysis (Endogenous
Hormones and Breast Cancer Collaborative Group, 2010), which was
independent of IGFBP-​3, its main binding protein. The association
between IGF-​1 and breast cancer risk did not vary by timing of blood
collection in regard to menopause, but was only observed for ER+
tumors and not ER–​tumors. IGFBP-​3 was not associated with pre-
menopausal breast cancer, and a weak positive association of IGFBP-​
3 with breast cancer risk in postmenopausal women was attenuated
with adjustment for IGF-​1. While independent associations between
IGF-​ 1 and breast cancer, when demonstrated, have been modest,
there is some evidence of stronger associations with postmenopausal
breast cancer risk in the presence of elevated androgens or estrogens
(Tworoger et al., 2011).
The associations of greater circulating concentrations of IGF-​1 and
lower concentrations of IGFBP-​3, and perhaps IGFBP-​2, have been
found for risk of colorectal cancer and high-​risk adenoma, but not low-​
risk tubular adenomas (Giovannucci, 2001). IGF-​1 is positively asso-
ciated with prostate cancer risk, but an association for low IGFBP-​1
is inconsistent, and there is little evidence of associations with IGF-​2,
IGFBP-​1, and IGFBP-​2 (Rowlands et al., 2009). There are limited data
on IGFs and other cancers, particularly using pre-​diagnostic biosamples.
Studies have provided no evidence of an association of IGFs and ovar-
ian cancer (Tworoger et al., 2007) but have suggested the possibility of
reduced testicular cancer risk with high IGF-​1 levels (Chia et al., 2008).
Results from a meta-​analysis of studies assessing the effect of exog-
enous insulin use on cancer risk in diabetics suggested positive asso-
ciations for pancreas, liver, kidney, stomach, and respiratory cancer,
and a decreased risk for prostate cancer (Karlstad et al., 2013). The
data, however, were limited by lack of information on dose, duration,
and potential confounders.
Other Hormone Regulators of Energy Metabolism
Leptin, adiponectin, resistin, and ghrelin are important regulators
of energy homeostasis, and glucose and lipid metabolism. They are
involved in cell growth and proliferation and inflammation, as well
as tumor angiogenesis. Leptin, resistin, and ghrelin are associated
with insulin resistance; in contrast, adiponectin mediates insulin sen-
sitivity. This biological activity, in addition to their utility in assess-
ing tumor progression, has raised interest in whether the balance of
these hormones plays a role in cancers associated with obesity such
as colorectal, pancreatic, hepatic, ovarian, and postmenopausal breast
cancer.
While leptin and resistin were not associated with postmenopausal
breast cancer in a study nested within the Women’s Health Initiative
(Gunter et al., 2015), there was suggestion of an inverse trend in risk
with increasing adiponectin levels, the latter consistent with results of
meta-​analyses (Liu et al., 2013; Macis et al., 2014; Ye et al., 2014).
However, the positive association was not independent of circulating
insulin, suggesting that the effects of adiponectin on breast cancer
risk are partly mediated by insulin. In fact, insulin, estradiol, and C-​
reactive protein together appeared to explain the association of BMI
with breast cancer risk in this study.
Elevated leptin levels have been associated with increased risk of
endometrial and ovarian cancer (Wu et al., 2014). Reduced levels of
adiponectin have been associated with an increased risk of endometrial
cancer (Cust et al., 2007; Luhn et al., 2013; Wu et al., 2014; Zheng
et  al., 2015), with risk appearing to be higher among obese women
than non-​obese women and among post-​or perimenopausal women
compared with premenopausal women (Cust et al., 2007; Zheng et al.,
2015). In one study, much of the association between adiponectin and
endometrial cancer was attenuated after adjustment for other obesity-​
related physiological factors such as C-​peptide, IGFBP-​1, IGFBP-​2,
SHBG, estrone, or free testosterone (Cust et al., 2007).
Colorectal cancer risk also was assessed in relation to hormones
in postmenopausal women who participated in the Women’s Health
Initiative. Leptin, but not adiponectin or resistin, remained positively
associated with colorectal cancer risk after adjustment for insulin (Ho
et  al., 2012). Results of a meta-​analysis were consistent with these
findings for leptin, which showed a positive association with colorec-
tal cancer in prospective studies, while adiponectin was also shown
to be inversely associated with colorectal cancer risk (Joshi et  al.,
2014). Limited data suggest a positive association between resistin and
colorectal cancer risk (Joshi and Lee, 2014). In addition to their role in
obesity and metabolic syndrome, cytokines are of interest in carcino-
genesis because of their possible impact on the microbiome, given that
several are secreted in the gut.
Leptin concentrations have been positively associated (Stolzenberg-​
Solomon et  al., 2015), and adiponectin has been inversely associ-
ated, with pancreatic cancer risk (Stolzenberg-​Solomon et al., 2008).
Adiponectin concentrations have been inversely associated with pros-
tate cancer risk in several nested case-​control studies (Liao et  al.,
2015), but one study found no association with aggressive prostate
tumors (Stevens et al., 2014). A meta-​analysis of hepatocellular car-
cinoma showed an association with high adiponectin levels, but it is
unclear whether values were a result of the tumor or played a causal
role (Song and Gu, 2015).
Thyroid Hormones
While several studies have assessed the associations of thyroid condi-
tions or the use of thyroid hormones and cancer risk, few have pro-
spectively collected biological measures of thyroid hormones to assess
causality. Results for thyroid status and breast cancer based on cross-​
sectional studies have been mixed. Two prospective studies with thy-
roid measurements also had discrepant findings, with one showing
associations of a diagnosis of hypothyroidism, thyroid medication use,
and low thyroxine (T4) with an elevated breast cancer risk (Kuijpens
et  al., 2005), and one showing a positive association of triiodothy-
ronine (T3), which is more potent than T4, with breast cancer risk
(Tosovic et al., 2010) and mortality (Tosovic et al., 2013).
40
404 PART III:  THE CAUSES OF CANCER
In a nested case-​control study in the United Kingdom (Boursi et al.,
2015), colorectal cancer risk was increased in untreated hypothyroid-
ism and in those with hyperthyroidism compared with having no thy-
roid condition, while long-​term thyroid hormone replacement therapy
was protective, particularly in women.
Higher serum thyroid stimulating hormone (TSH), which activates
T3 and T4, has been associated with a decreased risk of prostate cancer
compared to men with lower levels, and hypothyroidism based on T4
and TSH measures was associated with a lower risk compared with
men classified as euthyroid (Mondul et al., 2012). The causal associa-
tion of thyroid hormones and thyroid cancer is surprisingly unclear.
A  prospective study in South Korea showed that T4 was positively
associated with thyroid cancer risk in women, but only in measure-
ments collected within 3 years before diagnosis (Cho et al., 2014).
Cortisol
Despite wide interest in the possible association of hormones indica-
tive of chronic stress and cancer risk, research has been limited by the
lack of a valid, reproducible biomarker. In a Danish study of women,
hormone-​dependent cancers were not associated with the ratio of cor-
tisol to estrogen, but neither was the ratio associated with self-​reported
stress (Rod et al., 2010). A positive association between the ratio of
cortisol to dehydroepiandrosterone sulfate (DHEAS) and cancer mor-
tality, adjusted for smoking and concurrent illness at diagnosis, was
found in a study of Vietnam-​era male veterans (Phillips et al., 2010).
Melatonin
Associations of night-​shift work with cancer incidence have raised
interest in disruption in secretion of the hormone melatonin, which is
linked to circadian rhythm. Evidence using this biomarker is limited
to studies of breast and prostate cancers. A meta-​analysis of five pro-
spective studies with concentrations of the primary urinary metabolite
of melatonin, 6-​sulfatoxymelatonin (aMT6s), showed an inverse asso-
ciation with breast cancer risk (Basler et al., 2014), although whether
this association holds in premenopausal women remains unclear
(Brown et al., 2015). Icelandic men with morning aMT6s levels below
the median compared with those with levels above the median had
no difference in prostate cancer risk overall, but an increased risk for
advanced disease (Sigurdardottir et al., 2015).
LESSONS LEARNED
We have tried to briefly describe the evolution of attempts to under-
stand the roles that hormones play in cancer etiology. This includes
many efforts over an extended period of time focused on several ste-
roid sex hormones, and more recent opportunities and initiatives for a
diverse set of other hormones. While important discoveries and mean-
ingful progress have been made, there is much that remains to be dis-
covered; with the remarkable recent advances in molecular science,
as well as in epidemiologic and statistical methods, the time may be
right to greatly expand our understanding of hormonal carcinogene-
sis in human populations. To that end, our past efforts have taught us
some useful lessons that we need to remember in starting ambitious
new initiatives.
Measurement
On first impression, it would seem that understanding hormonal effects
would be well suited to epidemiologic approaches. Active biologic
agents that are secreted into the bloodstream to travel to the organs
they regulate should be easily sampled in populations and related
to subsequent biological effects, including carcinogenesis. In some
instances this is the case, but often the amount of hormone secreted is
influenced by a variety of other factors. A few examples of this include
the following: in premenopausal women, concentrations of estrogens,
androgens, and progesterone vary substantially over the menstrual
cycle; secretion of insulin and several other hormones is profoundly
influenced by recency of food intake; other hormones have appreciable
diurnal variation, such as prolactin, for which secretion occurs episodi-
cally, peaking during sleep and substantially declining by late morn-
ing; and still other hormones vary substantially by levels of physical
or psychological stress. In some studies, these and other issues can
be taken into account by timed and/​or multiple blood collections.
However, often this is not possible, including in the common practice
of using large established prospective cohorts. In these circumstances,
it is hoped that biologic collections would have been conducted in a
systematic manner, or at least that the timing and circumstances of the
collections would have been recorded, allowing for some control in the
analysis, but frequently even this is not possible. The result of inad-
equate control for these determinants of hormonal exposures would
likely result in random misclassification of exposure and the resulting
biasing of any association toward the null. This has been speculated
as the reason for the unexpectedly weak associations of prolactin and
estrogen with breast cancer risk in premenopausal women.
A recurring measurement dilemma in designing studies of hormone-​
related cancers is when, if ever, to use a case-​control design. Certainly
these can be done more quickly and can more easily achieve larger
sample sizes with considerable cost-​efficiency compared to de novo
cohort studies. However, they are rarely conducted because of two con-
cerns. If hormones are localized or stored in certain organs, a malig-
nancy in the organ may disrupt homeostasis and thus release more
hormones into circulation. Alternatively, if the tumor can manufacture
the hormone, an established capability of breast cancers, then circulat-
ing levels may not represent those during carcinogenesis. All of this
certainly supports the cohort approach. However, as noted previously,
case-​control studies of early-​stage breast cancer have found associa-
tions with circulating estrogens similar to those from prospective stud-
ies. Perhaps in a practical sense, doing such studies on early-​stage
cancers could inform the level of enthusiasm for developing compre-
hensive cohort studies, particularly for less common malignancies.
A much less well-​recognized measurement issue is whether (and
if so, how) to accommodate paracrine signaling, a form of local cell-​
cell communication that uses the same pathways as hormonal signals
(Melmed et al., 2016). Because of this shared response machinery, tar-
get cells respond similarly to the signals from the blood and from adja-
cent cells. Indeed there are several analytes, most notably testosterone
and IGF-​1, that function both as hormones and paracrine signals. The
amounts of paracrine factors produced per cell are very small. In addi-
tion, because the paracrine factor’s point of action is so constrained
(often one cell), elaborate cellular mechanisms have evolved to con-
strain its diffusion. Thus any attempts to measure it require tissue sam-
ples and often single-​cell assays. While this is not particularly practical
in epidemiologic studies, it also would not likely reflect total organ
doses. While some studies of tumor specimens use these techniques to
address specific molecular questions, for both practical and scientific
reasons it seems that answering epidemiologic questions relating to
normal tissue exposure will, for the foreseeable future, need to rely on
circulating hormone measurements.
The central role of hormones in so many critical physiologic path-
ways has resulted in a number of homeostatic mechanisms to regu-
late their production, dissemination, and action. This has impacted
epidemiologic approaches in at least two ways. For one, this level of
control results in the typical distributions of exposure in studies being
constrained to the “normal range,” with little opportunity to study the
effect of the extremes (low or high) of exposure. In some instances,
therapeutic interventions have restored these opportunities (e.g.,
oophorectomy, sex hormone therapy). However, even without this,
because of the powerful biologic actions of some hormones, there are
also opportunities to observe important dose–​response effects within
the normal range, as seen with estrogens and IGFs.
The second way in which the homeostatic mechanisms of hormones
impact epidemiologic approaches is the value of, and sometimes the
necessity for, taking account of these physiologic mechanisms of
control when trying to get a clear picture of how hormones act in
neoplasia. As described earlier, one of these mechanisms involves
binding proteins in the circulation that can modify the availability
 405
Hormones and Cancer 405
of the hormones they bind and thus impact the total amount of hor-
mones available for the organs through which they travel (Thaler,
2015). Fortunately, these proteins can be measured and evaluated for
their impact. Various chemical modifications of hormones also rou-
tinely occur, particularly as they pass through the liver. One of the
more common modifications is conjugation, particularly sulfation and
glucuronidation. These changes are generally viewed as protecting
cells from genotoxic and cytotoxic effects, as well as allowing excre-
tion via either urine or stool. However, it is also speculated that these
metabolites may provide a reserve supply of hormones that could be
made available, some of which can induce ER-​mediated signaling
pathways (Chang, 2011).
Finally, there is one measurement challenge in hormonal epidemi-
ology that may be more important than all of those mentioned in the
preceding: that is, that the biological effects of hormones depend not
only on the effects of the hormones themselves, but also on that of
their receptors—​agents that are not easily measured or evaluated using
common epidemiologic methods (Eyster, 2016; Katzenellenbogen
et al., 2000; Zhu et al., 2006). In terms of their mechanisms of action,
there are two types of hormones—​those that do not enter cells, but
bind with receptors at the cell surface and regulate gene expression
through second messengers via this interaction, and those that enter
cells and bind to intracellular receptors in the nucleus of target cells,
resulting in gene expression. Thus, the effects of hormones are not
only a result of the “dose” of the hormone but also the presence, num-
ber, and activity of relevant receptors. As noted in the discussion of
the exogenous sex hormones, there is a general observation that the
number of active receptors is often inversely related to the circulat-
ing level of their ligands, representing a sort of host-​cell mechanism
to prevent too much or too little hormonal stimulation. One can see
how this might lead to an alteration of our usual expectations for evi-
dence of dose–​response relationships. But it is probably even more
complicated than that. Multiple co-​activators and co-​repressors exist
that can affect the activity of receptors and thus their ability to activate
gene transcription (Shibata, 1997). Indeed, transcriptional activity can
occur with unliganded receptors that “are able to have a life on their
own” (Stellato, 2016).
While all of the complexities of receptor activity need not be
accounted for in assessing the relationship between a hormonal ligand
and cancer risk, it could represent a key interactive piece in trying to
understand hormonal carcinogenesis. Being able to measure activated
hormone receptors in malignant tumors has been a key element in clar-
ifying etiologically distinct types of breast cancer. The ability to assess
receptor status of normal tissue might well be an important contributor
to understanding organ-​specific hormonal carcinogenesis.
Hypotheses
While there are remarkable new opportunities to pursue the carcin-
ogenic potential of hormones and their metabolites, perhaps equally
important in this pursuit is to question old “knowledge.” The use of
quotation marks here is purposeful, since we are not referring nec-
essarily to specific facts or results, but more often to the ways these
results have been interpreted and/​or combined. The frequent result of
this activity is one or more hypotheses to explain the observations.
This is a critical piece of the scientific method. Unfortunately, when
attractive and logical hypotheses are not quickly robustly tested, they
may become accepted as fact. This seems to occur relatively frequently
in studies of hormones, perhaps because for many hypotheses in this
area, the populations, technologies, or science required to test them
simply do not exist at the time they are developed. The example of
cumulative lifetime estrogen exposure being a “unifying hypothesis”
explaining virtually all of breast cancer risk factors was discussed in
our section on breast cancer. Another example is the attempt to explain
the underlying biologic mechanism for the protective effect on breast
cancer risk of a woman having her first birth at a relatively young age.
Initial attempts to explain the effect on the basis of a change in the
post-​pregnancy hormonal profile of the mother were not supportive.
The next most popular hypothesis was a molecular change in breast
epithelium at the time of the pregnancy—​specifically, terminal dif-
ferentiation of the ductal epithelium (Russo and Russo, 1995). This
seems to have become accepted as the definitive explanation for many
working on breast cancer, even though it has not been proven, and
there are a number of other hypotheses that seem as plausible (Medina,
2004, 2005).
The tendency to embrace attractive hypotheses before they are tested
has extended to the pursuit of very early-​life exposures and cancer
risk. This is easy to understand, since these are very difficult hypothe-
ses to test directly. However, often there are opportunities to assess the
general credibility of such hypotheses. A provocative example of both
of these points was the hypothesis that breast cancer risk in women
is related to the levels of circulating estrogens they were exposed to
while they were in utero (Trichopoulos, 1990). An appreciable portion
of this hypothesis was based on two observations:  that offspring of
pre-​eclamptic pregnancies had a lower risk of breast cancer than those
from normal pregnancies (Ekbom et al., 1992), and that among female
migrants from Asia to the United States, those who were born in Asia
had lower breast cancer rates than those living in the United States for
a comparable period of time but who were born in the United States
(Ziegler et al., 1993). Since pre-​eclampsia was known to be associated
with lower levels of estrogen, and Asians in Asia were known to have
lower levels of estrogen than Western women, the hypothesis that low
levels of estrogens during pregnancy might be protective for breast
cancer seemed quite logical. It took about a decade before replacing
assumptions with facts severely undercut this hypothesis. Specifically,
the lower levels of estrogen in pre-​eclampsia were based on urinary
measurements:  pre-​eclampsia affects liver function through its hall-
mark, hypertension, resulting in a decreased capacity of the liver
to conjugate estrogens so they can be excreted. The lower levels of
excretion and a metabolic backup of estrogen actually result in slightly
higher levels in circulation (Troisi et al., 2003). In addition, compara-
tive measurement of circulating estrogen levels in normal pregnan-
cies in the United States and China determined that, contrary to the
circumstance in non-​ pregnant women, circulating estrogens were
actually higher in Asian versus Western pregnant women (Lipworth
et al., 1999).
So while creatively developing hypotheses has been and will con-
tinue to be a major aspect of hormone research in cancer etiology, for
a research area where relevant measurements are often lacking and/​or
difficult to do, the approach to new hypotheses should probably be to
robustly challenge them before they become dogma.
In addition, mechanistic hypotheses to explain the biology of hor-
monally related risk factors are almost solely based on the assump-
tion that hormonal carcinogenesis is the result of a hormone’s direct
action on susceptible cells to stimulate pathways resulting in increased
growth and/​or DNA damage. While this is undoubtedly the case for
some malignancies, there are other scenarios worth considering.
Specifically, as noted, hormone receptors exist in many organs that are
not hormone-​dependent. It may be that alterations in cancer risk in one
organ may not be due to direct hormonal action, but may be mediated
through the effects on another organ system. A leading candidate for
such a scenario would be hormonal effects on the immune system. The
sex hormones, particularly estrogen, have major effects on immune
function, and are linked to some of the significant gender differences
in autoimmune disease risk (Khan and Ansar, 2016; Kovats, 2015). As
we begin to learn more about the role of immune function and the risks
of various cancers, the more attention we will need to devote to fac-
tors influencing such function. A prime candidate might be malignant
melanoma. The more we learn about the role of the immune system
in its etiology, prognosis, and treatment (Guennoun et al., 2016), the
more relevant its somewhat enigmatic relationships with sex hormone
variables (gender differences in age-​incidence, pregnancy, exogenous
hormones) seem to become.
New Knowledge and Opportunities
Recent dramatic advances in etiologic research in general, along with
several preceding decades of research on reproductive hormones,
406
406 PART III:  THE CAUSES OF CANCER
have taught us a number of lessons about how we might make more
progress in trying to understand the role of hormones in carcinogen-
esis in human populations. The advent of new technologies allowing
extensive measurement of broad categories of biologically important
analytes (genes, RNAs, metabolites, microbes, etc.) have opened up
whole new vistas of opportunities to use molecular epidemiologic
approaches to better understand cancer etiology, prevention, and con-
trol. In some instances we can actually interrogate agnostically large
categories of molecules for their impact on cancer risks. The poster
child for this is genomics where, by using these agnostic approaches,
in less than 10  years we have been able to increase the number of
known common genetic variants associated with cancer risk from less
than 6 to greater than 600. The challenge here is that most of those
identified have unknown functions, and it is likely to take some time
before their mechanisms of action in carcinogenesis can be identi-
fied and exploited. However, our laboratory colleagues are more than
happy to take on these tasks, since they know the answers will be
directly applicable to human cancer risk.
For the other “-​omics,” it is likely to be some time before we know,
and can measure, all possible analytes, and thus be able to comprehen-
sively and agnostically test to identify those associated with specific
cancer risks. However, until such a time when this becomes possible,
we can systematically assess all of the increasing families of analytes
that have been identified and for which reliable measurement is pos-
sible. This seems to have led to important new leads in studies of
micro-​RNAs (Cordero et  al., 2015), anti-​inflammatory agents (Lang
Kuhs et al., 2015), microbiomics (Bultman et al., 2016) and metabo-
lomics (Fages et  al., 2015). Fortunately, but not widely appreciated,
these same approaches can also expand our opportunities to more
comprehensively pursue already known or highly suspect candidate
carcinogenic exposures. For example, as described in the discussion
of sex hormones, the recent advances in our ability to comprehen-
sively measure estrogen metabolites has led to confirmation in human
populations of a decades-​old hypothesis from laboratory studies—​a
finding that may have prevention implications. By the nature of their
role in organ development and function, hormones have been leading
candidates for a potential role in carcinogenesis, and our enhanced
opportunities to understand and measure their functions at a metabo-
lite level should lead to powerful new insights in studies of the long list
of candidate hormones and their metabolites outlined in this chapter.
One other lesson learned is appropriate to mention in the context of
these new opportunities—​that is, the wisdom of, bordering on neces-
sity for, truly interdisciplinary studies in order to exploit these oppor-
tunities. Unfortunately, for several decades hormonal carcinogenesis
was not a pursuit characterized by true collaborations between basic
scientists and population scientists. Quite the contrary; more notable
were animated disagreements (Cole and MacMahon 1970; Fishman
et al., 1986; Lipsett, 1971; Smith and Smith, 1970; Sumoff et al., 1975).
More recently these features have subsided, but while, by necessity,
both laboratory scientists and epidemiologists interested in hormonal
carcinogenesis work closely with analytic chemists, there is still very
little active collaboration with each other. Given the rapidly increasing
opportunities to understand hormonal carcinogenesis at the molecular
level in human populations, the relevant disciplines will need to work
together to maximally exploit these opportunities.
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 41
23 Pharmaceutical Drugs Other Than Hormones
MARIE C. BRADLEY, MICHAEL A. O’RORKE, JANINE A. COOPER, SØREN FRIIS,
AND LAUREL A. HABEL
OVERVIEW
Drug prescribing is one of the most common medical interventions. Yet,
current regulatory programs for drug safety are not designed to identify
adverse events that are very rare or have a long latency, such as most
cancers. Meta-​analyses of randomized clinical trials of medications
can sometimes provide information on shorter-​term risk of common
cancer types, though large observational studies with long follow-​up
are needed to examine the majority of drug–​cancer associations. Over
the last few decades, a number of new methods have been developed
to address several types of confounding and bias of particular con-
cern in pharmacoepidemiology studies, and better data sources have
become available. Of the approximately 20 medications with sufficient
evidence to be classified by the International Agency for Research on
Cancer (IARC) as human carcinogens, most are anti-​neoplastic agents
or immunosuppressants. Substantial data from studies in humans indi-
cate that use of aspirin and other nonsteroidal anti-​inflammatory drugs
(NSAIDs) protects against colorectal cancer and possibly a number of
other common cancers. In the last decade, many other non-​hormonal
drugs have been examined for their suggested carcinogenic or chemo-
preventive effects, but additional human data are needed. In the future,
new drugs, databases, and analytic methods are all likely to contribute
to an increase in the number of pharmacoepidemiology studies and
reported drug–​cancer associations. Given their potential public health
importance, it will be essential to carefully examine identified drug–​
cancer associations within multiple, well-​conducted studies. Before
translating findings into regulatory action or clinical care, it also will
be essential that both the benefits and harms of a medication are care-
fully assessed.
INTRODUCTION
Global Trends in Drug Utilization
The use of drugs is increasing dramatically worldwide and each year
hundreds of new pharmaceutical products are approved by the US Food
and Drug Administration (FDA) and the European Medicines Agency
(EMA) (CenterWatch, 2016). Currently, more than 4000 new medica-
tions are being evaluated in clinical trials worldwide (CenterWatch,
2016). Within the European Union alone, there were 81 new medica-
tions recommended by the EMA for marketing authorization in 2013,
of which 38 contained a de novo active substance (EMA, 2014).
Drug use varies substantially by country. For example, compared to
the United Kingdom, France, and Spain, the United States and Denmark
generally have higher medication usage, although not for all diseases
(Richards, 2010). The use of specific drugs also varies markedly.
For example, atorvastatin is the preferred statin in the United States,
whereas simvastatin is the most commonly prescribed statin (and the
top prescribed drug) in the United Kingdom (Figures 23–1 and 23–2).
International variations in drug use can be attributed to differences in
healthcare system factors, such as the use of restrictive formularies,
reimbursement initiatives such as drug copayments, regulatory policies
influencing prescribing practices, clinical culture, and the incidence
and prevalence of various diseases and conditions (Richards, 2010).
Pharmaceutical Drugs
The FDA defines a drug as a substance (other than food) that is
intended to affect the structure or any function of the body and is used
in the diagnosis, cure, mitigation, treatment, or prevention of disease
(FDA, 2015). Some drugs are enzyme inhibitors, others interfere with
molecular transport mechanisms, and some bring about their effects
entirely through physicochemical properties, or by interfering with
specific proteins essential for signal transduction (Hill, 2010). Most
drug effects are achieved by the interaction of a drug with receptors in
target tissues. The intensity and duration of the effects (i.e., pharma-
codynamics) are usually determined by the number of drug molecules
present, their receptor site binding affinity, and whether the binding
is reversible or irreversible (Hill, 2010). Considerable inter-​individual
variation in drug response has been documented (Hill, 2010). These
are induced by differences in pharmacokinetic processes (absorp-
tion, distribution, metabolism, and excretion) and pharmacodynamic
effects, as well as by cofactors such as age, gender, comorbidity, drug
interactions, and genetic factors.
Pharmaceutical Drugs as Chemical Carcinogens
Although drugs enter the body in typically higher concentrations
than most other chemicals in the environment that are known or sus-
pected to be carcinogens, only a couple dozen medications have been
established as human carcinogens (Table 23–​1). However, several
additional drugs are suspected to be carcinogenic based on labora-
tory data, but lack sufficient or consistent human data (Table 23–​2).
In addition, a number of drugs have been found or suggested to pos-
sess chemopreventive effects (Friis et al., 2015a; Kelloff et al., 2006).
Carcinogens, including carcinogenic drugs, may act at any stage of
carcinogenesis, including initiation, promotion, progression, invasion,
or metastasis (Hanahan and Weinberg, 2011). Mechanisms influenc-
ing carcinogenesis include mutation, DNA repair, cell proliferation,
differentiation, angiogenesis, immunosurveillance, and apoptosis. In
addition, candidate carcinogenic and chemopreventive agents, includ-
ing drugs, can affect DNA methylation patterns, endogenous synthesis
of carcinogens, absorption or metabolism of carcinogenic chemicals,
generation of free radicals and activated forms of oxygen, or covalent
binding of carcinogens to DNA (Erson and Petty, 2006). While many
carcinogens have induction periods of 20 years or more, several drugs
appear to affect cancer development much earlier after initiation. For
example, some immunosuppressants increase the risk of lymphomas
after only a few years of treatment (Kotlyar et al., 2015), and aspirin
appears to reduce colorectal cancer risk after 5 years (Cuzick et al.,
2015; Friis et al., 2015b).
Drug Safety
All drugs are evaluated in Phase I–​III clinical trials for efficacy and
safety before they are approved for marketing by regulatory authori-
ties, such as the EMA in the European Union, the FDA in the United
States, and similar agencies in other countries (CenterWatch, 2016).
When a drug is first marketed, its efficacy and safety have typically
been tested for a maximum of 3–​4  years in relatively small and
411
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412 Part III: The Causes of Cancer

Levothroxine 119.9
Acetaminophen/hydrocodone 119.2
Lisinopril 103.7
Metoprolol 85.3
Atorvastatin 80.7
Amlodipine 78.3
Metformin 76.9
Omeprazole 75

Drug Name
Simvastatin 72.8
Albuterol 67.1
Amoxicillin 54.5
Fluticasone 50.8
Gabapentin 50.7
Alprazolam 49.4
Hydrochlorothiazide 49.1
Azithromycin 47
Furosemide 46.5
Tramadol 44.2
Sertraline 44.2
Losartan 39.5
0 20 40 60 80 100 120 140
Number of dispensed item (millions)

Figure 23–​1.  Top 20 dispensed prescriptions in the United States in 2014. Source: IMS Health, National Prescription Audit, 2014.

homogeneous patient populations. Thus, pre-​marketing trials will miss
rare and long-​term adverse drug reactions (ADRs), such as cancer, that
occur after long exposure duration or latency.
Passive Surveillance of Adverse Drug Events
In many countries, drug regulatory authorities rely heavily on spontaneous
ADR reporting systems to monitor drug safety (Dal Pan et al., 2012). In
the spontaneous reporting systems, suspected ADRs are usually reported
to a central agency by healthcare professionals, manufacturers, or directly
by patients. The most important function of these systems is the early
identification of drug safety signals (Harmark and van Grootheest, 2008),
which may generate hypotheses, requirements for manufacturers to spon-
sor post-​marketing safety studies, or regulatory warnings and changes of
product information labels or leaflets. A major limitation of the spontane-
ous reporting systems is the high level of under-​reporting by healthcare
professionals and manufacturers. In addition, the programs are generally
unable to estimate rates of ADRs because the sizes of the underlying
patient populations are unknown (i.e., no denominators). They are also
unlikely to detect ADRs with only moderate associations with a particular
type of drug and ADRs with long latencies, such as cancer.
Active Surveillance of Adverse Drug Events
Both the United States and the European Union have recently initi-
ated systems for active surveillance of ADRs to complement their
spontaneous reporting systems (Dal Pan et  al., 2012). In the United
States, the Sentinel Initiative was launched in 2008 to enable the FDA
to evaluate potential safety issues quickly and securely using elec-
tronic health records, administrative and insurance claims databases,
and registries covering approximately 100 million individuals (Avorn
and Schneeweiss, 2009). However, because many of the contributing
healthcare systems have high enrollee turnover and databases without
ready linkage to cancer registries, the Sentinel Initiative is not cur-
rently an optimal setting for studies of drug use and cancer risk.
In the European Union, the “Exploring and Understanding Adverse
Drug Reactions” (EU_​ADR) project uses integrative mining of various
electronic healthcare data for approximately 30 million EU citizens to
conduct large-​scale monitoring of drug safety signals and rare ADRs.
Detected signals are evaluated by semantic mining of the current lit-
erature and computational analysis of pharmacological and biologi-
cal information on drugs, molecular targets, and pathways (Coloma
et al., 2011).
A small number of non-​regulatory-​based surveillance programs
have been developed to identify drug–​cancer signals for hypothesis
generation. These include the Kaiser Permanente Drug Surveillance
Program, which has been exploring drug–​cancer signals for com-
monly prescribed pharmaceuticals since the 1970s by linking the
electronic pharmacy records of health plan enrollees to cancer regis-
try and other health records (Friedman et al., 2009a), and a recently
developed Danish surveillance program, linking pharmacy records
to cancer registry and other national healthcare data (Pottegård
et al., 2016a).

Figure 23–​2.  Top 20 dispensed prescriptions in the United Kingdom in 2014. Attribution statement: This chart contains public sector information licensed
under the Open Government licence v3.0 http://www.nationalarchives.gov.uk/doc/open-government-licence/version/3/ Sources: Business Services
Organisation (Northern Ireland), ISD National Services Scotland (Scotland), Welsh Assembly Government (Wales) and the Health and Social Care
Information Centre (England).
 413

Pharmaceutical Drugs Other Than Hormones 413

Table 23–​1.  Non-​Hormone Drugs Evaluated by the IARC Monograph Program* and Classified as Carcinogenic to Humans

Cancer Sites with Sufficient Evidence of

Group 1 Agents Carcinogenicity in Humans Established Mechanisms

Anti-​neoplastic Agents
Busulfan Acute myeloid leukemia Genotoxicity (alkylating agent)
Chlorambucil Acute myeloid leukemia Genotoxicity (alkylating agent)
Chlornaphazine Bladder Genotoxicity (alkylating agent, metabolism to 2-​
naphthylamine derivatives)
Cyclophosphamide Acute myeloid leukemia, bladder Genotoxicity (metabolism to alkylating agents)
Etoposide (Group 2A in 2000) —​ Genotoxicity, translocations involving MLL gene
Etoposide in combination with cisplatin and Acute myeloid leukemia Genotoxicity, translocations involving MLL gene
bleomycin (etoposide)
Melphalan Acute myeloid leukemia Genotoxicity (alkylating agent)
MOPP combined chemotherapy Acute myeloid leukemia, lung Genotoxicity
Semustine (methyl-​CCNU) Acute myeloid leukemia Genotoxicity (alkylating agent)
Thiotepa Leukemia Genotoxicity (alkylating agent)
Treosulfan Acute myeloid leukemia Genotoxicity (alkylating agent)
Immunosuppressive Agents
Azathioprine Non-​Hodgkin lymphoma, skin Genotoxicity, immunosuppression
Cyclosporin Non-​Hodgkin lymphoma, skin, multiple other sites Immunosuppression
Other Carcinogenic Agents
Analgesic mixtures containing phenacetin Renal pelvis, ureter Increased cancer risk cannot be explained by other
components of the analgesic mixtures, i.e., aspirin,
codeine phosphate, or caffeine
Aristolochic acid (Group 2A in 2002) —​ Genotoxicity, DNA adducts in animals are the same as
those found in humans exposed to plants, A:T →
T:A transversions in TP53; RAS activation
Methoxsalen plus ultraviolet A radiation Skin Genotoxicity following photo-​activation
Phenacetin (Group 2A in 1987) Renal pelvis, ureter Genotoxicity, cell proliferation
Plants containing aristolochic acid Renal pelvis, ureter Genotoxicity, DNA adducts in humans, A:T → T:A
transversions in TP53 in human tumours

* IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Volume 100A (2012), http://​monographs.iarc.fr/​ENG/​Monographs/​vol100A/​.
MOPP = Chlormethine (mechlorethamine), vincristine (oncovin), procarbazine, and prednisone
Source: Table adapted from Grosse et al., Lancet Oncol 2009 10(1): 13–​14.

Targeted Assessments of Drug Carcinogenicity
In addition to regulatory agencies, the International Agency for
Research on Cancer (IARC) and the US National Toxicology
Program (NTP) conduct regular assessments of the evidence of the
potential carcinogenicity of medical exposures, including drugs.
The IARC has conducted systematic evaluations of human carcino-
gens since the 1970s; the evidence for carcinogenicity is evaluated
by expert committees and is based on comprehensive literature
reviews of data from animal experiments, bioassays, mechanistic
studies, epidemiologic studies, or clinical trials (Cogliano et  al.,
2011). Of the over 900 potential carcinogens evaluated, slightly
over 100 have been classified as carcinogenic to humans (IARC,
2012), including approximately 20 non-​ hormonal medications
(Table 23–​1). Another nearly 40 non-​hormonal medications have
been classified as probably or possibly carcinogenic to humans,
because epidemiological or clinical evidence has not been defin-
itive, or because carcinogenicity has been demonstrated only in
experimental animals (Table 23–​2).
METHODOLOGIC ISSUES IN STUDIES OF DRUGS
AND CANCER
Although a randomized clinical trial (RCT) is the optimal design for
studies of both drug efficacy and safety (Grossman and Mackenzie,
2005), large observational studies with long-​term follow-​up are gener-
ally needed to examine drug–​cancer associations. Since findings from
such pharmacoepidemiologic studies can have clinical, regulatory, and
economic implications, consideration of methodologic issues is of par-
amount importance. There are several types of confounding, selection,
and information biases of particular concern in studies of drugs. In
addition, the prevalence of most drug use and the incidence of most
specific cancer types are rare, necessitating special requirements and
diligence in the choice of study designs and data sources.
Study Designs and Data Sources
Many case-​control and cohort studies have examined drug–​cancer
associations using interviews or postal surveys. Increasingly, phar-
macoepidemiologic studies are being conducted using large health-
care databases, either from healthcare insurers or providers or from
national databases and registries, such as those in the United Kingdom
and other northern European countries (Strom et  al., 2012). While
large healthcare databases linkable to cancer registries generally pro-
vide high-​quality data on prescription drugs and enable studies of rare
exposures and outcomes (such as drug–​cancer associations), these
databases typically do not hold information on non-​prescription drugs
or on lifestyle factors (e.g., smoking), introducing potential residual
confounding (Strom et al., 2012). In addition, some databases include
populations with high turnover or non-​continuous registration, com-
plicating studies of long-​term effects. Further, drug formularies are
common in many healthcare systems and can result in nearly exclusive
use of one or two drugs within a class (e.g., one type of statin). Such
formularies limit the ability to examine multiple drugs within a class
or to examine the same specific drug in large, collaborative studies.
Most healthcare databases are not designed for research, but rather
for administrative or clinical purposes (Strom, 2005). When designing
studies, it is important to understand the strengths and limitations of
the source databases (e.g., claims vs. electronic health records) and to
recognize that special procedures and expertise are often needed to
create research-​quality data sets (Ross et al., 2014). Given the diver-
sity of data sources and coding, collaborative studies using multiple
healthcare databases may benefit from using a common data model
to help standardize and harmonize pharmacy and other data elements
(Curtis et al., 2012; Ross et al., 2014).
41

414 Part III: The Causes of Cancer

Table 23–​2.  Non-​Hormonal Drugs Evaluated by the IARC Monograph Program and Classified as Probably (Group 2A) or Possibly (Group 2B)
Carcinogenic to Humans

Summary of Evidence on Carcinogenicity

Monograph
Drug Group Human Datac Animal Datac Volumes Year

α-​Blockers, Cardiac Glycosides, and Diuretics

Digoxin 2B L I 108 2015
Hydrochlorothiazide 2B L L 50, 108 2015
Phenoxybenzamine hydrochloride 2B ND S 24, Suppl 7b 1987
Triamterene 2B I S 108 2015
Analgesic
Phenazopyridine hydrochloride 2B I S 24, Suppl 7b 1987
Antibiotic and Antifungal Agents
Chloramphenicol 2A L I 50 1990
Griseofulvin 2B I S 79 2001
Metronidazole 2B I S 13, Suppl 7b 1987
Anticonvulsants
Phenytoin 2B I S 66 1996
Primidone 2B I S 108 2015
Antidiabetic
Pioglitazone 2A L S 108 2015
Anti-​HIV
Zalcitabine 2B I S 76 2000
Zidovudine 2B I S 76 2000
Anti-​inflammatory
Sulfasalazine 2B I S 108 2015
Anti-​neoplastic Agents
Adriamycin 2A I S 10, Suppl 7b 1987
Azacitidine 2A ND S 50 1990
Aziridine 2B ND L 9, Suppl 7b, 71 1999
Bleomycin 2B I L 26, Suppl 7b 1987
Chlorozotocin 2A ND S 50 1990
Cisplatin 2A I S Suppl 7b 1987
Dacarbazine 2B I S 26, Suppl 7b 1987
Daunomycin 2B ND S 10, Suppl 7b 1987
Lomustine 2A I S Suppl 7b 1987
Merphalan 2B ND S 9, Suppl 7b 1987
Mitomycin C 2B ND S 10, Suppl 7b 1987
Procarbazine hydrochloride 2A I S 26, Suppl 7b 1987
Streptozotocin 2B ND S 17, Suppl 7b 1987
Teniposide 2A L I 76 2000
Anxiolytics and Antidepressants
Mitoxantrone 2B L I 76 2000
Oxazepam 2B I S 66 1996
Sedatives and Hypnotics
Chloral 2A I S 63, 106 2014
Chloral hydrate 2A I S 84, 106 2014
Phenobarbital 2B I S 79 2001
Thyroid Medications
Methylthiouracil 2B I S 79 2001
Propylthiouracil 2B I S 79 2001
Thiouracil 2B I S 79 2001
Miscellaneous
Pentosan polysulfate sodium 2B I S 108 2015

a
http://​monographs.iarc.fr/​ENG/​Classification/​
b
IARC Monographs Supplement No 7. Overall Evaluations of Carcinogenicity: An Updating of IARC Monographs Volumes 1 to 42.
c
I = inadequate, L = limited, S = sufficient, ND = no data

Confounding An example is the use of diabetes drugs in relation to breast cancer

One of the most important potential confounders in studies of drug use
is the indication (or contraindication) for the treatment. Confounding
by indication can occur when the condition treated by the medication
is also a risk factor for the outcome of interest (Signorello et al., 2002).
risk, since diabetes is associated with an elevated risk of breast cancer.
Methods to address this type of confounding include restricting the
population to patients with the condition being treated (e.g., restrict
studies of diabetes drugs to patients with diabetes), although this does
not preclude confounding by disease severity when this is associated
 415
Pharmaceutical Drugs Other Than Hormones 415
with the outcome (Salas et al., 1999). An optimal strategy, when pos-
sible, is to compare risk among users of the drug of interest to risk
among users of another drug prescribed for the same indication (i.e.,
an active comparator drug) and, ideally, with the same severity of dis-
ease (Yoshida et al., 2015). Many patients, especially the elderly, often
use more than one type of drug. For example, patients with diabe-
tes are often treated with multiple diabetes drugs (sequentially and/​or
concurrently) as their disease progresses. Similar combination therapy
is also seen in patients with hypertension or depression. Such poly-
pharmacy adds substantial complexity to studies of drug efficacy and
safety, as the additional drugs may be time-​varying confounders if they
are also associated with the outcome of interest. Confounding can also
occur when patients using a particular drug differ from the general
population (of healthy individuals or patients) on overall health sta-
tus, life-​style factors, or drug adherence, introducing “healthy user” or
“healthy adherer” effects (Shrank et al., 2011).
There is typically greater potential for confounding in studies of
drug use and cancer outcomes than in studies of cancer risk. While
most risk factors are only modestly associated with cancer risk, dis-
ease characteristics (e.g., stage, lymph node involvement, tumor size)
are generally strong risk factors for both recurrence and progression.
Thus, disease characteristics can be important confounders if they are
also associated with use of the drug of interest. Likewise, in studies
of cancer mortality, disease recurrence and progression can be strong
confounders if they have an impact on drug use (Chubak et al., 2013).
Standard methods can be used to improve comparability between
exposed and unexposed groups (Jager et  al., 2008), including restric-
tion, matching, stratification, and multiple regression techniques.
Among more recent methods is propensity score (PS) analysis, which
uses information on a large number of covariates to predict the prob-
ability of use of the specific drug(s) of interest and consequently to help
balance observed and unobserved characteristics between treatment
groups (Austin, 2011). Analogous to the PS approach, the disease risk
score (DRS) calculates a summary measure as a function of confound-
ers, but it is based on the probability of disease, rather than the exposure
(Arbogast and Ray, 2011). The DRS is particularly appealing in analyses
of multiple drugs or multiple levels of drug exposure in relation to can-
cer risk, in which the PS approach is unwieldy. Confounding can also be
addressed by sensitivity analyses incorporating external data to estimate
associations adjusted for unmeasured confounders (Schneeweiss, 2006).
Marginal structural modeling can be used when the confounder is also
an intermediate variable in the causal pathway between the exposure
(drug) and the outcome (Robins et al., 2000). While this is common in
studies of drug efficacy, it can also be an issue in studies of unintended
drug effects, such as drug safety or chemoprevention. Marginal struc-
tural models can also be used to control for confounding by recurrence
in studies of drug use and cancer mortality (Chubak et al., 2013).
Instrumental variable (IV) analysis is a method that can potentially
be used to mitigate unmeasured confounding. A  good IV is a vari-
able that is strongly associated with the exposure of interest, is not
associated with other risk factors (including other drugs) for the out-
come, and is only associated with the outcome through its association
with the exposure. However, examples of well-​suited IVs are few, and
the underlying assumptions are easily violated (Martens et al., 2006).
Mendelian randomization (MR) is a variation of IV analysis that is
being used increasingly in epidemiology. The principle in the MR
approach is that a genetic variant (or combination of variants) is used
as an IV to estimate a causal effect between a potential risk factor and
an outcome of interest (Verduijn et al., 2010). For example, MR has
been used to examine the association between body mass index (BMI)
and cancer risk using the FTO gene as an IV (Brennan et al., 2009).
However, the MR method is limited by the need for very large sample
sizes, as well as the difficulty in identifying genetic variants that meet
the other IV criteria (Bochud and Rousson, 2010).
Selection Bias
Selection bias occurs when factors involved in the selection of the
study population, or that influence study participation, are related to
both the exposure and the outcome (Hammer et al., 2009). Efforts to
maximize response rates or to obtain study data without patient contact
(and with waived consent) reduce this bias. Studies using large health
databases may limit selection bias, provided they are highly represen-
tative of the target population (Tanaka et al., 2015). In cohort studies,
selection bias may be present if losses to follow-​up are differential
with respect to both drug exposure and cancer risk.
In addition, selection bias may occur when most users of a drug
are prevalent users. Prevalent users are not a random sample of all
users, and they may under-​represent those at early risk of the disease
(Ray, 2003). Although risk of cancer is generally thought to increase
with longer exposure and after a minimum latency (i.e., under-​
representation of those at early risk is usually not an issue), restrict-
ing studies to new users allows for complete assessment of drug use
and for adjustment of covariates prior to drug exposure, thus avoiding
potential selection bias due to depletion of susceptibles and avoiding
adjusting for a factor that may have been affected by the medication
(i.e., on the causal pathway). However, restricting the cohort to first
initiators of a drug can substantially limit sample size, and thus the
statistical precision of the study. It can also limit follow-​up time and
the ability to examine long-​term drug use, which are important con-
siderations for cancer outcomes. For example, in the first report of the
Women’s Health Initiative (Rossouw et al., 2002), based on an average
of 5 years of follow-​up, risk of breast cancer associated with estrogen
plus progestin (vs. placebo) was not elevated among women who had
never used postmenopausal hormone therapy (PMT) prior to baseline
(i.e., new users). However, risk was increased over 2-​fold for women
with up to 5 years of prior PMT use, and over 4.5-​fold for women with
5–​10 years of prior use (i.e., prevalent users).
Information Bias
Information bias typically results from error in the measurement of an
exposure, covariate, or outcome and can either be differential (system-
atic) or non-​differential (random) between comparison groups (Tanaka
et  al., 2015). Non-​differential misclassification will usually bias the
exposure–​ outcome association toward the null, whereas differential
misclassification can lead to bias in either direction (Jepsen et al., 2004).
Outcome Misclassification
Cancer registries are considered the gold standard for information on
cancer diagnoses, although the time period covered, data collected,
and quality control procedures vary by registry program (Dreyer and
Velentgas, 2012). In addition to histologic subtypes, many registries
are increasingly recording information on clinical cancer stage and
tumor markers (e.g., estrogen receptor [ER] status), which allow for
improved examination of the specificity of drug–​cancer associations
and thus better evaluation of biologic plausibility. In some survey-​
based observational studies, linkages to cancer registries are not fea-
sible, and the information on cancer outcome must be obtained from
self-​reports, ideally with validation by review of available medical
records. If conducted within healthcare databases not linkable to can-
cer registries, the information can be obtained by diagnosis codes. The
accuracy of self-​report and diagnosis codes has been found to vary by
cancer type and stage (Bergmann et al., 1998). Algorithms for health-
care databases with varying sensitivity, specificity, and predictive
value have been developed to identify new cancer diagnoses or cancer
recurrences (Chubak et al., 2012).
Misclassification can also occur because cancer is a long-​term out-
come, and there is always a period of time before an existing cancer is
detected. Detection bias can occur if individuals receiving the drug of
interest are more or less likely to be seen by a healthcare provider or to
undergo cancer screening prior to clinical attention and cancer diagno-
sis. This can also occur in studies of drugs use and cancer recurrence,
if the users of the drug of interest are more or less likely to have routine
medical visits or to undergo disease surveillance. Detection bias can
be addressed using standard methods (e.g., restriction, stratification,
multivariable adjustment), although appropriate adjustment for cancer
screening can present challenges (Weiss, 2003).
416
416 Part III: The Causes of Cancer
When use of a drug is influenced by an early sign or symptom of
undiagnosed cancer, such reverse causation, also called protopathic
bias, can lead to spurious drug–​cancer associations (Faillie, 2015). For
example, some undiagnosed cancers may cause pain, which can result
in the use of analgesics. Other undiagnosed cancers may compromise
the immune system and lead to the use of antibiotics or other anti-​
infectives. Pancreatic cancer can interfere with insulin production, and
anti-​diabetic therapies are sometimes initiated prior to cancer diagno-
sis. A common approach to minimize this bias is to disregard drug use
within a period (e.g., 1 year) prior to cancer diagnosis or to conduct
sensitivity analyses using different intervals, since the period when the
cancer may cause signs or symptoms but remains undetected is usually
unknown.
Exposure Misclassification
Drugs can be taken for a single acute condition (e.g., antibiotic for an
infection), sporadically or intermittently over a lifetime (e.g., aspirin
for headache or muscle pain), or chronically for years (e.g., statin for
high cholesterol), which emphasizes the need for thoughtful data col-
lection and exposure definitions in accordance with existing knowl-
edge or hypotheses about the influence of the timing, strength, and
duration of drug use on the cancer outcome(s) of interest.
Self-​reported information can result in either non-​differential or dif-
ferential (e.g., recall bias) misclassification of medication histories.
Drug names can be unfamiliar and difficult to remember, especially if
individuals take a number of different medications or there is substan-
tial switching or stopping of drug use. Accuracy of self-​report can be
improved by providing study participants with lists of drug names, pic-
tures of tablets, and indications. Use of life calendars with important
events such as marriage, births, and new jobs can improve the accuracy
of the timing of drug use.
Electronic pharmacy records are usually considered the gold stan-
dard in observational pharmacoepidemiologic research, since they are
often required for patient management and/​or billing, and frequently
include strength and amount dispensed. However, many healthcare
databases do not include drugs given during hospitalizations and most
do not record non-​prescription drugs. While some pharmacy databases
record the actual dispensing of the drug prescription, outpatient phar-
macy databases will generally not have information on whether or not
filled prescription drugs were actually consumed by the patients. This
misclassification can be reduced by defining exposure as filling more
than one prescription during a certain time period (e.g., 6 months). In
addition, healthcare databases do not have prescription information for
the period prior to enrollment in the healthcare or insurance plan or
prior to the establishment of the pharmacy database.
In general, the etiologically relevant exposure period for a specific
drug–​cancer association is unknown, and may also vary by specific
agent, dose, or patient characteristics (Gottlieb and Altman, 2014).
Assessment of drug use outside the etiologically relevant exposure
period may attenuate measures of association and reduce the likeli-
hood of observing a true association. In order to identify the critical
exposure period, information on drug use should ideally be collected
according to different aspects of time (e.g., age of first use, time of first
use, time of last use, duration of use), allowing for the examination of
multiple exposure windows.
Drug use is a time-​varying exposure, and there are several time-​
related biases to consider in pharmacoepidemiology studies that can
greatly distort the measures of association (Suissa and Azoulay, 2012).
Immortal time bias occurs in cohort studies when unexposed time is
misclassified as exposed time. For example, if an individual is not
using a drug at cohort entry and later initiates drug use but the entire
follow-​up time is classified as exposed, the time until start of drug use
is “immortal” since the individual obviously must survive the unex-
posed time in order to become exposed. When this “immortal” time is
incorrectly attributed to exposed time of the drug of interest, the rela-
tive risk estimates will be reduced and the drug may appear more ben-
eficial than it is. This bias can be avoided by the use of time-​varying
exposure variables or by starting follow-​up at or after drug initiation.
Time-​window bias occurs in case-​control studies when cases and con-
trols have different opportunities for exposure or different periods of
time when the exposure of interest is measured. For example, in stud-
ies using electronic health records, a drug will look protective if cases
have health records of drug use for a shorter time than controls. This
bias can be avoided by matching cases and controls on, or adjusting
for, follow-​up time. In studies comparing drugs prescribed for the
same condition, a first-​line drug may appear protective when the com-
parison drug is second-​or third-​line therapy if longer disease dura-
tion is associated with increased risk of the outcome. Such bias can be
avoided by comparing therapies given for the same stage of disease, or
by matching on, or adjusting for, duration or stage of disease.
PHARMACOEPIDEMIOLOGY STUDIES OF DRUG–​
CANCER ASSOCIATIONS
As noted earlier, only about 20 non-hormonal medications have been
classified as human carcinogens by the IARC (Table 23–​1) (IARC,
2012). The majority of these agents derive from two therapeutic cat-
egories: anti-​neoplastic and immunosuppressant therapy. About twice
as many drugs have been classified as probably or possibly carcino-
genic to humans (Table 23–​2) (Friis et al., 2015a).
Over the last decade, an increasing number of pharmacoepidemi-
ology studies have explored hypotheses on the use of specific drugs
and cancer risk or prevention. Further, a growing number of studies
have examined whether medications used to treat a variety of common
conditions may be related to an increased or decreased risk of cancer
recurrence or mortality.
In the following, we summarize briefly the literature on non-​
hormonal drugs known or suspected of increasing or decreasing can-
cer risk or progression; focusing on those drugs that have received
the most attention during the last 10 years. Hormonal agents, such as
estrogens, are addressed in Chapter 22.
Anti-​neoplastic Agents
Anti-​neoplastic drugs are agents used primarily to inhibit or prevent the
growth and spread of cancer cells. These drugs include cytotoxic agents
and hormonal therapies, as well as the more recently developed tar-
geted or non-​specific immunotherapies. Whether used as single agents
or in combination therapy, these medications have yielded substantial
improvements in survival, attributable to an enhanced understanding
of the mechanisms of anti-​tumor activity and micrometastases (Chu
and Sartorelli, 2012), and the recognition of tumor heterogeneity and
molecular subtypes (Hoelder et al., 2012). Unfortunately, most cyto-
toxic agents also cause damage to healthy cells, especially in rapidly
proliferating tissues, such as hematopoietic tissue and gastrointestinal
epithelia, which may induce secondary malignancies. The exact carci-
nogenetic pathways of secondary neoplasms following chemotherapy
have not been fully elucidated (Travis et al., 2013), despite the long-​
known mutagenic and carcinogenic effects of many anti-​neoplastic
drugs (Dedrick and Morrison, 1992). A  mutual mechanism is DNA
damage (genotoxicity), leading to either clonal loss of chromosomes
or gene translocations (Sill et al., 2011).
Cytotoxic agents can be grouped into distinct categories based on
their pharmacodynamic mechanisms and include alkylating agents,
antimetabolites, cytotoxic antibiotics, plant alkaloids, and plati-
num compounds (WHO, 2015). At least 11 of these drugs have been
classified as carcinogenic to humans (Grosse et  al., 2009; IARC,
2012) (Table 23–​1). Of these, the majority are alkylating drugs, includ-
ing busulfan, chlorambucil, cyclophosphamide, melphalan, semustine
(methyl-​CCNU), thiotepa, and treosulfan, which all exhibit genotoxic
activity, commonly through alkylation of purine bases in DNA (Sill
et al., 2011). Typically, alkylating drugs induce acute myeloid leukemia
(Table 23–​1) (IARC, 2012), but these agents have also been related to
the development of some solid tumors, notably lung cancer (Swerdlow
et al., 2011), bladder cancer (Travis et al., 1995) and myelodysplastic/​
myeloproliferative neoplasms, particularly in patients with a prior his-
tory of Hodgkin lymphoma (Sill et al., 2011). In addition, a number of
other cytotoxic agents have been classified as probably carcinogenic to
 417
Pharmaceutical Drugs Other Than Hormones 417
humans (group 2A carcinogens), including azacitidine, cisplatin, pro-
carbazine, and teniposide (IARC, 2012) (Table 23–​2).
When examining the risk of secondary cancer following chemother-
apy, a particular difficulty is that these malignancies typically have a
very long latency and thus are inadequately captured in most observa-
tional studies and clinical trials. However, a few observational studies
have followed patients over several decades, corroborating a substan-
tial excess risk of secondary malignancies following chemotherapy
(Olsen et al., 2009). Another challenge is to isolate the carcinogenic
role of one particular antineoplastic agent, notably when evaluating
combination therapies or when patients also undergo other therapy
with carcinogenic potential (e.g., radiotherapy).
Several traditional anti-​neoplastic drugs have been supplemented or
superseded by newer molecularly targeted drugs (Hoelder et al., 2012),
and research continues to seek ways to reduce dosage or develop safer,
more efficient anti-​neoplastic agents (Travis et al., 2013). Obviously,
the carcinogenic potential of these new drugs, and combinations
thereof, should be monitored and evaluated closely (Boffetta and
Islami, 2013; IARC, 2012). The anti-​neoplastic mechanisms of new
drugs are often, but not always (e.g., immunotherapeutic agents), simi-
lar to those of the traditional drugs they are replacing. Focusing on
relevant mechanisms (i.e., mechanistic analyses) may therefore con-
tribute to improved identification of individuals susceptible to drug-​
induced cancers (Boffetta and Islami, 2013; IARC, 2012).
Anti-​infective Agents
Anti-​infective agents are a broad category of drugs that include anti-
bacterials, antifungals, antiprotozoals, and antivirals. They include
some of the most widely prescribed medications in both children and
adults (Figures 23–​1 and 23–​2). In adults, assessment of lifetime use
of anti-​infective agents is challenging, and most studies focus on a
relatively limited exposure period prior to cancer diagnosis. A small
number of anti-​infective drugs have been classified by IARC as prob-
ably (group 2A) or possibly carcinogenic to humans (group 2B)
(Table 23–​2) (Friis et al., 2015a).
Chloramphenicol, an antibiotic classified as group 2A, has been
shown to induce abnormal cell differentiation and inhibit apoptosis
in activated T-​cell models, which may contribute to leukemogenesis
(Yuan and Shi, 2008). To our knowledge, however, there are no new
human data addressing specifically the probable carcinogenicity of
chloramphenicol use. Recent epidemiological studies of the associa-
tion between use of antibiotics and cancer risk have mainly focused on
breast and prostate cancer. A meta-​analysis of five case-​control stud-
ies reported a slightly increased risk for breast cancer associated with
ever use of any antibiotics and a borderline dose–​response relation-
ship based on the number of prescriptions (Sergentanis et al., 2010).
However, residual confounding was likely, and the risk pattern for
individual categories of antibiotics could not be investigated. Some
large cohort studies have also reported an association between use of
various types of antibiotics and increased breast cancer risk (Friedman
et al., 2006; Kilkkinen et al., 2008). Other studies have examined the
association between antibiotic use and prostate cancer risk, and find-
ings have been inconsistent, albeit mainly null (Daniels et al., 2009;
Tamim et  al., 2010). Most studies may have missed associations if
antibiotic use requires long-​term chronic treatment to influence cancer
risk. However, a nationwide cohort study of 8445 patients with endo-
carditis, who are typically on long-​term therapy with antibiotics, found
only weak associations for several cancers, including cancers of the
prostate, stomach, and breast, which might be explained by non-​causal
factors (Thomsen et al., 2013a).
Griseofulvin is an antifungal drug classified as a group 2B car-
cinogen (Table 23–​2). A large nested case-​control study reported an
increased risk of breast cancer with griseofulvin use, with a sugges-
tive dose–​response relationship (Friedman et al., 2009b). However,
the study could not adjust for risk factors other than age and a
crude measure of hormone use. More recently, there has been inter-
est in the role of adjuvant griseofulvin in the treatment of patients
with cancer, with in vitro cancer cell line studies suggesting that
griseofulvin exhibits antimitotic activity, inhibits proliferation,
and activates apoptosis (Mauro et  al., 2013; Panda et  al., 2005;
Rathinasamy et al., 2010).
Metronidazole is an antiprotozoal and antibacterial drug classified
as a group 2B carcinogen (Table 23–​2). A number of epidemiologic
studies conducted prior to 2005 examined metronidazole use and risk
of cancer overall or at specific sites and reported mainly null find-
ings (see previous edition of this textbook). More recently, metro-
nidazole has been shown to induce growth of breast and colorectal
cancer cell lines (Sadowska et  al., 2013a, 2013b). In a large cohort
study of antibiotics and risk of breast cancer, Friedman et al. (2006)
found no increased risk with use of metronidazole equivalent to at least
100 days of treatment.
The antiviral drugs zalcitabine and zidovudine have been catego-
rized as group 2B carcinogens (Table 23–​2). Recently, however, zido-
vudine has been suggested to possess chemopreventive properties by
inducing apoptosis and delaying cell cycle progression (Fang and
Beland, 2009), although clinical trials have shown limited evidence of
anti-​cancer effects (Chow et al., 2009).
Antihypertensive Drugs and Statins
Among drugs used to treat disorders of the cardiovascular system,
antihypertensives and statins have received the most attention in rela-
tion to cancer endpoints (Singh and Bangalore, 2012). Considering
the common use and proven tolerability of these agents, discovery of
any carcinogenic or chemopreventive effects would be of profound
clinical and public health importance. Given that these agents are
used to treat both hypertension and heart diseases, which are asso-
ciated with obesity, cardiometabolic abnormalities, and lifestyle fac-
tors, such as tobacco use, which may increase cancer incidence and
mortality, potential confounding is of concern. In addition, studies of
cardiovascular drugs should also account for the use of concomitant
medications associated with cancer risk, notably aspirin. Finally, the
presence of other diseases (e.g., colitis ulcerosa and other inflamma-
tory conditions, and diabetes mellitus) associated with risk of both car-
diovascular disease and cancer should also be considered as potential
confounders.
Angiotensin Converting Enzyme Inhibitors and
Angiotensin-​II Receptor Blockers
Some studies suggest that the renin-​angiotensin-​aldosterone system
may play a role in cancer development (Singh and Bangalore, 2012).
Angiotensin converting enzyme inhibitors (ACEIs) block the con-
version of angiotensin I to angiotensin II, a hormone that stimulates
neovascularization and promotes angiogenesis and thus may stimu-
late cancer development (Yoshiji et  al., 2001). Consequently, ACEI
use may reduce cancer risk. A number of observational studies have
found a reduced incidence of overall cancer (Chiang et al., 2014) or
of cancer at specific sites, including the colorectum (Dai et al., 2015),
esophagus (Sjøberg et al., 2007) and breast (Li et al., 2013). However,
a meta-​analysis of observational studies (Yoon et al., 2011) and a sec-
ondary analysis of RCTs (Bangalore et al., 2011) reported no associa-
tion between ACEI use and risk of overall cancer.
Angiotensin-​II receptor blockers (ARBs) share many properties of
ACEIs and are used for similar indications, including hypertension and
heart failure (Brayfield, 2014). ARBs selectively block the angiotensin
II type 1 receptor, which may explain the anti-​angiogenic and anti-​
proliferative effects observed in animal models of sarcoma, pancre-
atic, and breast cancer (George et al., 2010). This blockage, however,
induces overstimulation of angiotensin II type 2 receptors that may
result in cellular proliferation, angiogenesis, and tumor progression
(Walther et al., 2003), which has led to concerns about the potential
carcinogenicity of these agents.
Concern about the carcinogenic potential of ARBs was raised
after a secondary analysis of five RCTs of ARBs and cardiovascu-
lar disease (Sipahi et al., 2010) reported a slightly increased cancer
risk among ARB users. This prompted the FDA (2011) and EMA
(2011) to conduct safety reviews of the issue. However, two large
418
418 Part III: The Causes of Cancer
meta-​analyses (ARB Trialists Collaboration, 2011; Bangalore et al.,
2011)  showed no elevated cancer risk with ARBs. In the largest
meta-​analysis (Bangalore et al., 2011), the main limitation was that
follow-​up averaged just 3.5 years (range, 1–​9 years) for all 70 trials
combined.
Relatively little data are available on the potential association of
ARBs or ACEIs with cancer recurrence or survival, and the few avail-
able studies have provided conflicting results. A cohort study of breast
cancer patients found an increased recurrence risk associated with
post-​diagnosis use of ACEIs, although there was no evidence of a
dose–​response relationship (Ganz et al., 2011). In contrast, a review of
10 other studies reported that ACEI use was associated with improved
outcomes in patients with breast or other cancers (McMenamin et al.,
2012). A more recent observational study found little evidence for an
association between the use of ARBs and cancer-​specific mortality
among patients with breast, colorectal, or prostate cancer (Cardwell
et al., 2014a).
Calcium Channel Blockers
Calcium channel blockers (CCBs) decrease intracellular calcium,
which has been suggested to increase cancer risk by inhibiting apop-
tosis (Wu et al., 2014). An early observational study by Pahor et al.
(1996), which first raised concerns about CCB use and cancer risk,
reported an increased risk of fatal cancers in older patients using
nifedipine, a CCB. However, this study was prone to serious meth-
odologic shortcomings, and other observational studies (Assimes
et al., 2008; Boudreau et al., 2008; Devore et al., 2015; Grimaldi-​
Bensouda et al., 2016) reported no association between CCB use and
cancer risk overall or at specific sites, even among long-​term (>7.5
years) users. Particular emphasis has been placed on the association
between CCB use and breast cancer risk. A recent meta-​analysis of
17 observational studies indicated a slightly increased risk of breast
cancer associated with long-​term (>10 years) use of CCBs (Li W
et al., 2014), but other meta-​analyses (Chen et al., 2014; Saltzman
et al., 2013) and large observational studies (Assimes et al., 2008;
Devore et  al., 2015) found no association. In addition to observa-
tional studies, a number of large RCTs, such as the ALLHAT trial
(ALLHAT Officers and Coordinators for the ALLHAT Collaborative
Research Group, 2002) and large meta-​analyses of trial participants
(Bangalore et  al., 2011), have found no association between CCB
use and incidence or mortality of cancer overall; however, these
studies may have been limited by short follow-​up periods.
A recent Canadian cohort study reported improved survival among
breast and lung cancer patients using CCBs (Holmes et  al., 2013).
However, studies of CCB use and cancer prognosis have mostly pro-
vided null results. Within the COmmonly used Medications and Breast
Cancer Outcomes (COMBO) cohort, specifically designed to study
the influence of drugs and comorbidities on breast cancer prognosis,
Boudreau et al. (2014) observed no association between CCB use and
breast cancer recurrence or risk of contralateral breast cancer. Chen
et al. (2015) reported similar findings in regard to CCB use and contra-
lateral breast cancer among women diagnosed with estrogen receptor
(ER)-​positive invasive breast cancer.
ß-​blockers
Animal studies have shown that ß-​adrenergic signaling regulates mul-
tiple cellular processes involved in carcinogenesis, particularly in
pancreatic and breast cancer, and ß-​blockers have also been shown
to disrupt migratory activity and inhibit angiogenesis of cancer cells
(Pasquier et  al., 2011). Concern about the carcinogenicity of ß-​
blockers emerged when a clinical trial showed an increase in cancer-​
related deaths among men assigned to use of the ß-​blocker atenolol,
compared to men assigned to a diuretic or placebo (MRC Working
Party, 1992). A  subsequent large meta-​analysis of clinical trial data
found no association between ß-​blocker use and cancer risk or cancer-​
related mortality (Bangalore et  al., 2011). Similarly, a large case-​
control study nested in the UK Clinical Practice Research Datalink
(CPRD) reported no association between ß-​blocker use and the risk of
common cancers (lung, colorectal, breast, and prostate); however, the
exposure period prior to cancer diagnosis was relatively short and did
not allow examination of long-​term use (Numbere et al., 2015). Other
observational studies have reported an inverse association between
ß-​blocker use and cancer risk. In a large nested case-​control study,
Assimes et al. (2008) reported an approximate 10% reduction in over-
all cancer risk among ever users of ß-​blockers compared to ever users
of thiazide diuretics. This finding was driven primarily by a reduced
risk of colorectal cancer and to a lesser degree by risk reductions in
other gastrointestinal cancers, head and neck cancer, and hematologi-
cal cancer. Most recently, a meta-​analysis of RCTs suggested that use
of non-​selective ß-​blockers may reduce the risk of hepatocellular car-
cinoma in patients with liver cirrhosis (Thiele et  al., 2015). A  large
case control study in the UK CPRD (Hagberg et al., 2016), however,
found no association between ß-​blocker use and primary liver cancer.
Designing robust observational studies to examine liver cancer is chal-
lenging due to the considerable potential for unmeasured confounding,
especially when using healthcare databases that do not routinely col-
lect information on many important risk factors for liver cancer.
Several recent studies have examined a possible protective effect of
ß-​blockers on the progression of cancer. Some observational studies
have reported substantial reductions in risk of metastasis and cancer-​
specific death with the use of ß-​blockers, particularly propranolol or
other non-​selective agents, among patients with cancers of the breast
(Barron et al., 2011), prostate (Grytli et al., 2014), lung (Wang et al.,
2013), or ovary (Watkins et al., 2015), and with malignant melanoma
(Lemeshow et al., 2011). However, other studies have not consistently
supported these findings. Post-​diagnosis ß-​blocker use was associated
with a modestly reduced risk of breast cancer recurrence (without a
dose–​response relationship) in one study (Ganz et  al., 2011), but a
marginally increased risk of recurrence in another (Boudreau et  al.,
2014). In addition, studies conducted in the UK CPRD found little
evidence of an association between post-​diagnostic ß-​blocker use and
outcomes for breast (Cardwell et al., 2013), prostate (Assayag et al.,
2014; Cardwell et al., 2014b), melanoma, or colorectal cancer (Hicks
et al., 2013; McCourt et al., 2014).
Diuretics
An association between the use of diuretics and cancer risk was first
proposed in 1988 (McLaughlin et  al., 1988). Indeed, the diuretic
hydrochlorothiazide is a cyclic imide that can be converted in the
stomach to a mutagenic nitroso derivative (Gold and Mirvish, 1977).
A meta-​analysis of antihypertensive therapy found an increased risk
of renal cell cancer (RCC) in female, but not male, users of diuretics
(Corrao et al., 2007). Large across-​study heterogeneity, however, may
have compromised the pooling of results. Moreover, it is important
to acknowledge that hypertension per se may be associated with an
increased risk of RCC and thus that confounding by indication also
remains a possibility. The ALLHAT trial comparison of diuretic use
with use of other antihypertensives provided no evidence that diuret-
ics increased cancer risk (ALLHAT Officers and Coordinators for the
ALLHAT Collaborative Research Group., 2002). More recently, two
meta-​analyses of RCTs have corroborated a null association between
diuretic use and overall cancer risk (Bangalore et al., 2011). Null asso-
ciations have also been reported in observational studies of specific
cancer types, for example, kidney (Fryzek et al., 2005) and colorectal
cancer (Boudreau et al., 2008). However, diuretic use has been associ-
ated with an increased risk of basal cell carcinoma (particularly among
overweight or obese individuals) (McDonald et al., 2014) and squa-
mous cell carcinoma (Schmidt et al., 2015), the latter driven by results
for potassium-​sparing agents alone or in combination with low-​ceiling
diuretics. Hydrochlorathiazide, a photosensitizing low ceiling diuretic,
has also been associated with lip cancer (Friedman et al., 2012).
Statins
Hydroxy-​3-​methylglutaryl coenzyme A (HMG-​CoA) reductase inhib-
itors (statins) are among the most frequently prescribed drugs in the
world, and therapy is generally “lifelong.” Statins inhibit the rate-​
limiting step of cholesterol biosynthesis and are indicated for lowering
serum cholesterol and prevention of coronary artery and vascular dis-
ease (Maron et al., 2000). In addition to reducing cholesterol produc-
tion, statins target lipid metabolism, prevent inflammation, and induce
 419
Pharmaceutical Drugs Other Than Hormones 419
apoptosis, thereby modulating several cellular processes, including
those essential to carcinogenesis (Altwairgi, 2015; Matusewicz et al.,
2015). Statins also impair prenylation, an essential process in the post-​
translational modification of many proteins, including the Ras protein
family, which are involved in tumorigenesis and cancer progression.
In addition, statins target mevalonate synthesis, a precursor to several
major cellular products that are important in cell growth, signal trans-
duction, differentiation, and survival (Altwairgi, 2015).
Some epidemiologic studies have reported an association between
low cholesterol and increased cancer incidence (Liao and Farmer,
2013), although the underlying causality of the relationship is unclear.
If lowering cholesterol induces cancer, statin use should be associ-
ated with increased cancer risk. However, if undiagnosed cancer low-
ers serum cholesterol for an extended period prior to a clinical cancer
diagnosis, statin use could appear protective since there would be
less use among cases. Both possibilities should be considered when
designing studies and interpreting results of studies of statin use and
cancer risk.
Two large RCTs reported excess incidences of breast and gas-
trointestinal cancer, respectively, among patients assigned to statin
therapy (Sacks et  al., 1996; Shepherd, 2002). However, the larg-
est randomized statin trial, the Heart Protection Study, found no
increased risk of cancer or cancer mortality after a mean of 11 years
of follow-​up (Heart Protection Study Collaborative Group, 2011).
One randomized trial reported a significant increase in cancer risk
among patients assigned to a combination of simvastatin and ezeti-
mibe. This raised concern that the additional reduction in LDL cho-
lesterol induced by the combination therapy might increase cancer
risk (Rossebo et al., 2008). However, findings from subsequent stud-
ies, including the Heart Protection Study (Heart Protection Study
Collaborative et  al., 2011), did not support this hypothesis (Peto
et al., 2008).
Numerous observational studies have examined associations
between statin use and risk of cancer. Overall, the studies suggest a null
association between statin use and risk of smoking-​related cancers,
including cancers of the lung (Hippisley-​Cox and Coupland, 2010),
bladder (Zhang XL et al., 2013), kidney (Zhang et al., 2014), and pan-
creas (Cui et al., 2012; Simon et al., 2016). Meta-​analyses of breast and
skin cancers have also reported null associations (Undela et al., 2012).
In contrast, a number of observational studies and meta-​analyses have
found that statin use is associated with slight to modest reductions in
risk of gastric (Ma et al., 2014), colorectal (Lytras et al., 2014), pros-
tate (notably advanced) (Bansal et  al., 2012; Tan et  al., 2016), liver
(Singh et  al., 2013a), hematologic malignancies (Yi et  al., 2014),
and esophageal cancer (particularly in patients with Barrett’s esopha-
gus) (Singh et al., 2013b).
Reasons underlying the apparent discrepancy between the results
of numerous laboratory studies, demonstrating promising chemopre-
ventive effects of statins (Altwairgi, 2015), and those of clinical and
epidemiological studies are unclear. A possible explanation is differ-
ences between dosage levels of statins applied in the laboratory setting
and the recommended doses of statins used in patient treatment (Friis
and Olsen, 2006). Another explanation might be the extensive hepatic
“first-​pass metabolism” of most statins, resulting in low concentration
of statins in non-​hepatic organs and tissues (Friis and Olsen, 2006).
Several US groups have also suggested that “healthy-​user bias” may
account for a considerable part of the observed inverse associations
between statin use and risk of some cancer types, whereby statin use
may be associated with more “health-​aware” behavior, such as par-
ticipation in cancer screening and other preventive behaviors associ-
ated with a reduced risk of manifest cancer (Setoguchi et al., 2005).
However, surveys in Denmark and the United Kingdom indicate
that statin users are fairly representative of the general population,
and not a selected population of “healthier” individuals as reported
in the United States (Hippisley-​Cox and Coupland, 2010; Thomsen
et al., 2013b). A recent study with clinical laboratory data (Friedman
et al., 2016) suggests that the inverse association commonly observed
between statins and liver cancer may not be causal, but due to con-
founding by indication (elevated cholesterol levels) and contraindica-
tion (elevated liver enzymes).
There is increasing interest in the potential influence of statin use on
cancer prognosis and mortality. A meta-​analysis of RCTs did not show
reductions in overall cancer mortality with statin use, but several of the
trials were limited by short follow-​up and insufficient power to detect
a significant difference in cancer outcomes (Cholesterol Treatment
Trialists Collaboration, 2012). In contrast, a recent systematic review
and meta-​analysis of 39 cohort studies and two case-​control studies
showed about a 20% decrease in risk for both all-​cause and cancer-​
specific death, with both post-​diagnostic and pre-​diagnostic statin use
appearing beneficial (Zhong et al., 2015b). Most observational studies
of statin use and cancer mortality have focused on breast (Mansourian
et  al., 2016; Zhong et  al., 2015b) or prostate cancer (Raval et  al.,
2016). Studies of statin use and breast cancer recurrence or mortality
have quite consistently found a reduced risk of recurrence or cause-​
specific death associated with statin use (Mansourian et al., 2016). The
largest study, a Danish nationwide study including over 18,000 Danish
women diagnosed with stage I–​III breast cancer, reported a substantial
reduction in risk of breast cancer recurrence associated with statin use
during a median follow-​up period of 6.8 years (Ahern et al., 2011). The
results for prostate cancer are more heterogeneous, with some studies
suggesting null associations, and others a 20%–​40% reduction in risk
of prostate cancer recurrence, or prostate cancer-​specific or all-​cause
mortality (Raval et al., 2016; Yu et al., 2014). The most recent meta-​
analysis of 34 observational studies (Raval et  al., 2016)  indicated a
clear beneficial effect of both pre-​and post-​diagnostic use of statins on
prostate cancer mortality, as well as a reduction in biochemical recur-
rence among patients treated with radiotherapy. However, this meta-​
analysis and an earlier one that included eight cohort studies (Scosyrev
et al., 2013) failed to find a beneficial effect of statin use on biochemi-
cal recurrence among patients treated with radical prostatectomy.
Aspirin and Other Nonsteroidal
Anti-​inflammatory Drugs
There is convincing evidence that use of aspirin and other non-​steroidal
anti-​inflammatory drugs (NSAIDs) reduce the risk of colorectal cancer
and possibly a number of other cancers (see Chapter 62.5). While the
precise mechanisms by which these drugs may prevent cancer have
not been elucidated, the inhibition of cyclooxygenase (COX) enzymes
and prostaglandin activity appears to be important (Wang and Dubois,
2006). Prostaglandins are involved in a number of mechanisms that
may promote tumor growth and progression, such as cell proliferation,
promotion of angiogenesis, suppression of immune responses, inhibi-
tion of apoptosis, and stimulation of invasion and motility (Wang and
Dubois, 2004, 2006). Aspirin and non-​aspirin NSAIDs may affect car-
cinogenesis by inhibiting prostaglandin endoperoxide synthase-​2 or
type 2 of the COX enzyme (COX-​2), the rate-​limiting enzyme in the
prostaglandin pathway (Usman et al., 2015; Wang and Dubois, 2004).
There is also increasing evidence that the antiplatelet activity of low-​
dose aspirin may have a distinct role in reducing cancer risk, as well
as risk of metastasis, through inhibition of tumor angiogenesis (Thun
et al., 2012; Usman et al., 2015).
Over the past decade, numerous studies have explored the potential
chemopreventive effects of NSAIDs, in particular aspirin. As many
NSAIDs are available without a prescription, this has implications
for the choice of the optimal data source for epidemiological studies
(i.e., self-​reporting versus prescription records). There is evidence that
the accuracy of patient-​reported drug use and prescriptions records of
NSAIDs, and other drugs used to treat musculoskeletal disorders, dif-
fer by the type of drug and the reporting period (Grimaldi-​Bensouda
et al., 2012).
Multiple systematic reviews and meta-​ analyses have reported
that the use of aspirin or non-​aspirin NSAIDs reduces the risk of
colorectal cancer (Algra and Rothwell, 2012; Bibbins-​ Domingo
and US Preventive Services Task Force, 2016; Cuzick et  al., 2009;
Rothwell et  al., 2012a). The meta-​analyses indicate that long-​term
(> 5  years), consistent use of low-​dose aspirin is associated with a
significant reduction in the risk of colorectal cancer (Cuzick et  al.,
2015). However, the optimal dose and duration is still unclear, and
420
420 Part III: The Causes of Cancer
other important questions remain unresolved, including the optimal
age at initiation and whether other factors might help maximize the
benefits and minimize the harms of treatment (Drew et al., 2016). For
example, there is increasing evidence that the chemopreventive effect
of aspirin varies substantially with body mass and level of inflamma-
tory response (Movahedi et al., 2015), as well as with genetic markers
(Drew et al., 2016).
The potential use of aspirin for prevention of colorectal cancer
is limited by the risk for gastrointestinal bleeding and, less often,
cerebral bleeding (Dehmer et al., 2016; Drew et al., 2016) (see also
Chapter  62.5), and these potential harms will need to be balanced
against the preventive benefits against cancer and cardiovascular
disease.
There is also increasing evidence that aspirin use is associated
with a decreased risk of upper gastrointestinal cancer (Sahin et  al.,
2014). A recent meta-​analysis found that long-​term (≥4 years) and
low frequency (1–​4.5 times/​week) aspirin use was associated with
a substantial reduction in gastric cancer risk (Ye et al., 2013). Other
meta-​analyses have supported this inverse association (Sahin et  al.,
2014), although there is evidence of possible confounding by contra-
indication or publication bias. Consistent risk reductions with use of
aspirin have also been reported for esophageal cancer (Xiaohua et al.,
2014; see also Chapter 62.5).
In the largest meta-​analysis of NSAID use and risk of breast cancer
performed to date, which included case-​control (n  =  23) and cohort
studies (n = 24) and two randomized clinical trials, the pooled rela-
tive risk estimates were consistent with a slightly protective effect of
NSAID use against breast cancer (de Pedro et  al., 2015). Although
based on fewer studies, the meta-​analysis also indicated that the pro-
tective effect of aspirin pertained specifically to hormone receptor–​
positive breast tumors (de Pedro et al., 2015). Meta-​analyses of a large
number of studies have also reported a 5%–​10% reduced risk of pros-
tate cancer, or advanced prostate cancer, associated with aspirin use
(Liu et al., 2014).
Regarding other non-​gastrointestinal cancer sites, the evidence is
either inconsistent or nonexistent for a chemopreventive effect of use
of aspirin or other NSAIDs. For cancers of the lung (Hochmuth et al.,
2016; Jiang et al., 2015), pancreas (Cui et al., 2014), ovary (Baandrup
et al., 2013; Trabert et al., 2014), endometrium (Verdoodt et al., 2016),
and non-​melanoma skin cancer (Muranushi et  al., 2015, 2016), the
majority of studies have reported inverse associations with aspirin or
non-​aspirin NSAID use. Largely null results have been observed for
bladder cancer (Daugherty et al., 2011; Zhang H et al., 2013) and mel-
anoma (Hu et al., 2014). A recent meta-​analysis reported an increased
risk of kidney cancer with use of non-​aspirin NSAIDs (Choueiri et al.,
2014). Ongoing randomized controlled trials of aspirin in the preven-
tion of specific cancers will provide further information on aspirin use
and cancer risk. For example, the ASPirin in Reducing Events in the
Elderly (ASPREE) is examining the risk of cancer as a secondary out-
come (ASPREE Investigator Group, 2013).
The US Preventive Services Task Force (USPSTF) has recently
issued recommendations advising the use of aspirin to prevent cardio-
vascular disease and colorectal cancer in middle-​aged individuals with
modestly increased risk of cardiovascular disease (Bibbins-​Domingo
and US Preventive Services Task Force, 2016; Dehmer et al., 2016).
The USPSTF systematic review was based on the multiple lines of
evidence that aspirin use reduces the risk of colorectal adenoma and
cancer; however, the recommendation is not an explicit endorsement
of aspirin use for the sole purpose of colorectal cancer prevention.
Several questions remain to be addressed before recommendations for
primary prevention of cancer with aspirin can be established, includ-
ing the optimal dose of aspirin for cancer prevention and potential
effect modification according to genetic, medical, and lifestyle factors
(Drew et al., 2016).
Recent systematic reviews and meta-​analyses also suggest that aspi-
rin use may reduce cancer progression and mortality (Chubak et al.,
2016b; Elwood et al., 2016; Rothwell et al., 2011, 2012a, 2012b). A
pooled analysis of large cardiovascular trials found that daily aspirin
use was associated with a 34% reduction in mortality from all cancers
and a 54% reduction in death from gastrointestinal cancers (including
esophageal, pancreas, colorectal, and stomach) (Rothwell et al., 2011).
Of note, this improved prognosis was apparent after 5 years of follow-​
up (7 trials) and the mortality risk remained reduced at 20 years of
follow-​up among individuals who were assigned to the original aspirin
intervention arm compared to those in the control arm (three trials)
(Rothwell et al., 2011). There is also some evidence that the anti-​can-
cer effect of aspirin may extend to the prognosis of breast and pros-
tate cancer (Elwood et  al., 2016; Huang et  al., 2015); however, the
results are not consistent (Cardwell et al., 2014c; Zhong et al., 2015a).
Randomized controlled trials of aspirin in the treatment of cancer will
provide further information on cancer recurrence and mortality. For
example, the Add-​Aspirin Trial (phase III double-​blind placebo-​con-
trolled randomized trial) aims to examine the effect of aspirin exposure
after standard primary therapy on early-​stage common solid tumors
(Langley et al., 2013).
Bisphosphonates
Bisphosphonates (BPs) are potent inhibitors of osteoclast-​mediated
bone resorption, and are commonly prescribed in the management of
postmenopausal and glucocorticoid-​ associated osteoporosis, meta-
static bone disease, and other bone-​related conditions (Drake et  al.,
2008). In vitro and in vivo studies have suggested that BPs, particu-
larly those containing nitrogen, exhibit antitumor activity by promot-
ing apoptosis and by inhibiting angiogenesis, tumor cell adhesion, and
invasion (Clezardin, 2013).
However, in 2009, based on an accumulating number of spontane-
ous reports from the United States, Europe, and Japan, the FDA issued
a warning of a potentially increased risk of esophageal cancer associ-
ated with the use of oral BPs (Wysowski, 2009). This sparked a flurry
of epidemiological studies. Although results across meta-​ analyses
have been somewhat conflicting, the most recent (Wright et al., 2015),
based on five retrospective observational studies, did not find a signif-
icantly elevated risk of either esophageal or gastric cancer. However,
there was considerable heterogeneity in population characteristics
and definitions of drug exposure, and information was limited on the
effects of type, dose, or duration of BP use, as well as potential risk
variation by histologic subtype of esophageal cancer (i.e., adenocarci-
noma or squamous cell carcinoma).
A recent pooled analysis of eight epidemiological studies (Bonovas
et  al., 2013)  reported a statistically significant inverse association
between BP use and colorectal cancer risk. Long-​term (3 or more
years) use of BPs was associated with a 27% reduction in colorectal
cancer risk compared with non-​use. Some studies have also reported
a decreased incidence of postmenopausal breast cancer with BP use
(see Chapters  45 and 62.5). However, confounding by indication is
likely given the association between lower levels of endogenous
estrogen and both lower bone mineral density and lower breast can-
cer risk (Chlebowski and Col, 2012). Recent cohort (Alford et  al.,
2015; Newcomb et al., 2015) and case-​control studies (Rennert et al.,
2014)  have also reported reductions in risk of endometrial cancer,
particularly among postmenopausal women (Newcomb et al., 2015);
however, additional studies with larger sample sizes and more compre-
hensive adjustment for confounding are warranted.
Recently, there has been increasing interest in a potential therapeu-
tic role of adjuvant BPs in patients with breast cancer. A meta-​analy-
sis of individual patient data from RCTs of more than 18,000 women
conducted by the Early Breast Cancer Trialists’ Collaborative Group
reported a reduction in breast cancer bone metastases and improved
survival with adjuvant BP use among postmenopausal but not premen-
opausal women (Early Breast Cancer Trialists’ Collaborative Group
et  al., 2015). Subsequently, a European consensus panel suggested
that BPs have a clinically important role in early breast cancer in a
postmenopausal adjuvant setting (Hadji et al., 2016). Outcome stud-
ies have also been conducted among other cancer patients frequently
prescribed BPs. At present, there is some evidence that post-​diagnos-
tic BP use improves survival in localized or metastatic prostate (Vale
et al., 2016) or colorectal cancer (Hicks et al., 2015). A large Cochrane
review (Mhaskar et al., 2012) summarizing the findings from 20 RCTs
 421
Pharmaceutical Drugs Other Than Hormones 421
found no indication of improved survival among patients with multiple
myeloma. Notably, the across-​study heterogeneity was high (I2 =55%)
in this analysis, and several of the included studies may not have fol-
lowed standard clinical trial methods.
Digoxin
Digoxin, a cardiac glycoside derived from natural steroid compounds,
is widely prescribed for atrial fibrillation, congestive heart failure, and
related conditions (Brayfield, 2014). Early observational studies sug-
gested that digoxin use might protect against cancer, notably breast
cancer (Stenkvist et  al., 1979). It was hypothesized that the steroid
core of cardiac glycosides might reduce ER signaling analogous to
tamoxifen (Stenkvist, 1999). However, recently, the IARC has catego-
rized digoxin as possibly carcinogenic to humans (Group 2B) (Grosse
et al., 2013; IARC, 2015) because it has been associated consistently
with increased risk of both male and female breast cancer. Recent
findings from the Women’s Health Study and a nationwide Danish
case-​control study indicated an increased risk of invasive breast cancer
associated with current digoxin use (Ahern et al., 2014; Biggar et al.,
2011; Grosse et al., 2013; IARC, 2015). The association was strongest
for ER-​positive tumors (Biggar et  al., 2013), and laboratory studies
have demonstrated that digoxin acts like a phytoestrogen, binding to
ERs and stimulating the growth of ER-​sensitive tumors (Biggar et al.,
2013). Digoxin use has also been associated with an increased risk
of uterine and colorectal cancer (Grosse et  al., 2013; IARC, 2015).
However, the findings for digoxin are difficult to interpret, due to pos-
sible confounding factors, particularly obesity and alcohol consump-
tion (Grosse et  al., 2013). Moreover, some animal (Menger et  al.,
2012) and epidemiologic studies have indicated that digoxin also pos-
sesses anti-​neoplastic effects. Consistent with the possible estrogenic
effect, digoxin use has been suggested to reduce the risk of prostate
cancer. One study based on data from the Health Professionals Follow-​
up Study demonstrated an inverse association between digoxin use
and prostate cancer risk, especially after more than 10  years of use
(Platz et al., 2011). An additional US population-​based cohort study
reported a 40% reduced risk of prostate cancer among digoxin users
(Wright et al., 2014). In contrast, a recent case-​control study showed
no association between digoxin use and prostate cancer risk (Kaapu
et al., 2015).
A few studies have also examined the association between digoxin
use and cancer prognosis. A  large population-​ based cohort study
in the United Kingdom presented little evidence of an increase in
breast cancer–​specific mortality with post-​diagnostic use of digoxin
(Karasneh et al., 2015), and a recent cohort study showed no associa-
tion between digoxin and prostate cancer–​specific mortality (Flahavan
et al., 2014).
Drugs Used in Diabetes
Diabetes mellitus is associated with an increased or decreased risk of
several cancers (Vigneri et  al., 2009). Over the last decade, numer-
ous studies and meta-​analyses of antidiabetic drugs and cancer risk
have been published. In addition to potential confounding by indi-
cation (i.e., diabetes or diabetes severity), challenges to these stud-
ies include the cross-​over and treatment escalation often required to
manage the progressive hyperglycemia occurring with type 2 diabetes,
which accounts for up to 90% of diabetes in older adults (ages when
most cancers occur). Some antidiabetic drugs are also associated with
weight gain, an independent risk factor for several cancers (Renehan
et al., 2015).
Metformin, a first-​line therapy and the most commonly prescribed
antidiabetic drug, has been hypothesized to possess chemopreventive
properties. While several observational studies have reported inverse
associations for cancer at multiple sites (e.g., breast, colon, prostate,
and lung), many studies have suffered from time-​related biases that
may at least in part explain some of these protective associations
(Suissa and Azoulay, 2012). Given findings from in vivo and in vitro
studies as well as observational studies, several RCTs of metformin to
prevent cancer or cancer recurrence have been initiated (Cuzick et al.,
2015). Use of sulfonylurea, another class of first-​line therapy and the
comparator drug for many studies of metformin, has been reported
to increase the risk of cancer in some, but not other studies (Thakkar
et al., 2013).
Several second-​and third-​ line therapies have also been evalu-
ated. Some studies have indicated that insulin use may be associ-
ated with an increased risk of several cancer types (Carstensen et al.,
2012; Janghorbani et  al., 2012; Singh et  al., 2013c, 2013d). Insulin
analogues, in particular, have been suggested to increase cancer risk
(McFarland and Cripps, 2010). However, this association was not
supported in a recent update from the ORIGIN trial, where an insulin
analogue, glargine, was compared with standard care among 12,537
patients with diabetes for a median follow-​up of 6.2 years (Bordeleau
and Gerstein, 2014). Also, a previous meta-​analysis of 11 RCTs or
observational studies reported null effects of insulin analogues on can-
cer risk (Tang et al., 2012).
The thiazolidinediones also have been reported to increase the risk
of cancer, either overall or at specific sites, although findings have
been conflicting (Monami et al., 2014). Some of the most consistent
findings have been reported for pioglitazone, a thiazolidinedione, and
bladder cancer, with modestly increased risk occurring after 2+ years
of use (Ferwana et al., 2013). Pioglitazone has recently been classi-
fied by the IARC as probably carcinogenic to humans (Group  2A)
(IARC, 2015).
The recently marketed incretin mimetics (dipeptidyl peptidase-​4
inhibitors and glucagon-​like peptide-​1 analogues) have also been sug-
gested to possess a carcinogenic potential (Egan et al., 2014). Three
meta-​analyses yielded null findings for associations between use of
incretin mimetics and short-​term incidence of pancreatic or other can-
cers (Alves et al., 2012; Dejgaard et al., 2009; Monami et al., 2011).
However, additional studies with longer follow-​ up are warranted.
Several international research initiatives have recently been launched
to clarify issues related to diabetes and cancer.
Drugs Used in Acid–​Related Disorders
Proton pump inhibitors (PPIs) and histamine-​2 receptor antagonists
(H2RAs) inhibit or reduce gastric acid secretion and are commonly
prescribed for the treatment of gastrointestinal disorders such as dys-
pepsia, gastroesophageal reflux disease, and peptic ulcers. Inhibition
of acid secretion may increase bacterial growth, leading to the pro-
duction of N-​nitrosamines, which may promote carcinogenesis (Laine
et al., 2000; Stockbruegger, 1985). Inhibition of acid secretion can also
induce hypergastrinemia, and high gastrin levels have been suggested
to induce neoplasia in the gastrointestinal tract (Laine et al., 2000).
In recent years, several studies have examined the association
between PPI/​H2RA use and cancer risk across a number of gastro-
intestinal sites including esophageal, gastric, and colorectal cancer
(Ahn et al., 2013). Some PPI/​H2RA drugs are now available over the
counter, and thus some use will not be captured by electronic pre-
scription records. Prophylactic therapy with PPI for Barrett’s esoph-
agus has been of particular interest. A recent meta-​analysis (including
7 observational studies) reported that PPI use was associated with a
decreased risk of disease progression to esophageal adenocarcinoma
and/​or high-​grade dysplasia (Singh et al., 2014). However, there was
substantial heterogeneity in the results. Furthermore, only two of
the studies examined H2RAs, and most studies of PPI/​H2RA drugs
did not adjust for potential confounding factors, such as obesity and
smoking. The results of ongoing phase III RCTs of acid suppression
in patients with Barrett’s esophagus will likely provide more robust
evidence. For example, the multi-​center Aspirin and Esomeprazole
Chemoprevention in Barrett’s Metaplasia (AspECT) trial—​the larg-
est RCT of Barrett’s metaplasia performed to date—​will assess the
influence of varying doses of esomeprazole, with or without aspi-
rin, on cancer progression in patients with Barrett’s metaplasia (Das
et al., 2009).
Several studies have investigated the risk of gastric cancer associated
with use of PPIs/​H2RAs. A recent meta-​analysis of 11 observational
42
422 Part III: The Causes of Cancer
studies (9 case-​control and 2 cohort studies) reported that both PPI (10
studies) and H2RA (3 studies) use were associated with an increased
risk of gastric cancer (Ahn et al., 2013). Of note, site-​specific analy-
ses showed a significant increased risk for gastric non-​cardia cancer,
but no association with gastric cardia cancer. Use of PPI/​H2RA for
less than 5 years was significantly associated with an increased risk of
gastric cancer, with a non-​significant positive association observed for
long-​term use (greater than 5 years). However, this review could not
exclude protopathic bias (reverse causation), and no data were avail-
able on underlying gastric conditions. Furthermore, the results of the
meta-​analysis were heavily influenced by one case-​control study that
did not adjust for weight, smoking status, or alcohol consumption, and
only one of the included studies adjusted for NSAID use. In a meta-​
analysis of six randomized controlled trials, the authors reported no
association between PPI use and risk of gastric atrophic changes or
enterochromaffin-​like (ECL) cell hyperplasia over 3 years (Eslami and
Nasseri-​Moghaddam, 2013). Although four of the six studies were
prone to bias, a sensitivity analysis restricted to the two higher-​quality
studies showed similar results to the overall analysis with the exception
of PPI dosage, where ECL-​cell score was significantly increased with
esomeprazole (20 mg and 40 mg, but not 10 mg) compared to placebo.
A Cochrane review, which included seven randomized controlled tri-
als, reported no clear evidence that long-​term use of PPIs (greater than
6 months) was associated with the progression of corpus gastric atro-
phy or intestinal metaplasia (Song et al., 2014). However, PPI users
exhibited an increased risk of simple or focal ECL-​cell hyperplasia.
Relatively few studies have examined PPI use and risk of colorectal
cancer to date. A meta-​analysis of four large case-​control studies with
an average follow-​up period of less than 5 years showed no associa-
tion (Chen et al., 2011). A Cochrane review of six randomized con-
trolled trials (5 studies of cimetidine, 1 study of ranitidine) concluded
that H2RA use as adjunct therapy for resected colorectal cancer was
associated with improved survival (Deva and Jameson, 2012). A com-
bined follow-​up analysis of data from three adenoma prevention trials
(n = 2915 participants) based on self-​reported information on drug use
other than aspirin showed no association between H1RA or H2RA use
and adenoma risk during a maximum follow-​up of 4 years, although
H2RA use was associated with a reduced risk of adenomas in one of
the trial populations (Robertson et al., 2005).
Psychotropic Drugs
Antidepressants
Antidepressants (ADs) are widely used to alleviate mood disorders,
such as major depression and anxiety, and work by altering either the
re-​uptake of common neurotransmitters, such as serotonin, or enzymes
involved in their synthesis (Stafford et al., 2001). Immune system acti-
vation and inflammation have been suggested to be involved in the
pathophysiology of both depression and cancer, and chronic depres-
sion has been associated with increased cancer risk, progression, and
impaired survival, although the underlying mechanisms are unclear
(Currier and Nemeroff, 2014). It has been proposed that ADs may
attenuate any such effect (Currier and Nemeroff, 2014); however,
observational studies (Dalton et  al., 2008)  and a recent screening
study of commonly used drugs for carcinogenicity suggest that some
ADs may actually increase the risk of cancer (Friedman et al., 2009c).
Preclinical studies have also shown that ADs may influence various
processes in the cell cycle such as growth proliferation, metastasis, and
apoptosis (Frick and Rapanelli, 2013).
Some observational studies have shown an increased risk of breast
cancer associated with long-​ term use of tricyclic antidepressants
(TCAs) or selective serotonin reuptake inhibitors (SSRIs) (Cummings
et al., 2002; Moorman et al., 2003; Sharpe et al., 2002). However, a
recent well-​conducted meta-​analysis of 18 studies found no overall
increased risk of breast cancer among AD users, irrespective of AD
type (Eom et al., 2012).
SSRIs are purported to have antiproliferative effects on colon cancer
cells (Kannen et al., 2012), and some observational studies have also
suggested that SSRI use is associated with a reduced risk of colorectal
cancer (Chubak et al., 2011; Coogan et al., 2009). However, the results
are inconsistent (Cronin-​ Fenton et  al., 2011), and a recent meta-​
analysis of observational studies evaluating SSRI use and colon cancer
risk reported an overall null association (Lee et al., 2012). Failure to
account for colorectal cancer screening history and lack of adjustment
for concomitant drug use are important limitations of several of the
included studies, as both medical surveillance and drug use may differ
between AD users and non-​users in the general population. Regarding
other cancer sites, there is little evidence of an association with SSRI
use. A recent large case-​control study in Kaiser Permanente Northern
California (KPNC) found little evidence of an association between
fluoxetine, paroxetine, or other SSRIs and testicular cancer, although
a weak association could not be ruled out for individual histological
types (Friedman et al., 2014). One study reported that SSRI use was
associated with a reduced risk of lung cancer (Toh et al., 2007). The
authors of that study attempted to account for confounding by indi-
cation by adjusting for the severity of depression using information
on the length of depression history, use of other AD types, and over-
all healthcare utilization. However, adjustment for these factors and
restriction to individuals with more than 5 years of depression history
had only a modest impact on the association (Toh et al., 2007). The
authors also acknowledged the association of smoking and depression.
Smoking is associated with an increased risk of depression and, con-
sequently, certain unmeasured aspects of smoking might be associated
with AD use.
In a Canadian study, TCA use was associated with an elevated
risk of prostate cancer, although results may have been influenced by
detection bias (Tamim et al., 2008). Some studies indicate that long-​
term use of TCA may increase the risk of non-​Hodgkin lymphoma
(Dalton et al., 2008); however, the results are conflicting (Bahl et al.,
2004). In a recent study, Walker et al. (2011) found an inverse associa-
tion between TCA and risk of glioma or colorectal cancer, with the risk
of both decreasing with increasing TCA use. A second recent study
also observed an inverse association between TCA use and glioma risk
(Pottegård et al., 2016b).
Limited research has been undertaken on ADs and cancer outcomes.
It has been suggested that SSRI use (particularly paroxetine and fluox-
etine) may inhibit the effects of the endocrine therapy tamoxifen, thus
increasing the risk of breast cancer recurrence in concurrent tamoxi-
fen/​SSRI users. A  large study of breast cancer patients treated with
tamoxifen found little evidence for an association between concurrent
SSRI use overall, or paroxetine or fluoxetine specifically, and risk of
recurrence (Haque et al., 2016). A second study (Chubak et al., 2016a)
also found no association between breast cancer recurrence or mortal-
ity and use of different types of AD (SSRIs/​TCAs/​other). However, and
although the number of users was small, concurrent users of tamoxi-
fen and paroxetine appeared to have an increased risk of breast cancer
recurrence compared to tamoxifen-​treated patients not using an AD.
Benzodiazepines
Benzodiazepines are commonly used anxiolytic and hypnotic medi-
cations (Brayfield, 2014). Early animal studies suggested that these
agents may be carcinogenic and increase the risk of a number of can-
cers (IARC,1996), observations that are also inferred by some obser-
vational studies (Halapy et al., 2006; Rosenberg et al., 1995). Recently,
a US cohort study reported that use of hypnotic drugs, including ben-
zodiazepines, was associated with an up to two-​fold increased risk of
cancer overall (Kripke et al., 2012). However, this study has been criti-
cized due to its inappropriate and biased methods of selecting controls
(Pottegård et al., 2013a). A nationwide nested case-​control study using
data from Danish registries found no association between long-​term
benzodiazepine use and overall cancer risk, but did observe marginally
increased risks at a number of sites including the stomach, esophagus,
liver, lung, pancreas, and kidney. The authors interpreted these slight
risk elevations as residual confounding by lifestyle factors, such as
alcohol and tobacco use, which are known to have a higher prevalence
among individuals using psychotropic drugs, including benzodiazepines
(Pottegård et al., 2013a). Prompted by these findings, a team at Kaiser
Permanente Northern California examined the association of benzo-
diazepine use and liver cancer risk. Like the Danish study, the Kaiser
 423
Pharmaceutical Drugs Other Than Hormones 423
Permanente study revealed a slight excess risk in liver cancer associated
with the use of some types of benzodiazepines (diazepam/​temazepam
and oxazepam). However, again, since alcohol use, particularly heavy
use, is associated with both benzodiazepine use and liver cancer, the
association was likely due to confounding by alcohol, and the database
did not have sufficient information on lifestyle variables to evaluate this
interpretation (Friedman et al., 2015). For other ethnic populations, one
population-​based cohort study in Taiwan reported a 19% higher risk of
cancer overall, and a 45% elevated risk of liver cancer, among benzodi-
azepine users compared to non-​users (Kao et al., 2012).
To our knowledge, no studies have examined benzodiazepine use
in relation to cancer survival, despite the fact that the use of these
agents increases substantially following cancer diagnosis (Andersen
et al., 2015).
Miscellaneous Drugs
Tumor Necrosis Factor Inhibitors
Concerns have been raised about the new biological response modi-
fiers (e.g., tumor necrosis factor [TNF] inhibitors) (Singh et al., 2009).
TNF inhibitors have been suspected to increase the risk of certain can-
cers, including lymphoma in children and adolescents. A large meta-​
analysis of 61 RCTs of TNF inhibitors did not indicate an increased
risk of cancer, either overall or at specific sites, associated with use of
TNF inhibitors (Lopez-​Olivo et al., 2012). This was compatible with
findings from other meta-​analyses (Zhang D et al., 2013), except for
one meta-​analysis that reported a non-​statistically significant increase
in the risk of B-​cell lymphomas associated with TNF inhibitors (Wong
et al., 2012). TNF inhibitors were introduced on the market in 2002,
and thus, studies have generally only been able to evaluate effects of
shorter-​term treatment (Wong et  al., 2012). A recent Danish nation-
wide register-​based study showed that among 56,156 patients with
inflammatory bowel disease, long-​term (> 5 years) use of TNF inhibi-
tors was associated with a relative risk for cancer overall of 1.33 (95%
CI: 0.88, 2.03) (Nyboe Andersen et al., 2014). Continued monitoring
of TNF inhibitors is warranted.
Warfarin
In vitro and in vivo studies have shown that warfarin interferes with
cancer cell growth and development, inhibits angiogenesis, alters host-​
immune responses and prevents metastatic spread (Hejna et al., 1999).
Only a few clinical studies have investigated the association between
warfarin use and cancer risk, and the results are inconsistent (Schulman
et  al., 1995; Taliani et  al., 2003). Epidemiological studies have also
reported mixed findings. A large case-​control study in the United States
(Blumentals et al., 2004) reported no association between warfarin use
and bladder cancer, whereas a Canadian case-​control study found that
warfarin reduced the risk of prostate cancer (Tagalakis et  al., 2007).
Recently, a large Danish nationwide case-​control study found no asso-
ciation between long-​term use of warfarin or vitamin K antagonists
(VKA) and overall cancer risk, but the results indicated a protective
effect of VKA against prostate cancer (Pottegård et al., 2013b).
Several studies have investigated whether warfarin may improve
survival in cancer patients, but findings have been equivocal (O’Rorke
et  al., 2015). In addition, an extension of the above Canadian study
of bladder cancer indicated that long-​term warfarin use (> 4 years)
may be associated with an impaired cancer prognosis (Tagalakis and
Tamim, 2010), and a nested case-​control study found no evidence that
long-​term warfarin use improved prostate cancer survival (Tagalakis
et al., 2013), whereas short-​term use indicated an increased mortality.
Phosphodiesterase Type 5 Inhibitors
The target for several oral erectile dysfunction drugs, phosphodi-
esterase type 5 (PDE5), is part of a signaling pathway that may be
involved in the development of malignant melanoma. PDE5 inhibitors
have thus been suggested to increase the risk of cutaneous melanoma.
In 2014, a cohort study among US male health professionals (Li WQ
et al., 2014) reported an increased risk of melanoma associated with
use of sildenafil, a PDE5 inhibitor. Another recent study conducted
in Sweden (Loeb et al., 2015) also reported a statistically significant
increased risk of melanoma associated with the use of PDE5 inhibi-
tors, including sildenafil and other PDE5 inhibitors. However, the
association was limited to early stage disease and no dose–​response
relationship was apparent, suggesting non-​causal explanations, such as
increased disease surveillance among users of PDE5 inhibitors.
Immunosuppressants
Immunosuppressants are a class of drugs primarily used to avert rejec-
tion in solid organ transplant recipients (i.e., kidney, heart, liver, and
bone marrow), but may also form the cornerstone of management of
many chronic inflammatory and autoimmune diseases (Forsythe and
Paterson, 2014). There are four major types of immunosuppressants,
including corticosteroids (e.g., prednisolone and dexamethasone),
cytotoxic agents (e.g., cyclophosphamide, azathioprine, and myco-
phenolate mofetil), T-​cell suppressive agents (e.g., cyclosporine and
tacrolimus), and antibodies (e.g., rituximab).
Experimental and clinical data have established that suppression of
the immune system may induce several malignancies (see Chapter 25),
including skin cancers (Pedersen et al., 2014), lymphoma (Khan et al.,
2013), myeloid leukemia and myelodysplastic syndromes (Lopez et al.,
2014), bladder (Yan et al., 2014), and colorectal cancer (Gong et al., 2013).
The IARC Monographs Program (IARC, 2012)  recently assessed
all available experimental and clinical data and concluded that the
immunosuppressants azathioprine and cyclosporin are definitely car-
cinogenic in humans (Table  23–​1). Specifically, sufficient evidence
has shown that immunosuppressants induce non-​ melanoma skin
cancer and non-​Hodgkin lymphoma. Moreover, epidemiologic stud-
ies have indicated that long duration and high-​intensity exposure to
immunosuppressants is associated with an increased risk of several
other cancer types (Gutierrez-​Dalmau and Campistol, 2007). On bal-
ance, it would seem that the benefits of immunosuppressants outweigh
their carcinogenicity (Rama and Grinyo, 2010); however, each patient
eligible for immunosuppressive therapy should undergo a thorough
benefit–​risk evaluation (Friis et al., 2015a).
Only relatively few studies have examined the association
between immunosuppressive therapy and risk of cancer recurrence
or second primary malignancy. A recent systematic review (Shelton
et  al., 2016), including 16 studies (12 cohort, 3 case-​series, and
1 case-​control) and a total of 11,702 patients, reported that thiopu-
rines, methotrexate, and TNF inhibitors were not associated with an
increased risk of cancer recurrence. Limitations of this review, how-
ever, included substantial diversity in the included cancer types, dif-
ferences in the ascertainment of cancer recurrence, and small sample
sizes (3 studies included less than 20 cases). Another recent meta-​
analysis of 4621 non-​Hodgkin lymphoma patients from nine RCTs
found no increased risk of second primary cancers among users of
rituximab (Fleury et al., 2016).
FUTURE DIRECTIONS
New Drug Agents and Exposures
The development of new medications with de novo active substances
and new targets and mechanisms is expected to continue. In addition,
the increasingly global manufacturing of and marketplace for pharma-
ceuticals has the potential to result in rapid and large-​scale exposure
to medications. Thus, increasing proportions of children and adults
worldwide will likely be exposed to a diversity of both older and
newer medications. It is imperative to continue close monitoring of
both short-​and long-​term drug effects, including potential increases or
decreases in cancer risk.
New Classifications of Cancer and Cancer Subtypes
There is a growing appreciation of the molecular complexity of cancer
such that, even for patients with the same cancer and disease stage,
42
424 Part III: The Causes of Cancer
there are heterogeneous subgroups with varying risk factor profiles
and clinical outcomes (Ogino et  al., 2012). Most cancer registries
record information on histologic (or morphologic) subtype; however,
details of specificity, accuracy, and completeness vary. In addition, as
cancer therapies increasingly target specific tumor subtypes, the test-
ing of tumor tissue for genetic mutations and gene and protein expres-
sion is increasingly routine in clinical practice. Such routine testing
will facilitate studies of medication use and risk of specific molecular
subtypes of cancer.
Incorporating Germline Genetics into
Drug–​Cancer Studies
Germline genetic variants (e.g., single nucleotide polymorphisms
[SNPs]), may help identify subgroups of patients most likely to
benefit—​or to develop adverse effects—​from chemopreventive and
therapeutic agents (Mendes, 2015). For example, aspirin was recently
found to be beneficial against colorectal cancer only among individu-
als with at least one T allele associated with expression of the MYC
oncogene (Nan et al., 2013).
New Databases and Collaborative Opportunities
Studies of low-​prevalence medications, tumor subtypes, and genetic vari-
ants all require extremely large study populations. A growing number of
large healthcare databases with relatively easy linkage to cancer registries
are available for research. However, the level of data quality is inconsis-
tent across all health data sets and registries. Frameworks for improving
data quality have been suggested and may prove useful (Arts et al., 2002).
For example, the Surveillance, Epidemiology, and End Results (SEER)
Program and the IARC have provided guidelines to improve the quality
of cancer data. Ideally, high-​quality population-​based data should also be
available on genetic, lifestyle, and environmental factors.
Many of the large studies discussed in this chapter were unable to
adequately assess the drugs of interest, and even larger, collaborative
studies are clearly warranted. Such collaborations could follow the
example of the international research consortia for studying the genet-
ics of cancer and other complex diseases. The aims of these consortia
are to share and analyze the wealth of data from a number of already
established cohort or case-​control data sets (ENGAGE, 2012). While
such consortia can raise issues related to data harmonization, as well
as sharing of extremely large healthcare data sets, new methods and
strategies are under development to address privacy issues and other
challenges (Toh et al., 2014).
Advances in Pharmacoepidemiology
and Complementary Methods
In the past 20  years, numerous advances in epidemiologic methods
have been developed, many of which are particularly relevant to phar-
macoepidemiology, such as propensity scores, marginal structural
models, and methods for external adjustment. Conceivably, such meth-
odologic advances will continue, as will the development of new tools
to facilitate their use.
Translational bioinformatics also has the potential to complement
pharmacoepidemiology. Systems pharmacology is an emerging field
that applies systems biology approaches, combining large-​scale exper-
imental studies with model-​based computational analyses, often lever-
aging publicly available databases, such as PharmGKB and DrugBank,
to study drug activities, targets, and effects (Abernathy et al., 2011).
In the systems pharmacology framework, a drug interacts with multi-
ple targets that lie within interconnected biological pathways related
to one or more diseases (Berger and Iyengar, 2011). Computational
analyses of these drug–​disease networks are being increasingly con-
ducted to predict and understand why current drugs work, fail, and
result in deleterious outcomes, like cancer. In addition to mechanistic
insight, systems pharmacology can potentially help guide drug–​cancer
studies by identifying other medications and health conditions that
may act as confounders or effect modifiers, and by identifying cancer
subtypes that may exhibit stronger or weaker associations with use of
the drug(s) of interest (Gottlieb and Altman, 2014).
Translational Research: Discovery, Validation,
and Clinical Utility
New drugs, molecular testing, databases, and analytic methods are
all likely to increase the number of pharmacoepidemiology studies
and findings. In the future, new drug–​cancer signals and hypotheses
will continue to arise from animal and in vitro studies, clinical trials,
and epidemiologic studies, as well as from complementary bioinfor-
matics, such as systems pharmacology. However, while “Big Data”
promises to provide important insights into the causes and outcomes
of diseases, better drug targets and improved disease prediction, it can
also be subject to “Big Errors” (Khoury and Ioannidis, 2014). Thus,
given the potential public health importance of drug–​cancer signals, it
will be essential to carefully examine these findings within multiple,
well-​conducted studies that address potential selection bias and con-
founding, as well as biologic plausibility (e.g., latency, cumulative
exposure). For some replicated drug–​cancer associations, it may be
possible to subsequently conduct RCTs. However, observational stud-
ies will be the only option for evaluating the majority of drug–​cancer
associations. Before translating findings into regulatory action or clini-
cal care, it will also be essential that both the benefits and harms of a
medication are carefully considered.
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432
 43
24 Infectious Agents
SILVIA FRANCESCHI, HASHEM B. EL-​SERAG, DAVID FORMAN,
ROBERT NEWTON, AND MARTYN PLUMMER
OVERVIEW
Eight volumes in the International Agency for Research on Cancer
(IARC) Monographs on the Evaluation of Carcinogenic Risks to
Humans have been dedicated to infectious agents (Monographs 59,
61, 64, 67, 70, 90, 100B, 104; IARC, 1994a, 1994b, 1995, 1996,
1997, 2007, 2012a, 2014). The current classification of infectious
agents is reproduced in Table 24–1, along with the cancer sites or
types for which there was “sufficient evidence” or “limited evi-
dence” of carcinogenicity in humans according to the IARC crite-
ria (Monograph preamble) (IARC 2012b). Eleven infectious agents,
comprising seven viruses, three parasites, and one bacterium, have
been classified as carcinogenic to humans (group 1): hepatitis B virus
(HBV); hepatitis C virus (HCV); 13 types of human papillomavirus
(HPV); human immunodeficiency virus type 1 (HIV-​1); human T-​cell
leukemia virus type 1 (HTLV-​1); Epstein-​Barr virus (EBV); Kaposi
sarcoma herpesvirus (KSHV); Helicobacter pylori; Opisthorchis
viverrini; Clonorchis sinensis; and Schistosoma haematobium. There
is sufficient evidence for all of these agents that they cause cancer in
humans in at least one cancer site, and that some of them cause can-
cer in many sites. Infectious agents that did not reach the evidence
threshold to be classified as carcinogenic to humans according to
IARC’s criteria are also shown in Table 24–1. These agents have,
at best, limited evidence of carcinogenicity in humans, and varying
degrees of evidence for carcinogenicity in experimental animals that
may allow them to be classified as “probably carcinogenic” (group
2A) or “possibly carcinogenic” (group 2B) to humans. Agents clas-
sified in group 2B may have limited evidence of carcinogenicity in
humans, or sufficient evidence of carcinogenicity in experimental
animals without sufficient evidence in humans. Some HPV types
(HPV 30, 34, 69, 85, 97)  are classified in group 2B because they
are closely related to other types in group 1. The agents marked as
“not classifiable” (group 3) were considered in the same monograph
volume as the other infectious agents, typically because they were
closely related, but did not have sufficient evidence for their own
evaluation.
It should be noted that the classification scale used by the IARC
Monographs is not based on the strength of the association, but the
weight of evidence from studies in humans and animals and on mecha-
nisms. In particular, the HPV types in group 1 may differ by an order
of magnitude in risk for cervical cancer (IARC, 2007).
One way to judge the relative importance of carcinogenic infec-
tions is by estimating the global burden of cancers due to these
infections. From this perspective, an important distinction emerges
between infections that are found worldwide and those that have a
limited geographical distribution. The limited infections are HTLV-​1,
O.  viverrini, C.  sinensis, and S.  haematobium. HTLV-​I is primarily
vertically transmitted through breastfeeding and is therefore limited
to endemic populations. The others are helminths with complex life
cycles involving human and non-​human hosts, so that exposure is
only possible under specific geographical conditions. The geographi-
cally limited infectious agents do not make a major contribution to the
global burden of cancer even if they are important causes of cancer in
endemic populations.
GLOBAL BURDEN AND GENERAL FEATURES
We present estimates of the global burden of cancer attributable to
infection for 2012 (Plummer et al., 2016). The methodology is based
on estimating the population attributable fraction (PAF) from the prev-
alence of infections in cancer cases. The PAF is the proportion of can-
cer cases that would not have occurred if the exposure—​in this case,
an infectious agent—​had not been present in the population. The PAF
shows the relative importance of any exposure as a cause of cancer in a
given population. It does not correspond to the number of cancers that
can be prevented in practice, but may nevertheless be used as a guide
to priorities in future cancer control.
HIV-​1 causes a particular difficulty with PAF calculations as it
causes cancer indirectly through immunosuppression, increasing the
risk of cancer due to other oncogenic viruses. In order to avoid double
counting, we do not attribute cases to HIV-​1 but to the other infec-
tious agents. HIV-​infected people have a distinct profile of cancer
incidence (Robbins et  al., 2015), with a high proportion of cancers
caused by other viral infections. As an example, in the United States,
HIV-​infected people have an estimated fraction of infection-​associated
cancer that is 10-​fold higher than the general population (de Martel
et al., 2015b).
Out of 14  million incidence cases of cancer that are estimated to
have occurred worldwide in 2012 (Ferlay et al., 2013), 2.2 million were
caused by infectious agents classified in group 1. Table 24–2 shows
the breakdown of these 2.2 million cases by agent. H. pylori causes
770,000 cases and so is the single most important agent worldwide
when both sexes are combined. HPV causes 640,000 cases worldwide,
mainly of cervical cancer, but also other anogenital cancers and a frac-
tion of cancer of the head and neck. HBV causes 420,000 cases of
liver cancer. HCV causes 170,000 cases, mainly liver cancer, but also
non-​Hodgkin lymphoma. Epstein-​Barr virus causes Hodgkin lym-
phoma, Burkitt lymphoma, and nasopharyngeal carcinoma with a total
of 120,000 cases. The remaining agents cause less than 60,000 cases.
Although one out of six cancers worldwide is caused by infec-
tion, this proportion varies widely by geographic region. Table 24–3
shows the number of incident cases by region, as well as the num-
ber attributable to infection with the corresponding PAF. The low-
est PAF is seen in North America, where only 4.0% of cancers are
caused by infections. The highest PAF is seen in Sub-​Saharan Africa,
where infections cause 31.3% of cancers. A  more detailed view of
the variation in PAF by country is shown in Figure 24–1. The United
States, Canada, Australia, New Zealand, and several countries in
Western and Northern Europe have a PAF below 5% for infectious
agents. Conversely, several countries in Sub-​Saharan Africa as well
as Mongolia have a PAF over 40%. Table 24–3 also shows the varia-
tion when countries are grouped by their human development index
(HDI) (Bray et al., 2012; United Nations Development Programme,
2013) into four categories: very high, high, medium, and low HDI.
The PAF shows a gradient with HDI with a high PAF in the low
(25.3%) and medium (23.0%) HDI countries, lower PAF in the
high HDI countries (13.2%), and the lowest found in the very high
HDI countries (7.6%). Countries with very high HDI have the most
resources to prevent the circulation of HBV and HCV through unsafe
433
43

434 PART III:  THE CAUSES OF CANCER

Table 24–​1. Classification of Infectious Agents by the IARC Monograph Program

Evidence of Carcinogenicity in Humans (Animals)

Infectious Agent Volume Sufficient Limited

Group 1: Carcinogenic to humans
Hepatitis B virus 59, 100B Liver Non-​Hodgkin lymphoma
Hepatitis C virus 59, 100B Liver; Non-​Hodgkin lymphoma
Helicobacter pylori 61, 100B Stomach; MALT lymphoma
Opisthorchis viverrini 61, 100B Bile duct
Clonorchis sinensis 61, 100B Bile duct
Schistosoma haematobium 61, 100B Urinary bladder
Human papillomavirus type 16 64, 90, 100B Uterine cervix; anus; vulva; vagina; penis; oral Larynx
(HPV 16) cavity; tonsil; pharynx
HPV 18 64, 90, 100B Uterine cervix Anus; penis; vulva
HPV 33 64, 90, 100B Uterine cervix Anus; vulva
HPV 31,35,39,45,51,52,56,58,59 64, 90, 100B Uterine cervix
Human immunodeficiency virus-​I 67, 100B Lymphoma; Kaposi sarcoma; uterine Liver and bile duct; skin; Vulva; vagina;
(HIV-​I) cervix; anus; eye penis
Human T-​cell leukemia virus 67, 100B Adult T-​cell leukemia/​ lymphoma
type I (HTLV-​I)
Epstein-​Barr virus 70, 100B Lymphoma; nasopharynx Stomach
Kaposi sarcoma herpesvirus 70, 100B Kaposi sarcoma; primary effusion lymphoma
Group 2A: Probably carcinogenic to humans
HPV 68 100B Uterine cervix
Merkel cell polyomavirus 104 Skin
Plasmodium falciparum 104 Burkitt lymphoma
Group 2B: Possibly carcinogenic to humans
Schistosoma japonicum 61 Liver and bile duct;
colon and rectum
HIV-​2 67 Kaposi sarcoma; lymphoma
HPV 26,53,66,67,70,73,82 100B Uterine cervix
HPV 30,34,69,85,97 100B
HPV 5, 8 100B Skin1
JC polyomavirus 104 (Brain)
BK polyomavirus 104 (Sarcoma; brain)
Group 3: Not classifiable with regard to carcinogenicity to humans
Hepatitis D virus 59
Opisthorchis felineus 61
Schistosoma mansoni 61
HTLV-​II 67
HPV 6, 11 90, 100B
HPV genus beta and gamma 90, 100B
SV40 polyomavirus 104

1
Limited evidence in individuals with epidermodysplasia verruciformis.

injection practices and contaminated blood and blood products, and
also to implement screening programs to prevent HPV from causing
cervical cancer. They are similarly well placed to prevent HPV infec-
tion in young people through as yet expensive HPV vaccines. Most
very high HDI countries have avoided extensive iatrogenic transmis-
sion of HBV, HCV, and HIV, although Japan and some Southern
European countries were historically notable exceptions.
Figure 24–2 shows the number of infection-​attributable cancers by
HDI category, as well as the breakdown by agent. Half of the cases of
infection-​attributable cancer occur in medium HDI countries that rep-
resent 50% of the world’s population. HBV is an important cause of
cancer in medium HDI countries and is relatively much more impor-
tant than HCV. This is reversed in high HDI and very high HDI coun-
tries where HCV is relatively more important than HBV. H. pylori is
an important infectious cause of cancer across medium, high, and very
high HDI countries. In low HDI countries, H. pylori is responsible for
a relatively small proportion of infection-​attributable cancers. Gastric
cancer reaches its highest incidence at much older ages than cervi-
cal cancer and HBV-​associated liver cancer and so cannot account
for a large proportion of cancers when the population age structure is
skewed toward younger ages. The relatively early age at onset of cervi-
cal cancer may also explain why HPV is the dominant infectious cause
of cancer in low HDI countries.
Detection and Attribution
Good-​quality biomarkers of infection are important for accurately esti-
mating risk and ascribing a causal role to infectious agents in cancer.
In their review of causes of cancer, Doll and Peto (1981) hypothesized
that 10% of US cancer deaths were due to infection, with substan-
tial uncertainty surrounding this estimate. This review was made at a
time before H. pylori and HCV had been identified, and before HPV
had been confirmed as a major cause of cervical cancer. Progress in
the epidemiological study of infections and cancer has been highly
dependent on improvements in biomarkers of infection. Improvements
in sensitivity come from the ability to detect a lower burden of infec-
tion. The most sensitive biomarkers are DNA detection methods that
use polymerase chain reaction (PCR) to amplify few DNA or RNA
 435

Infectious Agents 435
Table 24–​2. Number of New Cancer Cases Occurring in 2012
1
Chronicity
Attributable to Infection by Infectious Agent
A universal feature of carcinogenic infectious agents is that chronic
Infectious Agent N % infection is a necessary condition for cancer to develop, with a latent
period between first infection and cancer incidence usually lasting
Helicobacter pylori 770,000 35.4 decades in immunocompetent individuals. For some agents, short-​
Human papillomavirus 640,000 29.5 term infections are also possible, but these do not entail any can-
Hepatitis B virus 420,000 19.2 cer risk. For example, the majority of HPV infections of the cervix
Hepatitis C virus 170,000 7.8 are transient and clear within 1 year, with a minority persisting and
Epstein-​Barr virus 120,000 5.5 progressing to cancer. Likewise, HBV and HCV may either cause a
Kaposi sarcoma herpesvirus 44,000 2.0 short-​term infection or lead to a chronic carrier state. The risk of an
Schistosoma haematobium 7,000 0.3 HBV infection leading to a chronic carrier state depends strongly on
Human T-​cell leukemia virus type I 3,000 0.1 age at exposure, with children at very high risk but adults at low risk.
Opisthorchis viverrini, 1,300 < 0.1 Conversely, a majority of HCV infections lead to a chronic carrier
Clonorchis sinensis state at any age.
Total infectious agents 2,200,000 100.0 Although chronicity is a universal feature of carcinogenic infec-
tions, it is attained by a wide variety of different mechanisms. For
example, HBV, HCV, H.  pylori, and helminth infections all cause a
1
Numbers are rounded to two significant digits.
chronic inflammatory response, but HPV achieves persistence by
evading immune surveillance. S. haematobium lives only 3–​5 years in
copies of the infectious agent. However, PCR detection methods may the human host without multiplying, but chronic exposure is attained
not be feasible, especially in large epidemiological studies, if the in endemic areas by repeated reinfection.
affected tissue is not readily accessible for sampling. In contrast, sero- The importance of length of exposure for cancer risk has long been
logical measurements of antibodies are easier to obtain and to use in recognized for strong carcinogens such as tobacco and asbestos (Doll,
prospective studies but may have poor sensitivity. The importance of 1978; Peto, 1979) and mathematical risk models have been developed
good biomarkers can be illustrated with H. pylori and non-​cardia gas- to explain the relationship between exposure time and risk based on the
tric cancer (see section in this chapter on H. pylori). multistage model of carcinogenesis (Armitage and Doll, 1954). Most
Improvements in specificity for infection biomarkers come of the infectious agents classified in group 1 are acquired in childhood,
from two sources. The first is to distinguish between agents that especially in endemic areas, leading to the maximum lifelong expo-
may be closely related, but differ in their carcinogenic potential. sure and hence maximum risk. The exceptions are HCV and HIV-​1,
This is shown by the different types of HPV, which are represented which are often acquired in adulthood. Although mucosal HPV types
across the whole spectrum of classifications from group 1 to group are sexually transmitted, they are highly transmissible, so first exposure
3 (Table 24–2). The second way to improve sensitivity is to distin- occurs soon after sexual debut. The risk of cervical cancer is higher
guish between transforming infections and those in which the agent among women with earlier age at first intercourse, and this relationship
is merely present. For example, EBV is ubiquitous in humans. Its is consistent with the multistage model (Plummer et al., 2012).
causal involvement in lymphomas and nasopharyngeal carcinoma
has been demonstrated by its latency pattern and the corresponding
gene products expressed in tumor cells (IARC, 2012a). Similarly, in HELICOBACTER PYLORI
head and neck cancer, the detection of HPV DNA in tumor cells by
in situ hybridization or detection of HPV E6/​E7 RNA as a marker of
transforming infection shows that HPV-​attributable cancer is rare in Nature of the Exposure
the oral cavity, larynx, and hypopharynx (Combes and Franceschi, H. pylori is a spiral Gram-​negative bacterium, with unipolar flagella,
2014). evolved and uniquely adapted to live within the highly acidic envi-
ronment of the human gastric mucosa (Wroblewski et  al., 2010).
Table 24–3. Number of New Cancer Cases1 Occurring in 2012 Although observed in the human stomach since at least the begin-
Attributable to Infectious Agents by Geographic Region and Human ning of the twentieth century (Krienitz, 1906), H. pylori (originally
Development Index termed Campylobacter pylori) was not characterized and cultured
until the early 1980s (Warren and Marshall, 1983); shortly after, it
Number was shown to be strongly associated with the etiology of both gastritis
Number of New Attributable PAF2 and peptic ulcer disease (Marshall and Warren, 1984). Although there
Region Cases in 2012 to Infection (%) are now over 30 Helicobacter species identified (http://​www.bacterio.
net/​helicobacter.html), most of which do not colonize humans, only
Sub-​Saharan Africa 630,000 200,000 31.3
H.  pylori has been intensively studied and clearly identified as a
Northern Africa and 540,000 70,000 13.1
Western Asia human pathogen.
Central Asia 1,500,000 290,000 19.4 The genome of H.  pylori has been fully sequenced (Tomb et  al.,
Eastern Asia 4,900,000 1,100,000 22.8 1997), and the organism exhibits considerable genomic diversity, with
South and Central America 1,100,000 160,000 14.4 infected humans sometimes harboring multiple strains (Suerbaum
North America 1,800,000 72,000 4.0 and Josenhans, 2007). The two major pathogenicity factors are CagA,
Europe 3,400,000 250,000 7.2 encoded by the cagA gene within the cag pathogenicity island (Censini
Oceania 160,000 7,600 4.9 et al., 1996), and VacA, encoded by the vacA gene (Cover et al., 1994).
CagA is highly immunogenic and elicits potent host antibody responses,
Human development index while VacA is a highly cytotoxic protein. Whereas there are genetic dif-
Very high 5,700,000 430,000 7.6 ferences leading to CagA negative and positive strain types (Suerbaum
High 2,200,000 290,000 13.2 and Josenhans, 2007), the vacA gene is conserved in all H. pylori strains,
Medium 5,200,000 1,200,000 23.0 although it is subject to allelic variation (Atherton et  al., 1995). The
Low 940,000 240,000 25.3 combination of CagA and VacA activity is the principal known mechan-
WORLD 14,000,000 2,200,000 15.4 ism giving rise to strain variation in H. pylori pathogenicity.
Although primary acquisition of H. pylori infection can occur in
1
Numbers are rounded to two significant digits. adults, it most typically arises in children and, once established, usu-
2
Population attributable fraction. ally persists for life in the absence of treatment (Malaty and Graham,
436

PAF < 5%
PAF in 5%−15%
PAF in 15%−25%
PAF in 25%−40%
PAF > 40%

Figure 24–​1.  Geographic variation in cancers attributable to infectious agents using the population attributable fraction (PAF). Source: Modified from
Plummer M, de Martel C, Vignat J, Ferlay J, Bray F and Franceschi S, Global burden of cancers attributable to infections in 2012: a synthetic analysis.
Lancet Glob Health, 4(9) (2016), e609-e616, with permission from the authors.

1200
Helicobacter pylori
Human papillomavirus
1000 Hepatitis B virus
No. of cancer cases attributable to

Hepatitis C virus
Other infectious agents
infection (thousands)

800

600

400

200

0
Low HDI Medium HDI High HDI Very High HDI
1,303,000 3,553,000 1,042,000 1,129,000
DEVELOPMENT STATUS
Population size (thousands)

Figure 24–​2.  Number of new cancer cases in 2012 attributable to infection by infectious agent. Source: Modified from Plummer M, de Martel C, Vignat
J, Ferlay J, Bray F and Franceschi S, Global burden of cancers attributable to infections in 2012: a synthetic analysis. Lancet Glob Health, 4(9), (2016),
e609-e616, with permission from the authors.
 437
Infectious Agents 437
1994). Humans are the only known reservoir of H. pylori (Oderda,
1999), and person-​to-​person contact, especially within the family, is
believed to be the primary route of transmission (Brown, 2000). There
is evidence for both oral–​oral and fecal–​oral routes of transmission;
in developing countries, consumption of contaminated water may
also act as an additional source of infection (Brown, 2000).
Although there are many means of identifying H.  pylori infection
from gastric biopsy material, including direct histological visualization,
the most commonly used noninvasive test in epidemiological studies
has been serology for H.  pylori immunoglobin G (IgG) antibodies
using enzyme-​linked immunosorbent assay (ELISA) (Megraud and
Lehours, 2007). Several other noninvasive tests are available, including
the urea breath test (UBT), stool antigen test (SAT), and immunoblot
procedures (Megraud and Lehours, 2007). The latter have been espe-
cially useful in the determination of specific H. pylori antigens (notably
CagA) and in situations when sensitivity to past infections, which may
have resolved, is of importance (Peleteiro et al., 2010). Tests making
use of urine and saliva samples have been developed but are rarely
employed in epidemiological settings (Megraud and Lehours, 2007).
There are many options for treatment of H.  pylori infection, usu-
ally involving a combination of two or three antibiotics in combination
with a proton pump inhibitor for periods of 7–​14 days (Li et al., 2015).
There is an expected eradication rate of around 80% generally associ-
ated with such regimens, although this depends on compliance with
the treatment and the antibiotic resistance profile within the population
(Gisbert and Greenberg, 2014).
Epidemiology of H. pylori Infection
Infection with H. pylori is quite common, with many adult populations
having a prevalence of over 50%, although it may be as low as 10%
in some while exceeding 70% in others (Brown, 2000; Peleteiro et al.,
2014). As prevalence has been declining in recent decades and is also
dependent on age, comparisons between prevalence surveys need to
make due allowance for both time period and age range of the study.
However, in age-​stratified population-​based samples of adults taken
since 2000, there remains substantial variation in prevalence, ranging,
for example, from 15% in Australians (1–​59 years) to 79% in Latvians
(17–​99 years) (Peleteiro et al., 2014). The association with age is evi-
dent in most populations studied and, although not invariably so, after
the first decade of life, there is an age-​related increase in prevalence up
until around 60 years, after which there tends to be a plateau or slight
reduction in prevalence. However, with infection acquisition predomi-
nantly occurring in childhood (Malaty and Graham, 1994), the observed
age relationship is believed to result primarily from a cohort effect with
those born more recently having lower levels of acquisition as children
compared with those born further back in time (Banatvala et al., 1993).
Taking account of the age and period effects, there appears to be a
generally higher prevalence of infection in Central and South America,
parts of Asia and Eastern Europe, in comparison with North America,
Australia, and Western Europe (Peleteiro et al., 2014).
In general, poor socioeconomic status is strongly related to a high
prevalence of infection (Brown, 2000). Socioeconomic-​related factors
that contribute to this relationship include hygienic conditions, house-
hold density/​crowding, and the number of young children in the house-
hold (Goodman et  al., 1996). This is consistent with the fecal–​oral,
person-​to-​person mode of bacterial transmission and provides a coher-
ent explanation for the consistent decline in infection prevalence over
time observed in those countries where sanitation has improved over
recent decades (Peleteiro et  al., 2014). The long-​term persistence of
childhood-​acquired infection into adult life means that improvements
in hygiene will rapidly impact on infection prevalence in the young but
have little immediate effect on adults.
Association with Cancer of the Stomach
(Gastric Cancer)
The cancer most intensively studied in relation to H. pylori infection
and with clear evidence of association is gastric cancer. The IARC
reviewed the evidence for this association (IARC, 2012a), after a prior
evaluation in 1994 (IARC, 1994b), and confirmed the categorization of
H. pylori infection as carcinogenic to humans (Group 1) (Table 24–1).
The IARC evaluation specifically indicated gastric carcinoma, exclud-
ing the cardia region of the stomach adjacent to the esophagus (non-​
cardia gastric carcinoma), and low-​grade B-​cell mucosa-​associated
lymphoid tissue (MALT) gastric lymphoma as the two forms of gastric
cancer caused by chronic infection with H. pylori.
Recent estimates indicate that there are approximately 823,000
new cases of non-​cardia gastric cancer diagnosed per annum (Forman
and Sierra, 2014), making it one of the most frequent cancer diag-
noses worldwide, while there is also an annual burden of approxi-
mately 20,000 gastric MALT lymphomas (Plummer et  al., 2016). It
is estimated that a total of 770,000 of these two (93.6%) cancers are
attributable to H. pylori infection and, considering all infection-​related
cancers (2.2 million), this contributes the largest burden (Table 24–2).
Non-​Cardia Gastric Cancer
Mechanism.  The dominant model for carcinogenesis in the non-​
cardia stomach is the one originally proposed by Correa in 1975 (Correa
and Piazuelo, 2012), involving a series of sequential pathological
transformations of the gastric mucosa from gastritis through atrophy,
intestinal metaplasia, dysplasia, and ultimately cancer (Figure 24–3).
H.  pylori is thought to act as the initial driver of this process, with
the inflammation resulting from infection resulting in chronic gas-
tritis. Over subsequent decades, inflammation and accompanying
oxidative stress, upregulated by bacterial virulence factors, create an
environment promoting DNA damage and leading to genetic instabil-
ity, metaplasia, and ultimately neoplastic transformation (Hardbower
et al., 2014). This model is conceived as the process underlying the
more common, “intestinal,” histological form of non-​cardia gastric
cancer (Correa and Piazuelo, 2012). The other “diffuse” histological
form is also associated with H. pylori infection and associated chronic
gastritis but, in this case, there are different genetic sequelae, particu-
larly involving e-​cadherin genes (Peek and Blaser, 2002).
Epidemiological Evidence. There have been several correla-
tional studies providing evidence in support of the association between
non-​cardia gastric cancer and H. pylori infection. These include geo-
graphical comparisons, where populations at high gastric cancer risk
have been shown to have a high prevalence of infection (EUROGAST,
1993; Peleteiro et al., 2014; Figure 24–4) and temporal studies, where
the decline in gastric cancer incidence (or mortality) within a pop-
ulation is preceded by an equivalent decline in H.  pylori prevalence
(Sonnenberg, 2013). There have also been a large number of case-​
control studies to investigate the association (Cavaleiro-​Pinto et  al.,
2011). There are, however, substantive problems in the sensitivity of
standard ELISA procedures to detect H. pylori retrospectively in cases
with a prior diagnosis of gastric cancer. This is due to atrophic gastritis,
a precancerous lesion that reduces the bacterial load of H. pylori in the
stomach and subsequently can reduce IgG antibody titers (Peleteiro
et  al., 2014). More reliable epidemiological evidence has been that
derived from prospective cohorts, including case-​control comparisons
nested within cohorts, which make use of serum samples collected
prior to cancer diagnosis. Studies in which immunoblot assays have
been employed in preference to ELISA have also provided impor-
tant evidence because of their improved assay sensitivity (Plummer
et al., 2015).
A pooled analysis of 12 nested case-​control studies, including 762
cases of non-​cardia gastric cancer and 2250 controls, derived an odds
ratio of 2.97 (95% confidence interval [CI] = 2.34–​3.77) for H. pylori
infection assessed by ELISA increasing to 5.93 (95% CI = 3.41–​10.3)
when restricted to cases diagnosed at least 10 years after blood sampling
(Helicobacter and Cancer Collaborative Group, 2001). Comparisons
making use of immunoblot assays applied to prospective studies show
substantially elevated risks with a pooled odds ratios of 17.0 (95%
CI = 11.6–​25.0) (Plummer et al., 2015). Alongside these results are those
from cohort studies in Japan (Take et  al., 2011; Uemura et  al., 2001;
Yanaoka et al., 2009) and Taiwan (Lee et al., 2013), all showing reduced
438

438 PART III:  THE CAUSES OF CANCER

Multifocal
Intestinal Intestinal
atrophic
Normal Non- metaplasia metaplasia
gastritis Low-grade High-grade Invasive
gastric atrophic of the of the
without dysplasia dysplasia adenocarcinoma
mucosa gastritis complete incomplete
intestinal
type type
metaplasia

Figure  24–​3. Consecutive steps for development of gastric adenocarcinoma of the intestinal type. Source: Reprinted from Park JY, Forman D,
Greenberg ER, and Herrero R, Helicobacter pylori eradication in the prevention of gastric cancer: are more trials needed? Curr Oncol Rep 15 (2013),
517–​527, with permission from Springer International Publishing AG.

risks of gastric cancer following H. pylori eradication and confirming a
primary role for infection as a risk factor for this form of cancer.
Parameters That Influence Risk.  Several environmental expo-
sures have been considered as potential cofactors in the relationship
between H. pylori infection and non-​cardia gastric cancer, including
tobacco smoking, salt and dietary antioxidant intake, coinfection with
helminths (reviewed in Wroblewski et al., 2010), and possibly Epstein-​
Barr virus infection (see related section in this chapter). Both host
genetic polymorphisms, especially in the interleukin 1 family (Persson
et al., 2011), and variation in bacterial pathogenic factors have also been
investigated in terms of their impact on cancer risk. Of the latter, most
attention has been paid to CagA strain variation. Meta-​analyses of con-
ventional ELISA studies show raised risks of non-​cardia gastric cancer
associated with CagA-​positive H. pylori strain infections in comparison
with CagA-​negative strains (Cavaleiro-​Pinto et al., 2011). A cross-​sec-
tional analysis using PCR to detect H. pylori in gastric biopsies found
that cagA-​positive strains are associated with severity of precancerous
lesions of the stomach, while cagA-​negative strains were associated
only with chronic gastritis (Plummer et al., 2007). It is conceivable that
most non-​cardia gastric cancers have a CagA-​positive infection as their
primary cause. Although environmental, host, and bacterial factors, and
their joint effects (Figueiredo et al., 2002), may modify the effect of H.
pylori to a considerable extent, none has yet been able to offer a satis-
factory explanation for the reason that certain populations, sometimes
labeled as “enigmatic,” have apparently a low cancer risk despite a high
prevalence of H. pylori infection (Ghoshal et al., 2010).
Intervention Studies.  Given the importance of H. pylori infection
as the dominant risk factor for non-​cardia gastric cancer, eradication

KOR KOR
40
Age-standardized incidence rate/100.000 (Log scale)

30 Age 20 years JPN

Age 60 years

20
CHL CHL

LTV LTV

10

CZE DEU CZE MEX MEX

ARG

AUS AUS
FRA FRA

USA USA
SWE SWE

0 20 40 60 80 100
Prevalence of Helicobacter pylori infection (%)

Figure 24–​4.  Gastric cancer incidence retrieved from GLOBOCAN, 2008 (Ferlay et al.) as a function of the prevalence of Helicobacter pylori infection in
different countries considering the data from samples evaluated mostly in the late 1990s/​early 2000s, according to age groups (strata with median age clos-
est to 20 and 60 years). ARG: Argentina; AUS: Australia; CHL: Chile; CZE: Czech Republic; DEU: Germany; FRA: France; JPN: Japan; KOR: Republic
of Korea; LTV: Latvia; MEX: Mexico; SWE:Sweden; USA: United States of America. Source: Reprinted from Peleteiro B, Bastos A, Ferro A and Lunet N,
Prevalence of Helicobacter pylori infection worldwide: a systematic review of studies with national coverage, Dig Dis Sci 59 (2014), 1698–​1709, with permission
from Springer International Publishing AG.
 439

Infectious Agents 439
No of events/total
Study H pylori control Risk ratio Weight Risk ratio
eradication (95% Cl) (%) (95% Cl)

Correa 2000 3/437 2/415 4.0 1.42 (0.24 to 8.48)

Wong 2004 7/817 11/813 14.2 0.63 (0.25 to 1.63)
Leung 2004–Zhou 2008 2/276 7/276 5.2 0.29 (0.06 to 1.36)
Saito 2005 2/379 3/313 4.0 0.55 (0.09 to 3.27)
You 2004–Ma 2012 34/1130 52/1128 70.2 0.65 (0.43 to 1.00)
Wong 2012 3/225 1/258 2.5 3.04 (0.32 to 28.99)
Total 51/3294 76/3203 100.0 0.66 (0.46 to 0.95)
Test for heterogeneity: τ2 = 0.00, χ2 = 3.62, df = 5,
P = 0.60, l2 = 0% 0.1 0.2 0.5 1 2 5 10
Favors Favors
Test for overall effect: z = 2.27, P = 0.02
eradication control

Figure 24–​5.  Forest plot of randomized controlled trials of Helicobacter pylori eradication therapy: effect on subsequent occurrence of gastric cancer.
Source: Reprinted from Ford AC, Forman D, Hunt RH, Yuan Y, and Moayyedi P, Helicobacter pylori eradication therapy to prevent gastric cancer in
healthy asymptomatic infected individuals: systematic review and meta-​analysis of randomised controlled trials, BMJ 348 (2014), 3174, with permission
from BMJ Publishing Group Ltd.

of the infection through the use of prescribed antibiotic regimens pro-
vides a means of cancer prevention. The large numbers and lengthy
time required for follow-​up, together with logistical and ethical con-
cerns relating to such an intervention in the general population, how-
ever, makes randomized controlled trials of this subject particularly
challenging. Results from six such studies have now been reported,
and these have been combined in a Cochrane Collaboration systematic
review and meta-​analysis (Ford et  al., 2014). All these studies com-
pared the incidence of subsequent gastric cancer in individuals who
have tested positive for H. pylori and who were randomized to receive
either eradication therapy or placebo/​no treatment and followed up for
at least 2 years. Based on approximately 6500 individuals randomized,
and 127 cancers diagnosed, the summary relative risk for those in the
eradication group was 0.66 (95% CI = 0.46–​0.95). This can be trans-
lated into a number needed to treat to prevent one gastric cancer of 124
(95% CI = 78–​843) (Figure 24–5). A Japanese trial of a slightly differ-
ent group of 544 patients, who had all undergone endoscopic resection
for treatment of early gastric cancer, were randomized to receive either
H. pylori eradication therapy or standard care after resection. After 3-​
year follow-​up, there was a 65% reduction in the risk of metachronous
gastric cancer in the intervention group (9 versus 24 cancers) (Fukase
et al., 2008). This finding has not, however, been reproduced in other
trials in Japan (Maehata et al., 2012) and Korea (Choi et al., 2014).
Screening Strategies.  The randomized trial evidence, in com-
bination with the observational epidemiological results and the cur-
rent mechanistic understanding of gastric carcinogenesis, provides
compelling support for the protective effect of H.  pylori eradication
in gastric cancer prevention. In addition, evaluations of population-​
based screening for H. pylori and eradication of the infection in those
found positive have been shown to be cost-​effective under a large
range of assumptions about both effectiveness and costs (Areia et al.,
2013). There is, therefore, a compelling basis for such an interven-
tion, especially in populations with a high non-​cardia gastric cancer
risk. Nevertheless there remain substantive concerns regarding the
generalizability of existing trials and the possibility of deleterious
consequences of population-​ wide antibiotic administration. Aside
from the possibility of diseases potentially protected by the presence
of H.  pylori (see discussion later in this chapter), the promotion of
enhanced antibiotic resistance, together with the unknown impact of
alterations to the human microbiome, is of serious public health con-
cern (Park et  al., 2013). Ongoing randomized trials (summarized in
IARC Helicobacter pylori Working Group, 2014) are likely to address
some of these issues; currently, although an IARC Working Group
recommended the development of further “screen and treat” programs
in high cancer-​risk populations, they also advised that such programs
be implemented in conjunction with a scientifically valid assess-
ment of their effectiveness and possible adverse consequences (IARC
Helicobacter pylori Working Group, 2014).
Gastric MALT Lymphoma
B-​cell gastric MALT lymphoma is a relatively rare form of cancer
representing a component of gastric non-​Hodgkin lymphoma. A sys-
tematic review (Asenjo and Gisbert, 2007) has shown that H. pylori
infection has been diagnosed in around 80% of MALT lymphomas,
increasing to 90% when the diagnosis is of low-​grade disease. There
are very few case-​control studies of the association between infection
and the risk of MALT lymphomas and, while they show a positive
effect (reviewed in IARC, 2012a), the decisive evidence for the rela-
tionship is provided by clinical trials showing that when H. pylori is
eradicated in patients with such lymphomas, in low-​grade form, com-
plete remission is obtained in 60%–​80% that may be sustained up until
10 years (Wundisch et al., 2012).
Cardia Gastric Cancer
For gastric cancer occurring in the proximal region of the stomach,
adjoining the esophagus (cardia gastric cancer), meta-​ analysis of
results from case-​control studies shows no overall association with H.
pylori infection (odds ratio [OR] 1.08; 95% CI = 0.83–​1.40), although
there is an important heterogeneity between those studies conducted
in low gastric cancer–​risk settings (OR = 0.78; 95% CI = 0.63–​0.97,
based on 16 studies) and those in high-​risk settings (OR = 1.98; 95%
CI = 1.38–​2.83, based on 14 studies; Cavaleiro-​Pinto et al., 2011). The
latter positive result comprised studies in China, Japan, and Korea, and
this heterogeneity provides some support to the hypothesis of there
being two distinct subtypes of cardia gastric cancer, one etiologically
similar to non-​cardia gastric cancer and more common in populations
with a high incidence of gastric cancer overall, and the other resem-
bling esophageal adenocarcinoma (Hansen et al., 2007). A fraction of
cancer of the cardia in Asia has therefore been attributed to H. pylori
in Plummer et al. (2016).
Association with Other Cancers
Esophageal Cancer
Meta-​analyses of studies of squamous cell cancer of the esophagus do
not indicate any association with H.  pylori infection (OR  =  1.1; 95%
40
440 PART III:  THE CAUSES OF CANCER
CI = 0.78–​1.55, based on 9 studies; Islami and Kamangar, 2008). Infection
with H. pylori has, however, been identified as a possible protective factor
for adenocarcinoma of the esophagus. One meta-​analysis has estimated a
statistically significant reduced odds ratio of 0.56 (95% CI = 0.46–​0.68)
for this association, based on 13 studies (Islami and Kamangar, 2008).
When stratified, the reduced risk was confined to the association with
CagA-​positive strains (OR = 0.41; 95% CI = 0.28–​0.62), with no rela-
tionship for CagA-​negative strains (OR  =  1.08; 95% CI  =  0.76–​1.53;
Islami and Kamangar, 2008). This is consistent with H.  pylori infec-
tion having an inverse risk of association with gastroesophageal reflux
disease (GERD) (Xie et al., 2013) and Barrett’s esophagus (Rubenstein
and Chen, 2014), important precursors of esophageal adenocarcinoma.
A  proposed mechanism for these effects relates to H.  pylori–​induced
atrophy reducing the acid secretory capacity of the gastric mucosa, as
the acidity of the gastric juice is its main damaging component (McColl
et al., 2008). It should be noted, however, that a meta-​analysis of 12 stud-
ies showed no association between H. pylori eradication (in contrast to
prevalence) and the risk of GERD (Yaghoobi et al., 2010).
Colorectal and Pancreatic Cancers
Results suggestive of a positive relationship with H. pylori infection
have been reported for colorectal cancer (meta-​analysis OR = 1.4; 95%
CI = 1.1–​1.8 based on 11 studies; Zumkeller et al., 2006) and pancre-
atic cancer (meta-​analysis OR = 1.38; 95% CI = 1.08–​1.75 based on 6
studies; Trikudanathan et al., 2011), and pathogenic mechanisms have
been advanced for both associations. However, the modest effect size
attaches some uncertainty to these results.
Other Diseases Associated with Infection
Apart from associations with cancer, H.  pylori infection has been
established as having a major causative role in both duodenal and gas-
tric ulcer, and antibiotic-​based eradication of the infection is now the
major therapeutic modality for treating these potentially fatal condi-
tions (Ford et al., 2006). H. pylori infection has also been proposed as a
risk factor for non-​ulcer dyspepsia (Moayyedi et al., 2006), and effec-
tive prevention of this common condition is an important consideration
in cost-​effectiveness models of H. pylori “screen and treat” programs.
There are also a wide range of extra-​intestinal conditions, including
those of metabolic, cardiovascular, dermatological, and hematological
origins that have been investigated for their association with H. pylori
infection with largely inconsistent results. It has also been suggested
that infection may protect against a number of extra-​intestinal condi-
tions, most notably childhood asthma (Parsonnet, 2014).
Future Research
Almost 90% of non-​cardia gastric cancers can be attributed to H. pylori
infection (Plummer et al., 2015). The strength of the association has led
some to propose that infection might be considered “a (close to) neces-
sary cause of non-​cardia gastric cancer” (Brenner et al., 2004). This is
unlikely to be correct, as there are other independent causes of at least
a small proportion of these cancers (e.g., Epstein-​Barr virus; see related
section in this chapter). Less controversial, however, is the call from the
same authors for a change in research emphasis away from considering
the certainty and magnitude of the association to questions of (1) the
cofactors responsible for cancer development among the large number
of infected people, and (2) how knowledge of the association can be
used to formulate cancer prevention protocols (Brenner et al., 2004).
These two questions represent the two major epidemiological issues
for future research as, in combination, they would address the current
uncertainties about using knowledge of the relationship as a means of
cancer control. It remains quite unclear, for example, how to implement
a “screen and treat” program to maximize benefits and to minimize any
risks. The optimal age group for intervention is unknown and, apart
perhaps from serum pepsinogen (Miki, 2011), biomarkers or other indi-
cators are not yet available that could help in stratifying the population
into risk groups. It also has not yet been established when the patho-
logical “point of no return” in H.  pylori carcinogenesis occurs, after
which eradication would be ineffective in cancer prevention. A move
from using gastric cancer to earlier endpoints would be critical in accel-
erating knowledge from eradication trials.
An evident weakness in management of H.  pylori infection is the
absence of a more effective therapy than the current multiple antibiotic/​
proton pump inhibitor regimens. The complexity of the regimens avail-
able and the required duration of administration make them suboptimal,
especially in the context of population-​based treatment programs and at
a time when there is heightened concern regarding antibiotic resistance.
In this respect, while effective vaccine development has not progressed
rapidly, the emergence of a candidate prophylactic vaccine reaching
phase 3 trials (Zeng et al., 2015) is potentially exciting.
MUCOSAL HUMAN PAPILLOMAVIRUS
Nature of the Exposure
Human papillomaviruses are small non-​enveloped icosahedral viruses
(50–​60 nm) that contain a circular double-​stranded DNA genome. They
belong to the Papillomaviridae family, which includes 16 different gen-
era classified into species and types (Figure 24–6). HPV species have
60%–​70% genomic nucleotide similarity. Conversely, types share less
than 90% homology in the L1 region. At a finer phylogenetic level, types
have evolved into variant lineages and sublineages (Cullen et al., 2015).
This section deals exclusively with the alpha genus, that is, mucosal
HPV types (hereafter referred to as HPVs) (IARC, 2007, 2012a) that
mainly infect the anogenital tract. The alpha-​9 (HPV 16–​related) and
alpha-​7 (HPV 18–​related) species groups contain the majority of known
carcinogenic (hereafter referred to as high risk, hr) types (Table 24–4).
The most important hrHPV in terms of frequency in invasive cervical
cancer (ICC) is HPV 16, then HPV 18, 45, 31, 33, 52, and 58, followed
by HPV 35, 39, 51, 56, and 59. The classification of rarer or weakly car-
cinogenic types (HPV 26, 53, 66, 67, 68, 70, 73, and 82) is challenging.
The HPV genome is divided into three regions:  the long control
region (LCR), which regulates viral gene expression and replication;
the early (E) region, which encodes proteins required for viral expres-
sion, replication, and survival; and the late (L) region, which encodes
the viral capsid. When overexpressed in eukaryotic cells, L1 can self-​
assemble in virus-​like particles (VLPs), the basis of current prophylac-
tic HPV vaccines (see Chapter 62.3 on HPV vaccination).
Molecular tests are available to detect HPV DNA or RNA in
exfoliated cells or tissue biopsies, and serological tests to detect
serum antibodies against L or E proteins. Molecular tests have been
used more extensively than serological tests due to their demon-
strated value in cervical cancer screening (Ronco et al., 2014) (see
Chapter  63 on screening). More than 100 HPV tests have been
developed (Poljak et al., 2012), of which the most widely used has
been Hybrid Capture version 2 (HC2). However, PCR-​based assays
are increasingly used not only in research, but also in clinical set-
tings, to detect individual HPV types. Test sensitivity and specificity
vary substantially across molecular assays, hampering comparison
between studies. From a practical viewpoint, analytical sensitivity
(minimal detectable copy number) should be distinguished from
clinical sensitivity (i.e., a test’s ability to correctly detect clini-
cally relevant infections and HPV-​associated precancerous lesions)
(Snijders et al., 2003). Additional tests are being considered to detect
hrHPV oncogenic activity (e.g., p16 overexpression) (Carozzi et al.,
2008), and distinguish productive infections from transforming
infection (e.g., E6/​E7 mRNA, and hypermethylation of host or viral
cells) (Steenbergen et al., 2014).
Serum antibodies (anti-​HPV), mainly against L1, have been used to
better reflect past and present (cumulative) infection with individual
HPVs. However, L1 antibodies are detectable in only about half of
women within 18  months of an HPV DNA-​positive test (Robbins
et al., 2014a). A fluorescent bead-​based multiplex platform has been
widely used in epidemiologic studies to measure seropositivity to
various HPV proteins (including L and E proteins) (Robbins et  al.,
2014a). The sensitivity and target (immunodominant epitopes or all
IgG) vary across serological assays, and none is commercially avail-
able (Crosbie et al., 2013).
 41

Infectious Agents 441
13
2
species 8
Genus 54 1
c91 10
Alpha-papillomavirus 6 94 43
77 78 42 7 40 12
29 3 28 10 32 6
7
66 5330 11
74
PcPV
68 39 56 55 CCPV RhPV1
70 44 9
59 c85 13 52 67
15 5 45
18 58
71 51 69 26 33 35
14 52 31
c90 11 16
73
34 3
61 72
81 49 75
3 c62 76 38 23
83 c87 22
c89
c86 2
84 2 9
37
4 27 17
57 5
4 BPV2 80
15 96
BPV1
92 4
EEPV 25
Delta-papillomavirus 1 20
19 Beta-papillomavirus
21
RPV 14
93 1
24
5
2 DPV
36
12
47
OvPV1 8
3 95
65
OvPV2 4 1
BPV5
50 2
Epsilon-papillomavirus
EcPV1 48
Zeta-papillomavirus 88
60 3 Gamma-papillomavirus
POPV 4
COPV 1 63 HaOPV 5
MmPV BPV6
CRPV FdPV BPV3
1 2 BPV4
Pi-papillomavirus
PsPV
Eta-papillomavirus FcPV 41
Omikron-papillomavirus
PePV Mu-papillomavirus Xi-papillomavirus
Theta-papillomavirus Lambda-papillomavirus
Kappa-papillomavirus Nu-papillomavirus
Lota-papillomavirus

Figure 24–​6.  Phylogenetic tree containing the sequences of the 118 papillomavirus types. Source: Modified from de Villiers EM, Fauquet C, Broker TR,
Bernard HU, and zur Hausen H, Classification of papillomaviruses, Virology 324 (2004), 17–​27, with permission from Elsevier. We would like to acknowl-
edge Arthur Bouvard for reworking this figure.

Epidemiology of HPV Infection HPV infection is the most common sexually transmitted infection
(STI) worldwide, and the majority of sexually active individuals of
Vast information is available on the prevalence of HPV types in cer- both sexes will acquire it at some time during their life (IARC, 2007).
vico-​vaginal samples in more than a million women with normal Around 300 million women in the world are estimated to have cervico-​
cytology (Bruni et al., 2010) and over 100,000 women with HPV-​pos- vaginal HPV infection at a given point in time (Bruni et  al., 2010),
itive cytological/​histological abnormalities of different severity (Guan corresponding to an average world prevalence of 12%. The highest
et al., 2012). Although the quantity and quality of data vary by region, prevalence has been reported in Sub-​Saharan Africa (24%), Eastern
a relatively comprehensive and consistent view of the world distribu- Europe (21%), and Latin America (16%). Globally HPV 16 is the most
tion of HPVs is available. common type (> 20% of HPV-​positive women with normal cytology)
and HPV 18, 31, 52, and 58 are among the 10 most common types,
with small variations across regions. HPV 6 is the most frequent
Table 24–​4. Classification of Selected Mucosal Human Papillomavirus low-​risk type. Multiple-​type infections are common (about a third of
Types by Alpha-​Species and Carcinogenicity According to IARC HPV-​positive women), but there is no evidence of synergy or antag-
Monograph 100B (2012) onism between HPV types in multiple-​type combinations (Vaccarella
et al., 2010).
Probably Possibly HPV prevalence rises rapidly after sexual debut and becomes rela-
Carcinogenic Carcinogenic tively low after 35 years of age, especially in more developed coun-
Carcinogenic to to Humans to Humans tries (Bruni et al., 2010). In some countries in Latin America and Asia
Alpha Species Humans (Group 1) (Group 2A) (Group 2B) (Zhao et al., 2012), a small second HPV prevalence peak in middle-​
aged women has been observed. However, HPV prevalence was similar
5 51 26 69* 82 across age groups in some African and Asian populations (Franceschi
6 56 30* 53 66 et al., 2006; Gage et al., 2012).
7 18, 45, 39, 59 68 70 85* 97* The IARC HPV Prevalence Surveys (Crosbie et al., 2013) include
9 16, 31, 33, 35, 52, 58 67 approximately 33,000 women aged 15–​64  years from 29 different
11 34* 73 areas, mainly in less developed countries (Figure 24–7). All sur-
veys used a standardized protocol to help overcome the problems
*Based on phylogenic analogy to HPV types with sufficient or limited evidence in of heterogeneity related to HPV detection methods and population
humans. recruitment.
42

442 PART III:  THE CAUSES OF CANCER

HPV Prevalence (%)
N 0 5 10 15 20 25 30 35 40 45 50 55
Guinea 833
Mongolia 969
Rwanda 2508
Vanuatu 987
Nigeria 932
Bhutan 2505
Fiji 1244
Poland 834
China, Shenzhen 1027
Argentina 978
India 1891
China, Shenyang 685
China, Shanxi 662
Chile 955
Colombia 1834
Georgia 1309
Korea 863
Mexico 1340
Vietnam, Ho Chi Minh 922
Italy, Turin 1013
Thailand, Lampang 1035
Nepal 932
Iran 825
Netherlands 3304 HPV 16 or 18
Algeria 759 Other high-risk type
Thailand, Songkla 706
Low-risk type only
Spain 911
Pakistan 899
Vietnam, Hanoi 994

Figure 24–​7.  Age-​adjusted prevalence of cervical human papillomavirus (HPV) DNA in sexually active women aged 15–​69 years by HPV type. Source:
Modified from Crosbie EJ, Einstein MH, Franceschi S, and Kitchener HC, Human papillomavirus and cervical cancer, Lancet 382 (2013), 889–​899, with
permission from Elsevier.

was on average 9.8 months (Rositch et al., 2013) and the longest dura-

Natural History of HPV Infection
Mucosal HPVs are very efficiently transmitted through direct skin-​
to-​skin or skin-​to-​mucosa contact, mainly during sexual intercourse,
including non-​penetrative intercourse. HPVs can reach basal cells
through micro-abrasions in the epithelium of the anogenital tract
and head and neck (see corresponding sections in this chapter). Rare
non-​sexual routes of transmission include perinatal transmission and,
possibly, transmission through fingertips, medical procedures, and
fomites (IARC, 2007).
HPV prevalence includes a mix of new incident infections and per-
sistent infections that have accumulated over time due to lack of viral
clearance (Castle et  al., 2009; Munoz et  al., 2004)  The vast major-
ity of new HPV infections at any age become undetectable over 6–​
18 months. In a large meta-​analysis, the duration of hrHPV infection
tions were found for HPV 16, 31, 33 and 52 (≥ 11 months). Longer
persistence of infection with a given HPV type reduces the probability
of subsequent clearance. Prevalent infections in older women are less
likely to regress (Figure 24–8) not because of a woman’s age, but as
they are more likely to be long-​duration infections (Maucort-​Boulch
et  al., 2010). In fact, age is not associated with HPV persistence in
incident infections.
HPV persistence is a prerequisite for progression to differ-
ent grades of cervical intra-​ epithelial neoplasia (CIN) that are
distinguished by depth of epithelial infiltration (Schiffman and
Wentzensen, 2013). Of note, CIN1 is only an insensitive histopath-
ological sign of HPV infection, whereas CIN2 includes a heter-
ogeneous group of lesions that are equivocal in cancer potential.
CIN3 represents the most clinically relevant lesion and is the best

Age (years) N infections OR (95% CI) FSE Relative Risk & 95% FCI

Prevalent infections
< 20 753 1.00 0.098
20–29 2600 1.09 (0.89–1.33) 0.035
30–39 525 1.30 (1.02–1.66) 0.076 Figure  24–​8. Odds ratios (ORs) for persis-
40–49 146 1.25 (0.88–1.77) 0.147 tence of human papillomavirus infections of
> = 50 62 2.14 (1.32–3.47) 0.224 any type, by age and prevalent versus incident
Incident infections infection. CI: confidence interval; FSE: floating
< 20 649 1.15 (0.80–1.66) 0.167 standard error; FCI: floating confidence inter-
val. Source: Reprinted from Maucort-​ Boulch D,
20–29 2100 1.14 (0.93–1.40) 0.040
Plummer M, Castle PE, Demuth F,
30–39 447 1.24 (0.96–1.61) 0.089 Safaeian M, Wheeler CM, and Schiffman M,
40–49 179 0.77 (0.55–1.08) 0.142 Predictors of human papillomavirus persistence
> = 50 53 0.93 (0.55–1.58) 0.250 among women with equivocal or mildly abnormal
cytology, Int J Cancer 126 (2010), 684–​691, with
0.0 1.0 2.0 3.0 permission from John Wiley & Sons.
 43

Infectious Agents 443
surrogate endpoint for efficacy against ICC in screening or vaccine
trials. The probability of progression from persistent infection with
hrHPV to CIN2 or worse (CIN2+) has been reported in many cohort
studies. Three-​year incidence rates of CIN2+ after persistent infec-
tion were 40.8%, 17.5%, and 10.0% for HPV 16, 18, and an “aver-
age” of other hrHPV, respectively (Castle et al., 2009). Cytologically
normal women with type-​specific persistent hrHPV infection have
a substantial risk of developing CIN3+, mainly depending on type;
for example, 12-​year absolute risk in a large Danish study was 47%
(95% CI = 35%–​58%) for HPV 16 but 6.0% (4%–​8%) for hrHPVs
other than HPV 16, 18, 31, or 33 (Kjaer et al., 2010). Laser capture
micro-​dissection showed that, despite frequent co-​presence of more
than one type, a single high-​grade CIN lesion is caused by a single
HPV type that can proceed to monoclonal ICC through multiple
transforming, carcinogenetic steps (Quint et al., 2012).
The natural history of HPVs has been much more frequently
studied in women than men. However, HPV prevalence appears
to be higher in men’s genitalia, mainly because it does not decline
with age (Giuliano et al., 2011). Conversely, HPV antibody level is
higher in women at any age (Markowitz et al., 2009). These obser-
vations point to the possibility that HPV infection of the keratin-
ized epithelium of the male genital tract is less likely to induce an
immune response than in the mucosal epithelium of the cervix and
vagina (Lu et al., 2012).
Data on the natural history of HPVs in anatomic sites other than the
cervix are limited for both sexes and will be briefly described in the
sections reviewing the corresponding cancer sites.
Types of Cancer Caused by HPV
HPVs are powerful carcinogens and are implicated in the etiology of
cancer in the anogenital tract and head and neck, causing approxi-
mately 640,000 cases per year (see section on global burden and gen-
eral features in this chapter, as well as chapters in Part IV, “Cancers by
Tissue of Origin,” elsewhere in this volume).
Cervix
The identification of hrHPVs as the necessary cause of ICC
(Walboomers et  al., 1999)  followed a century of epidemiologic
study that had highlighted the association of ICC with multiple
sexual partners (IARC, 2007, 2012a). Since the 1980s, numerous
case-​control studies have shown particularly strong associations
of ICC with hrHPVs reaching relative risks (RR) in the hundreds.
Prospective studies suggested that a single HPV measurement con-
fers a 10-​to 30-​fold increase in ICC risk if not detected and treated
(IARC, 2007, 2012a).
The proportions of HPV 16 and 18 among HPV-​positive samples are
approximately three and two times greater, respectively, in ICC com-
pared to normal cytology, in all world regions (Figure 24–9) (Guan
et al., 2012). Other hrHPVs mainly contribute to CIN2, and sometimes
CIN3, but become much less frequent in ICC (Figure 24–10). ICC
includes two major histological types: squamous-​cell carcinoma (about
70%–​80% of all ICC) and adenocarcinoma. Contrary to squamous-​cell
carcinoma, in which HPV 16 is predominant, the contributions of HPV
16 and HPV 18 are similar in adenocarcinoma. Precancerous lesions
of adenocarcinoma are called atypical glandular cells and adenocarci-
noma in situ, rather than CIN (Guan et al., 2013).
Anogenital Other Than Cervix
Meta-​analyses (de Vuyst et  al., 2009), large case series (Alemany
et al., 2015; de Sanjosé et al., 2013; Miralles-​Guri et al., 2009), and a
few case-​control studies (IARC, 2007) have shown that hrHPV infec-
tion, most often HPV 16, is a precursor state to cancer of the anus,
vulva, vagina, and penis.
The fraction of anal cancer (mainly squamous-​ cell carcinoma)
attributable to hrHPVs is similar to that for ICC. Anal cancer is rare
in the general population in both sexes (< 2 per 100,000) but is 20-​
fold more frequent in men who have sex with men (MSM), especially
among HIV-​infected MSM (de Vuyst et al., 2009). In fact, the major-
ity of information on HPVs and anal intra-​epithelial neoplasia derives
from HIV-​infected MSM (Machalek et al., 2012).

65%
60%
55%
50%
45%
40%
HPV Positivity

35%
30%
25%
20%
15%
10%
5%
0%
Normal ASCUS LSIL HSIL CIN1 CIN2 CIN3 ICC ICC: Normal ICC: CIN3
ratio ratio
HPV 16 20.5 ± 3.7 22.0 ± 2.9 24.9 ± 3.1 47.5 ± 5.7 27.5 ± 4.4 39.7 ± 5.0 58.2 ± 4.1 62.7 ± 2.3 3.06 1.08
HPV 18 8.4 ± 1.1 9.1 ± 1.8 8.4 ± 1.4 9.6 ± 1.6 9.1 ± 1.7 10.0 ± 1.0 8.0 ± 1.4 15.6 ± 2.9 1.85 1.94
HPV 45 4.9 ± 0.9 5.8 ± 1.5 4.1 ± 1.0 4.6 ± 1.3 4.1 ± 1.3 5.0 ± 1.7 3.7 ± 0.9 5.3 ± 0.7 1.08 1.44

Figure 24–​9.  Positivity (±1.96 SE) for human papillomavirus (HPV) types 16, 18, and 45 as a proportion of HPV-​positive samples, by cervical disease
grade. ASCUS:  atypical squamous cells of undetermined significance; LSIL:  low-​grade squamous intraepithelial lesion; HSIL:  high-​grade squamous
intraepithelial lesion; CIN: cervical intraepithelial neoplasia grade; ICC: invasive cervical cancer. Source: Reprinted from Guan P, Howell-​Jones R, Li N,
Bruni L, de Sanjosé S, Franceschi S, and Clifford GM, Human papillomavirus types in 115,789 HPV-​positive women: a meta-​analysis from cervical infection to
cancer, Int J Cancer 131 (2012), 2349–​2359, with permission from John Wiley & Sons.
4

444 PART III:  THE CAUSES OF CANCER

15%

HPV Positivity 12%

9%

6%

3%

0%
Normal ASCUS LSIL HSIL CIN1 CIN2 CIN3 ICC ICC: Normal ICC: CIN3
ratio ratio
HPV 33 4.8 ± 0.8 5.8 ± 1.6 6.1 ± 1.3 8.4 ± 1.2 6.2 ± 2.0 8.3 ± 1.3 9.0 ± 1.2 4.5 ± 0.8 0.94 0.50
HPV 58 6.3 ± 1.0 7.9 ± 2.1 7.1 ± 1.2 7.6 ± 1.6 9.8 ± 2.5 12.2 ± 4.3 8.9 ± 2.7 4.4 ± 2.2 0.70 0.50
HPV 31 8.0 ± 2.1 9.1 ± 1.4 9.1 ± 1.5 11.1 ± 1.6 11.4 ± 4.0 11.6 ± 2.8 11.6 ± 1.4 4.0 ± 0.4 0.50 0.34
HPV 52 8.0 ± 1.9 10.2 ± 2.5 8.0 ± 2.3 9.5 ± 2.1 14.1 ± 3.6 16.5 ± 5.2 10.1 ± 3.0 3.6 ± 0.9 0.44 0.35
HPV 35 3.4 ± 0.7 5.6 ± 1.6 4.7 ± 1.4 5.6 ± 1.6 4.1 ± 1.5 4.9 ± 2.1 3.5 ± 1.0 1.7 ± 0.3 0.51 0.48

Figure 24–​10.  Positivity (±1.96 SE) for human papillomavirus (HPV) types 33, 58, 31, 52, 35 as a proportion of HPV-​positive samples, by cervical dis-
ease grade. ASCUS: atypical squamous cells of undetermined significance; LSIL: low-​grade squamous intraepithelial lesion; HSIL: high-​grade squamous
intraepithelial lesion; CIN: cervical intraepithelial neoplasia grade; ICC: invasive cervical cancer. Source: Reprinted from Guan P, Howell-​Jones R, Li N,
Bruni L, de Sanjosé S, Franceschi S, and Clifford GM, Human papillomavirus types in 115,789 HPV-​positive women: a meta-​analysis from cervical infection to
cancer, Int J Cancer 131 (2012), 2349–​2359, with permission from John Wiley & Sons.

The relatively low fraction attributable to HPV in the vulva and
penis (≤ 50%) is largely accounted for by the coexistence of histo-
logical types that substantially differ in their association with HPV
infection. Basaloid and warty carcinomas of the vulva (de Vuyst et al.,
2009) and penis (Miralles-​Guri et al., 2009) are much more frequently
HPV-​positive and are detected in younger patients than other histologi-
cal types (mainly keratinized squamous-​cell carcinoma). HPV-​positive
vulvar intra-​epithelial neoplasias are often detected during cervical
cancer screening (de Vuyst et al., 2009).
Head and Neck
Head and neck carcinomas (HNCs) are the malignancies for which
an association with HPVs has been discovered most recently (IARC,
2007) and the fraction attributable to the infection is most uncertain

100
Oropharynx Oral cavity Larynx Hypopharynx
90

80

70

60

50
%

40

30

20

10

0
PCR p16 in situ hybridization E6/E7 mRNA

Figure 24–​11.  Prevalence of human papillomavirus molecular markers and 95% confidence intervals by head and neck cancer site. Source: Reprinted from
Combes JD and Franceschi S, Role of human papillomavirus in non-​oropharyngeal head and neck cancers, Oral Oncol 50 (2014), 370–​379, with permission from
Elsevier.
 45

Infectious Agents 445
and different across world regions (see global burden and general fea-
tures in this chapter).
Epidemiological studies have mainly evaluated the presence of
HPV in oral cells obtained by mouth brushing and gargle (Chung
et al., 2014). A large population-​based survey of oral HPV infection
is available only for the United States, and it showed a significantly
higher HPV prevalence in men (10.1%) than in women (3.6%), and
in current smokers (also after adjustment for gender) (Gillison et al.,
2012). Sexual transmission (including orogenital intercourse and pos-
sibly deep kissing) is the preponderant mode of HPV acquisition in the
head and neck (Chung et al., 2014).
HPVs were seldom found in the tonsil, regardless of whether
archival tissue specimens or fresh cell/​tissue samples had been used
(Palmer et  al., 2014). However, evidence incriminating HPV is far
stronger for the tonsil and oropharyngeal cancer (collectively referred
to as OPC) than other HNCs (Combes and Franceschi, 2014; IARC,
2012a; Mehanna et al., 2013). HPVs, in the vast majority HPV 16, are
two to four times more frequently detected in OPC than other HNCs,
and the difference is greater (> 10-​fold) using markers of HPV malig-
nant transformation (Figure 24–11) (Combes and Franceschi, 2014;
Ndiaye et al., 2014). An increase in incidence rates of OPC has been
reported in the past two decades in several high-​income countries
despite decreasing rates for other HNCs (Chaturvedi et  al., 2013).
The fraction of HPV-​positive OPC also increased over the same per-
iod (Chaturvedi et al., 2013; Mehanna et al., 2013).
A bulk of epidemiologic evidence supports the notion that two
main distinct entities exist for OPC, one driven by HPVs and the
other by the use of tobacco and alcohol (Marur et  al., 2010). These
entities also show differences in genetic alterations (Rietbergen
et  al., 2014)  and prognosis (i.e., better survival in patients with
HPV-​positive OPC) (Marur et  al., 2010). The fraction of OPC attrib-
utable to HPV varies by region and, in some regions, by gender
(Figure 24–12) (Combes et  al., 2014). However, the estimate of the
attributable fraction is hampered by lack of accurate data on the site
of origin of HNCs and the frequent co-​presence of HPVs and tobacco
exposure.
Mechanisms of Carcinogenesis
In vitro and in vivo models have elucidated how hrHPVs cause can-
cer (IARC, 2007, 2012a). HPV carcinogenic mechanisms involve
random integration of the viral genome in the human genome, cell
immortalization, transformation, inhibition of apoptosis, and accumu-
lation of genomic instability. E6 and E7 oncoproteins are principally
responsible for HPV neoplastic effects (i.e., inactivation of p53, induc-
tion of hTERT, and binding to PDZ for E6; inactivation of pRb and
related pocket proteins, and activation of E2Fs for E7). HPV E6 and
E7 genes must be present in every cancer cell to maintain tumor phe-
notype. Low-​risk types, notably HPV 6 and 11, do not share the car-
cinogenic mechanisms of hrHPV.
In addition to cell-​cycle deregulation, hrHPVs have also developed
sophisticated techniques of immune evasion in which E6 and E7 are
involved, for example, via suppression of innate immune response
(Crosbie et al., 2013). Cell-​mediated immunity is implicated in viral
clearance, but it fails in a small percentage of infections. Precancerous
lesion regression is associated with infiltrating CD8+ cytotoxic T-​cell
response, whereas regulatory T-​ cell infiltrates, which maintain an
immune-​tolerant environment, are associated with progressive lesions
(Crosbie et al., 2013).
Mechanisms are best understood for HPV 16, 18, 31, and 33 with
respect to infection of the cervix (IARC, 2012a). While the epithe-
lium of the entire anogenital tract and head and neck can be infected
by HPV, the transformation zone (TZ) of the cervix is especially sus-
ceptible to carcinogenesis. The TZ is an area of metaplastic tissue
between the squamous epithelium of the vagina and the columnar epi-
thelium of the endocervical canal (Schiffman and Wentzensen, 2013).
The size and location (exo-​or endo-​cervix) of the TZ is influenced
by changes in sex hormone levels and pregnancies (see section on
cofactors). The recent discovery of a population of cells of embry-
onic origin may, if confirmed by other investigators, help explain the
unique vulnerability to HPV carcinogenesis of the TZ (Herfs et al.,
2012). These cells have a unique cuboidal morphology and express
specific biomarkers and, although not permissive for the entire HPV
life cycle, can harbor the virus for extended periods of time (Herfs
et al., 2012). It has been proposed that these cells are the source of
most, if not all, CIN2–​3 and ICC, and do not regenerate after ablation
of the transformation zone.
In the head and neck, the tissue most susceptible to HPV carcino-
genesis is the thin epithelium of the deep crypts of the palatine and
lingual tonsils. Despite the characteristic abundance of lymphocytes
in the tonsils, the virus escapes immune elimination during malignant
transformation and progression. Precancerous lesions are ill defined
and rarely reported in the tonsils, even in the proximity of HPV-​
positive OPC (Pai and Westra, 2009). HPV 16-​E6-​mRNA was also

20

18 HPV–OPC
HPV+OPC
Age-standardized incidence rate/100 000

16

14

12

10

6 Figure  24–​12.  Age-​standardized (world)

incidence rates of oropharyngeal cancer
4 (OPC) per 100,000 persons stratified by
country, gender, and HPV status and cor-
2 responding male (M)  /​female (F)  ratios.
Source: Reprinted from Combes JD, Chen
0 AA, and Franceschi S, Prevalence of human
UK Australia US France
papillomavirus in cancer of the oropharynx
M F Ratio M F Ratio M F Ratio M F Ratio by gender, Cancer Epidemiol Biomarkers
HPV+OPC 2.8 0.9 3.3 2.8 0.6 4.4 4.8 1.0 4.9 7.2 1.7 4.3 Prev 23 (2014), 2954–​2958, with permis-
HPV–OPC 1.9 0.6 2.9 2.8 1.0 2.9 2.5 1.2 2.0 10.6 1.0 10.2 sion from the American Association for
Total OPC 4.7 1.5 3.1 5.6 1.6 3.5 7.3 2.2 3.3 17.8 2.7 6.6 Cancer Research.
46
446 PART III:  THE CAUSES OF CANCER
rarely detected in the mucosa surrounding HPV-​positive OPC, which
suggests the absence of a field cancerization effect so common around
tobacco-​associated OPC (Rietbergen et al., 2014).
Parameters That Influence Risk
The probability of HPV persistence and progression to cancer in the
anogenital tract is strongly influenced by the immune status, notably
HIV infection (see Chapter  25 on immunologic factors). Additional
risk factors are mainly related to an increased probability of HPV
infection (e.g., number of sexual partners of the individual and also
number of partners of his or her sexual partners). Anogenital inter-
course and orogenital intercourse are risk factors for anal cancer and
OPC, respectively. Condom use provides only partial protection due
the extension of HPV-​infected area. Risk factors associated with the
probability of HPV persistence and progression have been nearly
exclusively studied in the cervix and include high parity and recent
oral contraceptive use (Plummer et al., 2012). Large pooled analyses
have shown that all these preponderantly hormone-​related risk factors
are associated with an increased ICC risk also after careful adjustment
for lifetime number of sexual partners and socioeconomic factors
(International Collaboration of Epidemiological Studies of Cervical
Cancer, 2006, 2007).
In fact, the cervix is very sensitive to changes in levels of endogenous
and exogenous sex hormones during a woman’s life. The rise in ovar-
ian activity after menarche stimulates the transformation of columnar
reserve cells into squamous epithelium in the TZ. However, the tem-
poral proximity of first sexual intercourse to menarche per se does not
increase the risk of HPV infection and ICC, contrary to the hypothesis
of a special vulnerability of the “immature” cervix (Plummer et  al.,
2012). Young age at first sexual intercourse may rather be a proxy of
long-​duration exposure to HPV infection and hence high probability
of malignant transformation. In addition, incidence rates of ICC in
unscreened populations have been shown to stop rising after approxi-
mately 45 years of age (i.e., when peri-​menopausal hormonal decline
starts) (Plummer et al., 2012).
Full-​term pregnancies and oral contraceptives involve exposure to
high levels of both estrogens and progesterone, but which hormonal
pattern is associated with ICC is unclear. A few studies in women
(Rinaldi et al., 2011) and HPV16-​carrying transgenic mice (Chung
et al., 2010) suggested a role for high estrogen levels. In these mice,
ICC could even be controlled by treatment with raloxifene, an estro-
gen-​receptor antagonist (Spurgeon et al., 2014). In humans, estro-
gen signaling in cervical cancer was shown to be very different from
that in breast cancer (i.e., associated with estrogen receptors alpha
in stromal fibroblasts rather than in tumor cells) (den Boon et  al.,
2015).
Tobacco consumption represents another cofactor of HPV infection
in the anogenital tract. However, the role of tobacco in HPV-​associated
OPC is unclear. A departure from a multiplicative model (i.e., the OR
for tobacco use being smaller among HPV-​positive individuals, or
the OR for HPV infection being smaller among smokers) has been
suggested by case-​control studies (Combes and Franceschi, 2014).
However, the lack of prospective studies prevents the comparison of
the absolute risk of HPV-​associated OPC in combination with or in the
absence of tobacco use.
Future Research
Despite amazing progress, knowledge gaps remain in several aspects
of HPV infection and related cancer. An HPV epidemic due to the
consequences of the sexual revolution in women born after the 1940s
or 1950s has been inferred from trends in different STIs, CIN3 (Peto
et al., 2004), and age-​period-​cohort models of ICC (Vaccarella et al.,
2013), but, by now, high-​throughput molecular and serological tests
should make direct measurement of HPV trends in population-​based
surveys possible. Ideally, these tests might also be used on archi-
val samples. Trends in HPV prevalence by anatomic site and gen-
der would be essential to monitor the influence of changes in sexual
habits and, if introduced, the early impact of HPV vaccination and
HPV-​based screening in different populations. Decreases in the pro-
portion of CIN2–​3 and ICC associated with HPV 16 and 18 would also
be informative regarding the impact of HPV vaccination (see Chapter
62.3 on HPV vaccination).
Little is known on the probability of undetectable latent HPV
infection and on the degree of naturally acquired immunity or vac-
cine-​induced protection against reinfection with the same HPV type
(Safaeian et al., 2010). This information would be essential to opti-
mize the age range to be targeted by HPV vaccination and HPV
screening. How aggressive searching for and treating precancerous
lesions should be is an especially important question for cancer of the
anus and vulva, while the characterization of precancerous stages is
a priority for OPC.
Finally, the genomic variation of hrHPV that determines infection
persistence and malignant transformation is insufficiently understood.
Newly developed, next-​generation, whole-​genome sequencing permits
much larger studies and more complete HPV genotype-​phenotype
examinations than previously possible (Cullen et al., 2015).
HEPATITIS B VIRUS
Hepatitis B virus (HBV) is a DNA virus within the Hepadnaviridae
family, also including the woodchuck and the duck HBV that has a nar-
row host range as well as a striking tropism for hepatocytes (reviewed
in IARC, 2012a). The outer lipid bilayer envelopes the spherical HBV
virion of the hepatitis B surface antigen (HBsAg). Within the inner
nucleocapsid core (HBcAg) is a partially double-​ stranded, circu-
lar genome, as well as a DNA polymerase. Several HBV genotypes
(A–​H) with distinct geographical and ethnic distributions have been
identified based on differences of 8% or more in their whole-​genome
sequence. For example, genotypes A and D predominate in Africa,
Europe, and India; genotypes B and C predominate in Asia; geno-
type E predominates in West Africa; and genotype F predominates in
Central and South America. In the United States, HBV genotypes A
and D are more common in African Americans and whites, whereas
HBV genotypes B and C are more common among persons of Asian
ancestry (El-​Serag, 2012).
Natural History of HBV Infection
As shown in Table 24–5, in acute HBV infection, HBsAg is usually
the first marker detected, appearing within the first few weeks of infec-
tion. Anti-​HBcAG also appears during the early phase of infection,
with IgM-​specific antibody being a characteristic of acute infection
and declining within about 6 months, whereas anti-HBc IgG generally
persists indefinitely as a marker of past infection. As HBV is cleared,
antibody against HBsAg becomes detectable about 8 months after
infection and subsequent to the disappearance of HBsAg. HBeAg is
present at about the same time as HBsAg and then is lost after a few
days to weeks, with subsequent seroconversion to antibody against
HBeAg.
Chronic carrier state of infection is marked by the presence of
HBsAg for more than 6 months. In chronic HBV infection, HBsAg,
along with antibodies to HBc, remains persistently detectable, and
anti-​HBsAg does not develop. About 10%–​15% of HBV chronic car-
riers lose their HBeAg per year and seroconvert to anti-​HBe seropos-
itivity (Evans et al., 1997). HBsAg can disappear at a very low rate of
< 1% annually. HBV can become integrated into the host genome over
the course of chronic infection and represents an important step toward
hepatocarcinogenesis (IARC, 2012a).
The probability of chronic HBV infection is inversely related to
the age at which infection occurs (IARC, 2012a). Around 80%–​90%
of infants born to infected mothers become chronic carriers, as is
the case in endemic areas in Asia, whereas less than 10% of adoles-
cents and adults infected through sexual and parenteral routes will
develop a persistent infection, as is the case in areas of low HBV
prevalence. In Sub-​Saharan Africa, HBV transmission mainly occurs
in childhood.
 47

Infectious Agents 447
Table 24–​5. Typical Serological Patterns in Hepatitis B Virus Infection

Anti-​HBc

Infection Status HBsAg IgM Total HBeAg Anti-​HBe Anti-​HBs

Acute infection* + + + + − −
Chronic infection with high levels of viral replication + − + + − −
Chronic infection with low levels of viral replication† + − + − + −
Recovery from acute infection before development of anti-​HBs − + + − + −
Low titer; possible false positive − − + − − −
High titer; possible “low-​level carrier” − − + − + −
Recovery from acute infection, indicating immunity − − + − + +
Vaccine response‡ − − − − − +
Susceptible to HBV infection − − − − − −

Anti-​HBs: antibody to hepatitis B surface antigen; HBV: hepatitis B virus; HBsAg: hepatitis B surface antigen; anti-​HBc: antibody to hepatitis B core antigen; HBeAg:
hepatitis B envelope antigen; anti-​HBe: antibody to hepatitis B envelope antigen.
* Reactivated chronic disease may have this pattern with sensitive anti-​HBc IgM assays.
†
Some patients may be seronegative for HBeAg and anti-​HBe.
‡
In unvaccinated individuals, a high titer may represent immunity or be nonspecific; low titers are often nonspecific.

About 70%–​90% of chronic HBV carriers remain asymptomatic Hepatocellular Carcinoma

(IARC, 2012a). However, 10%–​30% develop chronic persistent or
chronic active hepatitis. Of those carriers with chronic active hep-
atitis, approximately 1%–​ 2% per year will progress to cirrhosis.
Hepatocellular carcinoma (HCC) develops at an annual rate of 1%–​6%
among those with cirrhosis. The latent period from infection to HCC
ranges from 30 to 50 years.
Epidemiology of HBV Infection
HBV is primarily a blood-​borne infection that is transmitted by per-​
cutaneous and mucosal routes. The major modes of infection are via
sexual, parenteral, and perinatal exposure. Multiple partners and a
history of sexually transmitted diseases appear to increase the risk of
infection (IARC, 1994a). Transfusion as a cause of HBV and HCV
has decreased dramatically in the past two decades since screening
has become increasingly sensitive and more cost-​effective. Parenteral
exposure often can occur via injection drug use and occasionally dur-
ing tattooing and body piercing. Medical personnel are at risk of HBV
transmission by contaminated needlesticks or other injuries with sharp
instruments. Since HIV and HBV have similar modes of transmission,
coinfection is quite common.
Perinatal infection, usually by contact with maternal blood during
delivery and possibly in utero, is an important transmission route in
high-​endemic areas, particularly in China and other parts of Southeast
Asia, where up to half of the chronic infections are due to neonatal
transmission (IARC, 2012a). Horizontal transmission of HBV also
occurs in childhood. In developing countries, the use of nondispos-
able, contaminated needles and syringes still plays a role in HBV
transmission (Dondog et al., 2011). In non-​endemic areas, transmis-
sion occurs mainly during adulthood and adolescence, with sexual
contact and parenteral exposure as the predominant modes of HBV
infection.
Approximately 5% of the world population (350–​ 400  million
people) has chronic HBV infection (McGowan et  al., 2015). In the
United States, 0.33% of the population has been estimated to be HBV
chronic carriers, based on data from NHANES III, conducted from
1988 to 1994 (McQuillan et al., 1999). Men are more likely to have
been infected than are women. Non-​Hispanic blacks (12.8%) have
higher levels of ever infection than do non-​Hispanic whites (2.8%)
and Mexican Americans (4.8%).
Types of Cancer Caused by HBV
Chronic HBV is a firmly established cause of HCC. The estimated
number of cancers caused by HBV is 420,000 per year (Table
24–2). Positive associations have been also reported between
HBV and both cholangiocarcinoma and non-​Hodgkin lymphoma
(IARC, 2012a).
Chronic HBV infection accounts for approximately 50% of total HCC
cases, and virtually all of childhood HCC (IARC, 2012a). It is the
dominant risk factor in most areas of Asia and Sub-​Saharan Africa
that have high incidence of HCC (de Martel et al., 2015a), with the
exception of Japan, where the major risk factor for HCC is chronic
HCV infection. HBsAg seroprevalence among persons with HCC
(i.e., a proxy of HBV attributable fraction) varies widely; for exam-
ple, it is less than 10% in HCC in Sweden and the United States,
and between 10% and 20% in Japan and most European countries
except Greece and Russia (> 40%). The largest proportion of HBV-​
associated HCC can be found in Asia, primarily in China and Korea
(> 70%), and in some Sub-​Saharan African countries (de Martel et al.,
2015a). HBV is estimated to cause 420,000 cases of HCC each year
(Table 24–2).
A meta-​analysis of case-​control and prospective studies indicated
that the lifetime relative risk (RR) for HCC is 15–​20 among HBsAg-​
positive individuals, compared with HBsAg-​negative individuals (Cho
et  al., 2011). Cohort studies estimate HCC incidence rates among
subjects with chronic HBV infection to be 0.02–​0.2 per 100 person-​
years in inactive carriers, 0.3–​0.6 per 100 person-​years for those with
chronic HBV infection without cirrhosis, and 2.2–​3.7 per 100 person-​
years for those with compensated cirrhosis (El-​Serag, 2012; Fattovich
et al., 2008).
Mechanisms of Carcinogenesis
As much as 80% of HCC is observed to occur in conjunction with cir-
rhosis (Okuda et al., 1982). Chronic HBV-​induced necro-​inflammatory
disease can lead to HCC through continuous cycles of hepatocyte
necrosis and regeneration that promote acquired mutations existing
in the liver cells (reviewed in IARC, 2012a). By virtue of its ability
to integrate into the host genome, HBV can initiate and potentially
cause mutation, as well as promote hepatocarcinogenesis via constant
immune-​mediated inflammation and cell turnover (Tabor, 1994). The
smallest HBV protein HBx is essential for viral replication and can
adversely modulate the turnover of cellular proteins involved in cell-​
cycle regulation.
Parameters That Influence Risk
Several demographic, viral, clinical, and environmental factors
increase HCC risk among individuals with chronic HBV infection.
Male HBV carriers are at a higher risk of HCC (as well as of cir-
rhosis) than are female carriers (Evans et al., 2002). Although some
of the gender differences may be due to higher prevalence of other
cofactors in men (e.g., high alcohol or tobacco consumption), endog-
enous hormones may also play a role. Cohort studies in Shanghai and
48
448 PART III:  THE CAUSES OF CANCER
Taiwan found a 50% to fourfold increase in rate of HCC for men in
the highest tertile of testosterone level (Yuan et  al., 1995). A study
in Taiwan found an association between fewer CAG repeats in the
androgen receptor gene and the incidence of HCC in male HBV car-
riers (Yu et al., 2002). Studies of HBV infection in transgenic mice
demonstrated that the androgen pathway can increase the transcrip-
tion of HBV genes (Yeh and Chen, 2010).
The risk of HCC is increased in patients with high levels of HBV
replication, determined by tests for HBeAg and levels of HBV DNA.
In a study among 11,893 Taiwanese men followed over a mean of
8.5 years, the incidence rate of HCC was 1169 per 100,000 person-​
years among men who were HBsAg-​positive and HBeAg-​positive, 324
per 100,000 person-​years for those who were only HBsAg-​positive,
and 39 per 100,000 person-​years for those who were HBsAg-​negative
(Yang et al., 2002). A community-​based Taiwanese prospective study,
the Risk Evaluation of Viral Load Elevation and Associated Liver
Disease/​Cancer–​HBV (REVEAL-​HBV), reported that in a cohort of
3653 HbsAg-​positive participants, the incidence of cirrhosis and HCC
increased in proportion to the serum level of HBV DNA, from < 300
(undetectable) to ≥ 1,000,000 copies/​mL. Studies with sensitive ampli-
fication assays have shown that HBV DNA can persist in serum or
liver, as an occult HBV infection, among persons who have serological
recovery from transient HBV infection (Huo et al., 1998). The stud-
ies arrived, however, at inconsistent findings (Shi et al., 2012), and in
aggregate there is no convincing evidence that occult HBV is an inde-
pendent risk factor for HCC or a cofactor with HCV infection in most
regions of the world (Lok et al., 2011).
In studies performed in Asia, there is a greater association between
genotype C infection and severe liver disease, cirrhosis, and HCC
than genotype B; in Western Europe and North America, individuals
with genotype D had a greater incidence of severe liver disease or
HCC than those with genotype A (Huang and Lok, 2011). Mutations
in the region of the HBV genome that encode the basal core promoter,
such as T1762 and A1764 (Liu et  al., 2006), have been associated
with increased incidence of HCC, whereas those in the precore region
(G1896A) have been associated with decreased incidence of HCC
(Yang et al., 2008).
Meta-​analyses of studies from various countries (Donato et  al.,
1998; Shi et al., 2005) reported additive effects of HBV and HCV
on HCC risk, but a sub-​additive effect was seen in more recent stud-
ies (2000–​2009), cohort studies, and studies conducted in areas
in which HBV and HCV infection were not common (Cho et  al.,
2011). A  sub-​additive effect may be explained by a negative cor-
relation between the detection of anti-​HCV and HBsAg in the same
individuals, suggesting virus interference (Donato et  al., 1998;
Thomas et al., 2000).
The consumption of alcohol is known to be hepatotoxic, although
not necessarily mutagenic (IARC, 2012d). Several studies suggest that
a more than additive effect of heavy alcohol consumption and chronic
HBV infection exists with respect to the development of HCC (Donato
et  al., 2002). A population-​based cohort study performed in Korea
found that among individuals with chronic HBV infection, the risk for
HCC increased significantly among subjects with an alcohol intake of
50 g/​day or more, with a relative risk of 1.2 for 50–​99 g/​day and of 1.5
for > 100 g/​day (Jee et al., 2004). Most studies have found a small but
positive significant interaction between increased smoking and HBV
infection for HCC (Chuang et al., 2010; IARC, 2012d).
Aflatoxin B1 (AFB1) is a mycotoxin produced by fungi of the
Aspergillus species that grows on foods such as corn and peanuts
stored in warm, damp conditions. AFB1 causes a mutation at serine
249 in the tumor suppressor gene TP53 that was detected in 30%–​
60% of HCC tumor samples collected from individuals in aflatoxin-​
endemic areas, most of whom had HBV infections (IARC, 2012c).
AFB1 in the pathogenesis of HCC is primarily mediated by its effects
on chronic HBV infection.
Host genetic factors might account for some of the variation in
the risk of developing cirrhosis or HCC. A meta-​analysis of variants
of glutathione S-​transferase (GST) genes, phase II isoenzymes that
protect against the endogenous oxidative stress causing deletions in
GSTM1 and GSTT1, indicated that forms of GSTM1 or GSTT1 that do
not produce a functional product (null genotypes) slightly increased
risk for HCC. Polymorphisms in tumor necrosis factor-​α (TNFα), IL-​
1B, and IL-​10 have also been associated with the risk for HCC (Yang
et al., 2011).
HCC risk scores for HBV-​infected patients are based on age, sex,
level of alanine aminotransferase, viral HBV load, HBeAg status, and
the presence of cirrhosis, or on the presence of cirrhosis and core pro-
moter mutations (Abu-​Amara et al., 2015). HCC risk scoring systems
for patients receiving antiviral therapy with adequate viral suppression
require further evaluation (Wong and Janssen, 2015) and possibly in
different populations.
Prevention
HBV vaccination is the main method of primary HCC prevention.
However, in patients already infected with chronic HBV, antiviral
treatment is the main method of secondary prevention. Currently,
there are five nucleoside analogues (NA) approved for the treatment
of patients with chronic HBV that can suppress HBV-​DNA suc-
cessfully in almost all patients. Lamivudine monotherapy has long
been used and is associated with ALT normalization, HBV-​DNA
suppression, HBeAg seroconversion, and histological improvement
in the long term. However, the development of resistant strains of
HBV has been a major problem for lamivudine, whereas telbivudine,
adefovir, entecavir, and tenofovir disoproxil have shown low rates
of drug resistance. Entecavir and tenofovir disoproxil are currently
the recommended first-​line medications (World Health Organization
[WHO], 2015).
A meta-​analysis of cohort studies and clinical trials indicated
beneficial effects of medium-​term NAs in the prevention of HCC
in chronic HBV, although treatment does not completely eliminate
the infection and HCC risk (Papatheodoridis et al., 2010). The three
studies including untreated controls detected HCC significantly
less frequently in treated than in untreated patients (2.8% vs. 6.4%,
respectively, P = 0.003). The rate of HCC was significantly higher
in lamivudine-​resistant than in NA-​naïve patients. Achievement of
virological response at rescue therapy did not significantly reduce
HCC risk in lamivudine-​resistant patients, suggesting that the main-
tenance of long-​term viral suppression is needed for cancer preven-
tion (Papatheodoridis et al., 2010).
Less data exist on HCC risk reduction with entecavir or tenofovir
than with lamivudine. In a large retrospective nationwide chronic
HBV cohort from Taiwan, the investigators included 21,595 matched
patients in the treatment and control groups. Although most patients
were treated with lamivudine, 5748 patients received 0.5 mg/​ day
entecavir. The entecavir-​treated cohort had a significantly lower 7-​
year incidence of HCC (7.3%; 95% CI = 6.8%–​7.9%) than controls
(22.7%; 95% CI = 22.1%–​23.3%) (Wu et al., 2014). In Japan, inves-
tigators found a significantly reduced risk of HCC in the entecavir-​
treated group compared to a matched historical cohort of untreated
patients. Five-​year incidence rates of HCC were 3.7% and 13.7%,
respectively (Hosaka et al., 2013).
HEPATITIS C VIRUS
Hepatitis C virus (HCV) is a small, enveloped RNA virus classified
as a separate genus in the Flaviviridae family, which includes yel-
low fever, dengue, and hepatitis G virus (reviewed in IARC, 2012a).
The positive-​sense, single-​stranded viral genome codes for the core
nucleocapsid protein, two envelope (E) glycoproteins (E1, E2), and six
nonstructural (NS) proteins (NS2, NS3, NS4A, NS4B, NS5A, NS5B).
With respect to the nonstructural proteins, NS2, NS3, and NS4A have
protease functions, with NS3 also demonstrating RNA helicase activ-
ity; NS5B functions as an RNA-​dependent RNA polymerase and is
important in genome replication. There are at least 6 HCV genotypes
which differ in 30%–​35% of nucleotides. There are also several sub-
types; HCV subtypes 1a and 1b are the most common in the United
States and Europe, whereas in Japan > 70% of HCV-​infected individu-
als carry subtype 1b.
 49
Infectious Agents 449
Natural History of HCV Infection
In acute HCV infection, virus RNA is detectable within 2 weeks of
exposure. A few weeks later, serum alanine aminotransferase (ALT)
levels begin to rise, with symptoms occurring soon after. Antibodies
against HCV become detectable about 8–​12 weeks after exposure, but
HCV RNA is detectable by reverse-​transcriptase PCR (RT-​PCR) 5–​6
weeks earlier (reviewed in IARC, 2012a).
Most newly acquired infections (75%–​85%) become chronic, as
demonstrated by the persistence of HCV RNA, the main biomarker
of active infection, for more than 6 months. In general, persistence of
infection is less frequent in women, younger persons, and individuals
with symptomatic acute infection (Armstrong et al., 2006) and more
frequent in African Americans and in persons with immunodeficiency.
Epidemiology of HCV Infection
The World Health Organization (WHO) estimates that approximately
3% of the world’s population is infected with HCV, and this varies con-
siderably among the different regions (Mohd et al., 2013). The highest
reported level of infection is in Egypt (Mohamoud et al., 2013), with
estimates of 20%–​30%, as well as in Pakistan (Umar et al., 2010) and
Mongolia (Dondog et al., 2011). Intermediate prevalence, up to 10%,
is found in some parts of Italy (Hahne et al., 2013) and of China (Gao
et  al., 2011). In the United States, HCV infection rose dramatically
through the 1970s and 1980s and showed a disproportionally high
burden among Americans born from 1945 to 1965. Anti-​HCV preva-
lence in this birth cohort was 3.2% (95% CI = 2.8%–​3.8%), substan-
tially higher than among adults born before 1945 or after 1965 (0.9%)
(Smith et al., 2014). Within the 1945–​1965 cohort, anti-​HCV preva-
lence was significantly higher among non-​Hispanic blacks (adjusted
OR = 2.3), income below poverty threshold (adjusted OR = 4.7), and
among those who reported blood transfusion before 1992 (adjusted
OR = 2.3) or intravenous drug use (adjusted OR = 98.4) (Smith et al.,
2014). Based on phylogenetic studies, HCV began to infect large num-
bers of young adults in Japan in the 1920s, in southern Europe in the
1940s, and in North America in the 1960s and 1970s (Mizokami and
Orito, 1999; Tanaka et al., 2006). High HCV prevalence has also been
recently reported in the Russian Federation (3% overall, and > 8% in
the 15–​44 age group) (Saraswat et al., 2015).
Prior to the screening of the blood supply for anti-​HCV, which
began in 1990 in the United States and Europe but much later in low-​
income countries, transfusion of contaminated blood and blood prod-
ucts was an important source of transmission (Alter and Seeff, 2000).
Injecting drug use represents the most frequently reported risk fac-
tor for HCV infection in the United States and many other countries
(Alter and Seeff, 2000; Nelson et al., 2011). Intranasal cocaine use,
tattooing, body piercing, and sharing of razors are also possible routes
of HCV transmission (Alter and Seeff, 2000).
Other percutaneous exposures associated with the transmission of
HCV include hemodialysis, organ transplantation, and accidental nee-
dle sticks in the health-​care setting (Alter and Seeff, 2000). In Egypt,
transmission likely resulted from insufficiently sterilized syringes
during the mass schistosomiasis intervention efforts (Frank et  al.,
2000). Transmission of HCV by the sexual route (Terrault, 2002) and
from mother to child (Roberts and Yeung, 2002) is rare although also
possible.
Types of Cancer Caused by HCV
Chronic HCV is a firmly established cause of HCC and non-​Hodgkin
lymphoma. The estimated number of cancers caused by HCV is
170,000 per year (Table 24–2). Positive association have been also
reported for cholangiocarcinoma (IARC, 2012a).
Hepatocellular Carcinoma
HCV infection accounts for approximately 20% of total HCC cases
worldwide. The risk of HCC in persons with HCV infection is substan-
tial, with RRs > 10 found in several cohort studies. Once HCV-​related
cirrhosis is established, HCC develops at an annual rate of 1%–​8%,
thus making cirrhosis an important precancerous condition. Most
cases of HCV-​related HCC occur among patients with advanced fibro-
sis or cirrhosis (de Mitri et al., 1995; Haydon et al., 1995). The inci-
dence of cirrhosis 25–​30 years after HCV infection ranges from 15%
to 35% (Freeman et  al., 2001), and is highest among recipients of
HCV-​contaminated blood products and hemophiliacs.
The relative burden of HCV in HCC, in absolute terms and in relation to
the burden of HBV, greatly varies worldwide. Egypt has the highest pro-
portion of HCC attributable to HCV (80% HCV only and 8% co-​infected
with HBV) (de Martel et al., 2015a). With the exception of Greece, where
HBV is dominant, European countries show a preponderance of HCV
over HBV (HCV close to 60% of all HCC in Italy and Spain) and also
a substantial fraction of viral marker negative cases (from 21% in Italy
to 82% in Sweden). A  preponderance of HCV is noted in most South
American countries and in the United States. In Asia, a large predomi-
nance of HCV infection in HCC is found in Japan (65%) and Pakistan
(54%). Mongolia and Taiwan also show a rather high prevalence of HCV
though inferior to that of HBV. In the last decade or two, the relative con-
tribution of HCV to HCC burden is declining in some countries impacted
by the earliest HCV epidemics, notably in Japan, but increasing in others
(e.g., the United States, Taiwan, and Egypt) (de Martel et al., 2015a).
Non-​Hodgkin Lymphoma
A number of extrahepatic malignancies have been associated with
HCV infection, especially non-​Hodgkin lymphoma. Case-​control stud-
ies and cohort studies found approximately two-​fold increased risk of
non-​Hodgkin lymphoma in HCV-​seropositive individuals (Giordano
et  al., 2007; IARC, 2012a). No clear or consistent difference was
found by histologic subtype or according to nodal or extra-​nodal pre-
sentation. Remission of non-​Hodgkin lymphoma in HCV-​seropositive
cases subsequent to treatment of the infection has also been reported.
The fraction of non-​Hodgkin lymphoma attributable to HCV infection
varies greatly by country but may be upward of 10% in areas where the
prevalence of the infection is high (Dal Maso and Franceschi, 2006).
Mechanisms of Carcinogenesis
As a nonintegrating virus, HCV is not likely to act as a cancer initiator.
As up to 90% of HCV-​associated HCC arises within a cirrhotic liver
(Alter and Seeff, 2000), HCV infection may lead to cancer through a
promoting process of recurring cycles of cell death and regeneration,
as would occur with cirrhosis. HCV is also thought to induce liver
steatosis by impairing lipid metabolism. The mechanisms by which
lymphoma is induced by HCV is ill understood, but a role for the con-
tinuous activation of B-​cells by chronic HCV infection is probable
(reviewed in IARC, 2012a).
Parameters That Influence Risk
Among HCV-​infected individuals, risk factors for HCC include dem-
ographic characteristics, viral factors, and lifestyle factors (El-​Serag
et al., 2014). There is strong evidence for a synergistic effect between
heavy ingestion of alcohol and HBV/​HCV infection, and this is greater
for HCV (these factors presumably operating together to promote cir-
rhosis) (Donato et  al., 2002; Hutchinson et  al., 2005). Among alco-
hol drinkers, HCC risk increased in a linear fashion with daily intake
> 60 g (Donato et  al., 2002). Concomitant HCV infection led to an
additional two-​fold increase in risk of HCC (Figure 24–13). The rela-
tionship between cigarette smoking and HCC has been established
in several studies among subgroups defined by HBV or HCV status
(IARC, 2012d).
Insulin resistance is associated with increased risk of hepatic steato-
sis, advanced fibrosis, and HCC among patients with HCV infection.
There is a significant (68%) increase in diabetes among HCV-​infected
individuals, compared with noninfected individuals, based on retro-
spective and prospective studies (El-​Serag et  al., 2006). However, a
few studies have found that HCV and diabetes synergize to increase the
risk of HCC (Arase et al., 2013; El-​Serag et al., 2006). Drinking coffee
450
450 PART III:  THE CAUSES OF CANCER
With HCV infection
20 With HBV infection
Without HBV and HCV infection
15
10
5 However, the public health impact of HCV treatment has yet to be
Odds ratio
1 the number of HCC cases by 30% versus 60%, respectively, over the
40 60 80 100 120 140
Alcohol intake (g/day)
Figure  24–​13. Odds ratios for hepatocellular carcinoma, according to
alcohol intake and the presence of hepatitis B virus (HBV) or hepatitis C
virus (HCV) infection. The plot was obtained by fitting spline regression
models on data obtained in Brescia, Italy, 1995–​2000.
Reprinted from El-​Serag, H.B., Epidemiology of viral hepatitis and hepatocel-
lular carcinoma, Gastroenterology 142 (2012), 1264–​1273.e.1, with permis-
sion from Elsevier. (Modified from Donato F, Tagger A, Gelatti U, Parrinello
G, Boffetta P, Albertini A, Decarli A, Trevisi P, Ribero ML, Martelli C, Porru
S, and Nardi G, Am J Epidemiol 155 [2002], 323–​331, with permission from
Oxford Journals.)
(though not decaffeinated coffee or tea) and the use of statin medications
(El-​Serag et al., 2009) have been associated with a reduction in HCC
risk among people with and without viral hepatitis (Bravi et al., 2013).
Viral factors are less influential on HCC risk for HCV than HBV.
Most studies from the United States and Europe have not found a cor-
relation between viral load counts and risk of HCC. Studies from the
United States reported that genotype 3 infection is associated with
higher risk of cirrhosis and HCC than other genotypes (Kanwal et al.,
2014). A  meta-​analysis of 21 studies reported that patients infected
with HCV genotype 1b had an almost two-​fold greater risk of devel-
oping HCC than patients with other HCV genotypes (Raimondi et al.,
2009). However, genotypes 1 are reported to respond more favorably
to antiviral treatment than other genotypes. Persons co-​infected with
HIV have faster progression to cirrhosis and decompensated liver dis-
ease, and the risk increase is correlated with the severity of immuno-
suppression (Clifford et al., 2008; Kramer et al., 2007).
Prevention
Successful HCV treatment has been reported to slow liver disease pro-
gression and reduce the risk of cirrhosis and HCC. Randomized con-
trolled studies and several non-​randomized studies of HCV-​infected
patients with and without cirrhosis indicate a 57%–​75% reduction in
risk of HCC in patients who received interferon-​based therapy and
achieved a sustained viral response (SVR) or virologic cure (Morgan
et al., 2013). Successful HCV treatment reduces but does not eliminate
HCC risk. Approximately 1.5% of patients with SVR develop HCC,
compared with 6.2% of those who did not respond. SVR was asso-
ciated with a similar reduction in the risk for HCC in patients with
cirrhosis: approximately 4.2% of patients with SVR developed HCC
compared to 17.8% of those without SVR (hazard ratio [HR] = 0.23;
95% CI  =  0.16–​0.35). Persons with cirrhosis or those of older age,
or persons with high levels of α-​fetoprotein, low platelet counts, high
stages of fibrosis, or diabetes, remain at risk for HCC (Arase et  al.,
2013; Chang et al., 2012). However, disabling side effects are associ-
ated with interferon-​based treatments.
The introduction of new but costly interferon-​free direct-​acting anti-
viral agents (DAAs) in 2014 has brought cure rates of more than 90%
and minimal side effects. For example, the combination of pan-​geno-
typic nucleotide polymerase inhibitor (sofosbuvir) with NS5A inhibi-
tor (ledipasvir or daclatasvir), and the combination of NS3/​4A protease
inhibitor (ABT-​450/​ritanovir) and a non-​nucleoside polymerase inhib-
itor (dasabuvir) with and without ribavirin have been approved and
recently have been used in the clinical setting with remarkable success.
realized. Data from the United States and Europe show that fewer than
20% of HCV-​infected patients are ever treated (Kanwal and El-​Serag,
2014) due to a combination of lack of screening for HCV carriage,
and limited availability and affordability of DAAs. Modeling studies
found that treatment of half versus all infected persons would reduce
next decade (Davis et al., 2010). Initiatives such as systematic screen-
ing for HCV of the highest-​risk birth cohorts (1945–​1965) have been
launched in the United States to increase HCV detection and linkage
to care (Smith et al., 2014).
EPSTEIN-​BARR VIRUS
Nature of the Exposure
Epstein-​Barr virus (EBV), or human herpesvirus 4, is a gamma herpes-
virus of the Lymphocryptovirus genus and was the first human tumor
virus to be identified (Epstein et al., 1964). Like all herpesviruses, it has
a linear double-​stranded DNA genome, within a lipid envelope, which
exists mainly in episomal form within infected cells. EBV exhibits
substantial heterogeneity across the genome, and there are two major
types (EBV-​1 and EBV-​2), differing in relation to genes that code for
nuclear antigens. EBV-​2 immortalizes B cells less efficiently than
EBV-​1 in vitro (reviewed in IARC, 2012a). While almost all primates
have EBV-​like viruses, humans are the only natural host for EBV, in
whom it establishes latent infection within lymphocytes, primarily B
lymphocytes but also T lymphocytes or, on occasion, epithelial cells.
In culture, EBV is the most potent transforming human virus,
although more than 90% of those infected develop no disease.
Transmitted via saliva, EBV enters the epithelium of Waldeyer’s ton-
sillar ring in the oropharynx and from there it infects naïve B cells
in lymphoid tissue. Primary infection provokes cellular immune
responses, which rapidly remove EBV-​infected cells—​EBV can per-
sist only in resting memory B cells in which no viral proteins are
expressed in immunocompetent individuals. These memory B cells
can return to the tonsil, where they occasionally trigger viral replica-
tion; the resulting virus may be released into saliva for onward trans-
mission (Thorley-​Lawson and Allday, 2008).
Detection of antibodies against EBV in biological fluids has been
the major means of diagnosis, and characteristic patterns of serologi-
cal response denote primary infection, latent infection, reactivation, or
specific disease states (reviewed in IARC, 2012a). EBV DNA can be
detected in the blood or saliva of healthy carriers, although it is more
often found in those with EBV-​related disease. In such individuals,
it can also be identified in tumor tissue and occasionally as cell-​free
DNA in sera.
Epidemiology of EBV Infection
Worldwide, more than 90% of adults have antibodies against EBV,
although the age at which primary infection occurs varies substan-
tially. In Uganda for example, by age 1 year, 80% of children are
infected, compared to only about 45% in rural United States. Primary
infection during early childhood is usually subclinical or associated
with mild respiratory symptoms. However, about 50% of those among
whom infection is delayed into older age develop infectious mono-
nucleosis (IM) (IARC, 1997). At all ages, transmission is primarily
oral, although infection via contaminated blood transfusion has also
been demonstrated. Early age at infection with EBV is the norm in
low-​and middle-​income settings and is associated with lower soci-
oeconomic status and crowding. Delayed infection is more common
in high-​ income countries. Balfour et  al. (2013) followed college
 451
Infectious Agents 451
students in the United States (37% of whom were EBV-​negative) and
reported that 75% of primary EBV infections were associated with
IM. Although the disease (125,000 new cases per year in the USA)
is usually self-​limiting, 10% of patients have fatigue that persists for
6  or more months, and about 1% of cases result in severe compli-
cations including encephalitis, hepatitis, severe hemolytic anemia, or
thrombocytopenia (Cohen et al., 2013).
Types of Cancer Caused by EBV
EBV is a firmly established cause of Burkitt lymphoma, Hodgkin
lymphoma, nasopharyngeal carcinoma, immune-​suppression-​related
non-​Hodgkin lymphoma, and extra-​nodal NK/​T-​cell lymphoma (nasal
type). The estimated number of cancers caused by EBV is 120,000
per year (Table 24–2). There is limited evidence of causality for a pro-
portion of gastric cancer and for lympho-​epithelioma-​like carcinoma
(IARC, 2012a).
Burkitt Lymphoma
There are three distinctive clinical variants of the aggressive B-​cell
non-​Hodgkin lymphoma, Burkitt lymphoma (BL): so-​called endemic
BL (eBL, found in areas of Falciparum malaria endemicity), sporadic
(the predominant type in non-​malarial areas), and immunodeficiency-​
related. It was the first human tumor associated with an infection
(Burkitt, 1962), the first shown to have a chromosomal translocation
that activates an oncogene, and the first childhood tumor success-
fully treated with chemotherapy alone (Molyneux et al., 2012). It is
also the fastest-​growing human tumor, with a cell doubling time of
24–​48 hours, and the most common childhood cancer in areas where
Falciparum malaria is holoendemic, particularly across parts of Sub-​
Saharan Africa and Papua New Guinea.
A direct causal role for EBV in eBL is indicated by its consistent
presence in tumors; the fact that infection of B cells precedes tumori-
genesis; that EBV induces immortalization of B cells in culture;
and that high anti-​EBV antibody titers precede disease development
(reviewed in IARC, 2014).
Hodgkin Lymphoma
The proportion of EBV-​positive Hodgkin lymphoma (HL) varies with
age, sex, geographical area, and histological subtype (reviewed in
IARC, 2012a). EBV is more commonly associated with nodular scle-
rosis and mixed cellular subtypes in all world regions (Stein et  al.,
2008). The bimodal age distribution of HL has a different shape in
more developed versus less developed countries. In less developed
countries, the first peak of HL incidence is seen well before the age of
15, and virtually all cases of pediatric HL are EBV-​related. In more
developed countries the first peak of HL is seen between the ages of
15 and 35. In both areas, a second peak is often seen in older adults.
In addition to the presence of monoclonal EBV genomes in malignant
cells, epidemiological evidence for an association with HL includes
a roughly four-​fold increase in risk of disease among those who
have been previously diagnosed with IM, together with a substantial
increase in risk of disease among those with higher titers of antibod-
ies against EBV. Increasing prevalence of detectable EBV-​DNA in
serum has also been associated with risk of HL (IARC, 1997, 2012a).
Finally, in the HIV-​positive population, the vast majority of HL is
EBV-​related and mainly consists of mixed cellular subtypes (Stein
et al., 2008).
Nasopharyngeal Carcinoma
A striking association of nasopharyngeal carcinoma (NPC) with
EBV was first identified in 1966 (Old et  al., 1966). NPC is a rare
cancer worldwide but shows exceptionally high incidence rates (10
to 30 per 100,000 men) in Southern China, Singapore, and Malaysia.
Intermediate incidence rates are found in the Arctic, Middle East,
Southeast Asia, and North Africa (Chang and Adami, 2006). EBV
genome or gene products have been detected in virtually all cases of
undifferentiated non-​keratinizing squamous cell carcinoma (histologic
type III), irrespective of the geographic origin (IARC, 2012a; Barnes
et al., 2005). Type III comprises over 95% of NPC in high and interme-
diate incidence areas. The development of IgA to EBV viral capsid or
EBV-​DNAs in serum or saliva correlates with an approximate 20-​fold
increased NPC risk (Cohen et al., 2013).
Gastric Cancer
A meta-​analysis of international literature showed that about 9% of
gastric cancer contains EBV (Murphy et  al., 2009). According to a
subsequent pooled analysis (Camargo et  al., 2011), EBV-​positivity
in gastric cancer cases was significantly higher in males, young sub-
jects, non-​antral subsites, diffuse-​type histology, and in studies from
the Americas. Findings from the The Cancer Genome Atlas Research
Network (2014) threw additional light on the issue, recognizing EBV-​
positive gastric cancer as one of the four subtypes of a new molecular
classification of gastric adenocarcinoma, but the relationship between
EBV and H.  pylori, the main cause of cancer and precancerous
lesions in the stomach, is unclear. Serologic profiles suggest a role
for H.  pylori in both EBV-​positive and EBV-​negative gastric cancer
(Camargo et al., 2015), and EBV may contribute with H. pylori to the
induction of severe inflammation and cancer progression (Cardenas-​
Mondragon et  al., 2015). When EBV was evaluated by the IARC
monograph program, epidemiological evidence for a causal role in
EBV-​positive gastric cancer was considered insufficient, despite posi-
tive mechanistic data (IARC, 2012a).
Immune-​Suppression-​Related Non-​Hodgkin
Lymphoma
Immune suppression, whether inherited, iatrogenic, or HIV-​related,
is associated with an increased risk of EBV-​ related lymphomas.
In 1969, McKhann and Penn reported independently on post-​trans-
plant lymphoproliferative disorders, which are now recognized to be
either polyclonal EBV-​driven lymphoproliferations or true monoclo-
nal malignancies. The risk is highest among previously EBV-​negative
children seroconverting after organ transplant possibly via the graft
(IARC, 1997). Immunosuppression caused by HIV is also strongly
associated with a range of EBV-​driven lymphomas. In addition to BL
and HL, diffuse large B-​cell lymphoma (DLBCL) is strongly asso-
ciated with HIV (IARC, 2012a). The risk of DLBCL, especially in
the central nervous system, is strongly correlated with the severity of
immunosuppression (CD4+ count) (IARC, 2012a). The introduction
of combined antiretroviral treatment (cART) was therefore associated
with a striking decline in EBV-​associated non-​Hodgkin lymphoma
incidence in HIV-​infected individuals. A record-​linkage study between
HIV/​AIDS registries and cancer registries in the United States sug-
gested, however, that also in the late-​cART era 12% of all cancers in
HIV-​infected individuals (with or without AIDS) were still attributable
to EBV (de Martel et al., 2015b).
Other Cancers
EBV is also an established cause of the rare extranodal NK/​T-​cell
lymphoma (nasal type), found most commonly in Central and South
America and in East Asia. A rare form of carcinoma with histological
similarities to NPC has also been linked to infection with EBV (IARC,
1997, 2012a). Such lymphoepithelial-​like carcinomas can occur at
multiple organ sites with epithelial linings, but most frequently in the
salivary gland and in the stomach.
Mechanisms of Carcinogenesis
Infection with EBV has been shown to induce a number of steps in
the process of malignant transformation. In particular, EBV immortal-
izes B cells in culture and EBV-​encoded gene products induce cell
proliferation, block apoptosis, induce genomic instability, and cause
cell migration. Several of these products are also associated with main-
tenance of malignant cell growth and tumor progression. A  number
of EBV gene products (i.e., EBV latent membrane proteins 1 and 2
[LMP1, LMP2]) and EBV nuclear antigens 1, 2, 3 (EBNA-​1–​3), are
expressed in EBV-​associated cancers according to distinct patterns
(Latency I, II, and III).
452
452 PART III:  THE CAUSES OF CANCER
Parameters That Influence Risk
The best-​understood cofactor of EBV is immunosuppression, as the
impairment of cell-​mediated immunity allows the spread of reactivated
EBV from memory B cells, which can result in various lymphopro-
liferative disorders (IARC, 2012a) (see Chapter 25 on immunologic
factors). Infections and chronic inflammation can also reactivate
EBV-​infected cells. In addition, the role of other genetic or environ-
mental risk factors in the etiology of many EBV-​associated cancers
is suggested by extreme geographic variations in their incidence. An
association between Falciparum malaria and endemic BL has been
demonstrated in numerous ecological studies that have identified
strong geographical and temporal correlations. More recently, case-​
control studies have demonstrated increased risk of eBL with increas-
ing antibody titers against Plasmodium falciparum (P. falciparum).
The parasitic infection expands the B-​cell pool from which eBL can
emerge, as well as reactivating latent EBV infection (Molyneux et al.,
2012). The association between IM and HL suggests that age at infec-
tion may be an important determinant of risk for certain EBV-​related
malignancies. Various genetic factors have been linked to the devel-
opment of NPC among EBV-​infected people, together with consump-
tion of salted fish during weaning in China, and other preserved food
preparation (e.g., “harissa” in Tunisia) (IARC, 2012a). Although the
association of NPC with tobacco use is firmly established, the strength
of association is weaker for undifferentiated than differentiated NPC
(Polesel et al., 2011).
Future Research
The importance of EBV as a cause of IM and several cancer types,
especially in immunosuppressed individuals, and the lack of specific
antiviral treatment have prompted a National Institutes of Health
(NIH) working group to issue recommendations for future research
and EBV vaccine studies (Cohen et al., 2013). A candidate vaccine
containing soluble glycoprotein gp350 in adjuvants reduced the rate
of IM in EBV-​negative adults, but did not affect the rate of EBV
infection (Sokal et al., 2007). Which combination of viral proteins
would be needed for a vaccine to prevent EBV-​associated malignan-
cies is a research priority. The likely candidates are EBV proteins
expressed in these malignancies (LMP1, LMP2, and EBNA-​1–​3).
The identification of good surrogate markers for cancer develop-
ment and immune correlates of protection against EBV and disease
are additional concerns (Cohen et  al., 2013). The potential for an
EBV vaccine to prevent malignancy could be directly evaluated
in transplant recipients, particularly EBV-​ seronegative children.
However, the prevention of IM may be the most powerful trigger
of further work on EBV vaccine in high-​income countries and,
therefore, a better evaluation of the burden of IM would be essential
to estimate the cost-​benefit of a vaccine against EBV infection or
related diseases.
KAPOSI’S SARCOMA-​ASSOCIATED HERPESVIRUS
Nature of the Exposure
Kaposi’s sarcoma-​associated herpesvirus (KSHV), or human herpes-
virus 8 (HHV-​8), is a gamma-​2 herpesvirus (rhadinovirus)—​the first
to be identified that affects humans (Chang et al., 1994; Moore et al.,
1996). Morphological characteristics are typical of herpesviruses, con-
sisting of a 100–​150 nm particle with a lipid envelope and a double-​
stranded DNA genome within, comprising a single contiguous region
containing all the viral genes, with terminal repeat regions of variable
length on either side. There are at least four major subtypes of KSHV
with a distinctive geographical distribution:  Africa (mainly subtype
B), Mediterranean (C), northern Europe and North and South America
(A), and the Far East (D).
Humans are the natural host for KSHV, in whom it can establish
lifelong latent infection within B cells (reviewed in IARC, 2012a).
Other cell types infected include endothelial and spindle cells of
Kaposi’s sarcoma (KS) lesions, macrophages, dendritic cells, and oro-
pharyngeal glandular epithelium. Lytic reactivation of latently infected
cells results in viral progeny and is normally tightly controlled by
the immune system. This appears to be an important step in disease
pathogenesis.
Diagnosis of the infection is by PCR or serological assays to
detect KSHV antibodies, usually against latent or lytic antigens orf73
and K8.1, respectively (reviewed in IARC, 2012a). ELISAs have
recently been developed using recombinant proteins and peptides.
Concordance between serological assays remains, however, moderate.
While antibody titers are very high in KS patients, titers are so low in
asymptomatic people that establishing a clear assay cutoff is difficult.
Comparison of studies using different assays or cutoffs is therefore
problematic.
Epidemiology of KSHV Infection
KSHV is the human herpesvirus that displays the most marked geo-
graphical variation in prevalence. Prevalence is highest in Sub-​Saharan
Africa (50%–​80% of men and women in most studies), intermediate
in Mediterranean countries (10%–​30%), and generally low (less than
10%) in other parts of the world (Engels et al., 2007). However, there
exist certain high-​risk populations with higher prevalence than in the
general population in those regions, such as among Amerindians in
South America and among men who have sex with men (MSM) in
Europe, Australia, and the United States (reviewed by Minhas and
Wood, 2014).
The main route of transmission of KSHV is via saliva and, in coun-
tries where prevalence is high, primary infection begins in childhood
and continues into adult life. In these settings, prevalence increases
with increasing age and is higher if family members—​ especially
mothers—​are infected (Dedicoat et al., 2004; Whitby et al., 2000). In
lower prevalence settings, transmission is rare among children but, in
adults, is probably still via saliva. There is no clear evidence of het-
erosexual transmission and no relationship between KSHV and being
a sex worker (Malope et al., 2008) or being HPV-​positive (de Sanjosé
et al., 2009). Conversely, among MSM, KSHV infection is very fre-
quent and is strongly associated with recent history of oral and anal sex
(Engels et al., 2007). In addition, KSHV can be detected in blood, and
transmission can also occur via blood transfusion and organ donation
(Minhas and Wood, 2014).
Types of Cancer Caused by KSHV
KSHV is a necessary but not sufficient cause of KS and primary effu-
sion lymphoma (PEL), and probably also of multicentric Castleman’s
disease (IARC, 2012a). The estimated number of cancers caused by
KSHV is 44,000 per year (Table 24–2).
Kaposi’s Sarcoma
KS is a locally aggressive, endothelial tumor that usually presents
with cutaneous lesions in the form of multiple patches or nodules
(Mentzel et  al., 2013). It can also involve mucosal sites, lymph
nodes, and visceral organs, especially in immunosuppressed indi-
viduals. The evidence linking KSHV to the development of KS
(including HIV-​associated, classical, endemic, and transplant-​asso-
ciated variants of the disease) is overwhelming, with over 100 epi-
demiological studies (both prospective and case-​ control, across
diverse populations) showing consistent and strong associations.
All cohort studies have, however, included only immunosuppressed
individuals, mainly HIV-​infected people. Dose–​response relation-
ships are seen between antibody titers against KSHV and risk of
KS, as well as with viral load in blood and risk of KS (reviewed by
IARC, 2012a).
Even before the HIV epidemic (see section on exposure parameters
that influence risk), KS had a much greater geographical variation in
incidence than most other malignancies. In Sub-​Saharan Africa, it
was common (> 6 per 1,000) in a belt that stretched westward and
southward from Uganda into Malawi, but was relatively rare in South
 453
Infectious Agents 453
Africa (Cook-​Mozaffari et al., 1998). In western Uganda, for instance,
it represented up to 9% of all cancers in men. KS was also endemic,
although much rarer, in countries around the Mediterranean, particu-
larly in Italy, Greece, and the Middle East, but was almost nonexis-
tent elsewhere, except in immigrants from these endemic countries
(Franceschi and Geddes, 1995). Variation in KS incidence before the
HIV epidemic correlates well with the subsequently discovered world-
wide distribution of KSHV infection. However, infection prevalence is
similar in the two sexes, whereas KS incidence is consistently higher
in men than in women (Bohlius et al., 2014; Franceschi and Geddes,
1995). In Sub-​Saharan Africa, KS is also found among children.
After the outbreak of the HIV epidemic in the 1980s, KS frequency
increased steeply until cART was introduced (i.e., in 1996 in high-​
income countries) (IARC, 1996, 2012a, 2014). In the United States,
KS incidence peaked in 1990–​1995 (1117 per 100,000 people with
AIDS) but declined in HIV-​infected people by 25% per year in 1996–​
2000 and by 6% in 2000–​2010 (Robbins et al., 2014b). Similar tem-
poral patterns were reported in Europe, although even in HIV-​infected
people with restored immunity, KS remained more frequent than in
the general population (Franceschi et al., 2010; Hleyhel et al., 2013).
HIV-​associated KS hit Sub-​Saharan African populations of both
sexes more heavily than populations in Western countries, and cART,
though clearly efficacious, has been scaled up only since 2004 and
is often started at a very low CD4 level (Bohlius et al., 2014). In the
general population of some countries (e.g., Uganda, in 1991–​1995),
KS was reported to be the most common cancer in men and the second
most common cancer in women (after cervical cancer). It subsequently
declined modestly from 1996 to 2010 by 2.1% per year in men and
0.3% in women (Wabinga et al., 2014).
Primary Effusion Lymphoma and Multicentric
Castleman’s Disease
Primary effusion lymphoma (PEL) is a rare subgroup of B-​cell malig-
nancies that presents with body cavity (pleural, peritoneal, or pericar-
dial) effusions usually, but not always, in the context of HIV infection
or other forms of immune suppression. KSHV is identified in all cases
and indeed the presence of the virus in tumor cells is now part of
the diagnostic criteria for PEL (IARC, 2012a). Castleman’s disease is
not strictly a malignancy, but rather a polyclonal lymphoproliferation
that can progress to lymphoma. Because of its rarity, evidence for an
association with KSHV comes mainly from case-​series, which are
consistent in linking the virus to the disease. A  number of tumors,
notably multiple myeloma, have been linked to KSHV in some stud-
ies, but for none of these is the evidence sufficient to suggest causality
(IARC, 2012a).
Mechanisms of Carcinogenesis
In KS, primary endothelial cells undergo spindle cell formation, which
express markers of the lymphatic endothelium. KSHV infection has
been shown to induce most steps in the process of malignant transfor-
mation, including cell proliferation, inhibition of apoptosis, genomic
instability, and cell migration with associated tumor progression. At
least one KSHV gene product is expressed in all infected tumor cells
in all KSHV-​associated cancers and in vitro (IARC, 2012a; Mesri
et al., 2010).
Parameters That Influence Risk
A number of cofactors have been suggested, but only for HIV and
other causes of immune suppression is there evidence that KS risk
is increased, significantly and consistently in all populations (see
Chapter 25 on immunologic factors).
The higher incidence of KS in men despite a similar KSHV preva-
lence in men and women points to the male sex as a cofactor for KS
onset (Bohlius et  al., 2014; Franceschi and Geddes, 1995). There is
also circumstantial evidence to suggest that later age at infection with
KSHV is associated with increased risk of KS, although this cannot
explain the development of tumors among young children seen in
KSHV endemic settings (Ziegler et  al., 1997; Ziegler et  al., 2003).
Furthermore, those who acquire KSHV subsequent to HIV infection
have substantially higher risk of KS than those who are infected prior
to acquiring HIV (Martin et al., 1998).
Other (as yet ill-​defined) cofactors may have the most effect on
KSHV transmission or KS development in the absence of concurrent
HIV infection or other forms of immune suppression (Dedicoat and
Newton, 2003). These include malaria (Franceschi and Geddes, 1995;
Serraino et al., 2003), volcanic soils (Ziegler, 1993), and exposure to
certain plants (Whitby et al., 2007).
Future Research
Although cART can prevent and control the disease, even if started
in the presence of very low CD4 levels, KS management remains a
significant clinical problem in HIV-​infected people (Nguyen et  al.,
2008). A systematic review (Gbabe et  al., 2014) showed that cART
plus chemotherapy may be beneficial in reducing disease progression
compared to cART alone in patients with severe or progressive KS, but
that there was no significant difference between the use of liposomal
doxorubicin, liposomal daunorubicin, and paclitaxel. In Sub-​Saharan
Africa, advanced stage at KS diagnosis and/​or late referral for treat-
ment is frequent and the availability of chemotherapy very limited
(Krown, 2011). Better understanding of KS pathogenesis is leading
to rational drug design, with a number of promising approaches under
investigation (reviewed by Mesri et al., 2010).
However, the absence of curative drugs or a safe and effective
vaccine against KSHV highlights the need to better understand the
genetic and environmental factors that impact on transmission. It is
an enigma as to why KSHV is not more widespread in human popu-
lations, but rather is sustained at much higher prevalence in parts of
Africa compared to the rest of the world. Although prevalent in West
Africa, KSHV is rare among black Americans—​transmission follow-
ing migration from Africa was clearly reduced and the strain of KSHV
present in North America is not that found in Africa, but that found
in Europe. A better understanding of cofactors for transmission may
provide novel insights into how best to reduce the burden of KSHV in
settings where infection is prevalent.
HUMAN T-​CELL LEUKEMIA VIRUS TYPE 1
Human T-​cell leukemia virus type 1 (HTLV-​1) is a retrovirus belonging
to the family retroviridae, genus deltaretrovirus. Discovered in 1980
(Poiesz et al., 1980), it has an RNA genome that is reverse transcribed
into DNA and then integrated into cellular DNA, predominantly of
CD4+ T cells. There are seven genotypes identified to date, five of
which are found only in Sub-​Saharan Africa and one of which is found
only in Asia; the human virus probably arose via interspecies trans-
mission of related simian viruses (Verdonck et al., 2007). An estimated
10–​20 million individuals worldwide are infected and 3–​8 million of
those are in Sub-​Saharan Africa. More than 90% of those infected
will remain asymptomatic carriers throughout their lives (Gessain and
Cassar, 2012).
Estimation of the global prevalence of HTLV-​1 is based primar-
ily on data from screening of healthy blood donors; for large parts
of the world, information is sparse or absent. Highest prevalence has
been reported in Japan, parts of Africa, the Caribbean Islands, areas of
Central and South America, and Northern Oceania. The southwestern
islands of Japan are particularly affected, with prevalence estimates of
up to 20% (IARC, 2012a), followed by the Caribbean and countries
in Sub-​Saharan Africa (up to 5%) (Fox et al., 2015). Contrary to HIV,
HTLV-​1 predominantly exists as a cell-​associated provirus, and it is
transmitted from human to human through infected lymphocytes. The
predominant route of acquisition is through mother-​to-​child transmis-
sion at birth and more commonly through breastfeeding (especially
≥ 6-​month breastfeeding), and has been correlated with mother–​child
concordance of HLA types and proviral load (Biggar et  al., 2006).
Other routes include sexual intercourse, blood transfusion, organ
transplantation, and contaminated needle reuse.
45
454 PART III:  THE CAUSES OF CANCER
HTLV-​1 is the causative agent of adult T-​cell leukemia/​lymphoma
(ATLL) with an estimated 3000 cases per year (Table 24–2). It also
causes the progressive, chronic, disabling HTLV-​1-​associated myelop-
athy/​tropical spastic paraparesis (HAM/​TSP), as well as other inflam-
matory conditions such as infective dermatitis and uveitis (Martin
et  al., 2014). ATLL is an aggressive malignancy of peripheral T
cells, with short survival in its acute form. Risk of disease increases
with age, time since infection, and is higher among male carriers of
HTLV-​1 compared to female carriers. It occurs almost exclusively in
areas where infection is endemic, such as Japan, the Caribbean, and
West Africa; in other areas, cases are generally among immigrants
from endemic populations. HTLV-​1 is considered a necessary cause
of ATLL, and presence of infection is part of the diagnostic criteria.
The host immune system is thought to play a critical role in control
of infection in the majority of carriers. Mechanistically, HTLV-​1 can
transform CD4-​positive T lymphocytes via the action of the Tax pro-
tein in vitro (reviewed in IARC, 2012a).
The prognosis of HTLV-​1 related diseases is poor and no vaccine
is yet available, highlighting the importance of prevention. Screening
of blood products has also been shown to be effective in reducing
parenteral transmission, and use of condoms should be considered
by HTLV-​ 1 serologic-​discordant couples. Prevention of HTLV-​ 1 Opisthorchis viverrini and Clonorchis sinensis
transmission in neonates appears to be especially important because
of the association of ATLL with childhood infection (IARC, 1996).
Limiting the duration of breastfeeding is of particular value. An inter-
vention program to screen and counsel HTLV-​1-​seropositive women
began in Japan in the late 1980s and has been shown to prevent 90%
of maternal transmission to infants (Hino, 1990). However, such a
policy can be adopted only where safe alternatives to breastfeeding
are available.
MERKEL CELL POLYOMAVIRUS
Merkel cell polyomavirus (MCV) is a recently discovered virus (Feng
et al., 2008) that affects epithelial-​neuroendocrine cells located in the
basal membrane of the skin (see IARC, 2014, for a review). MCV-​
DNA is detected by PCR using different primers specific to genes
encoding MCV large T-​antigen (LT), small T-​antigen (sT), and capsid
viral proteins. Case-​series showed that MCV-​DNA can be detected
in the vast majority of cases of Merkel cell carcinoma, a rare neu-
roectodermal tumor that tends to recur locally and can also produce
metastases. Quantitative analyses revealed that > 90% of Merkel cell
carcinomas bear > 0.6 viral copies per cell. Clonal integration of viral
DNA in the cell genome of MCV-​positive carcinomas has been con-
sistently reported. Among various MCV antibodies, seropositivity for
MCV LT and sT is specifically associated with cancer, while very
rare in healthy controls. Case-​control studies showed elevated and
consistent odds ratios for serological markers of MCV infection and,
especially, for markers of early gene expression. Immunosuppressed
persons are at > 10 times increased risk of Merkel cell carcinoma, and
sun exposure is suspected to contribute to MCV carcinogenicity (see
Chapter 25 on immunologic factors).
PARASITES
Three parasites are well-​established carcinogens in humans (reviewed
in IARC, 2012a).
Schistosoma haematobium
Schistosomes are parasitic trematode worms that live in the blood ves-
sels of human hosts. There are six species that cause significant pathol-
ogy in man, varying in their geographic distribution, intermediate
host, and location in human tissues; an estimated 200 million people
are infected globally. They have been linked to various human tumors,
including cancers of the bladder, cervix, prostate, liver and colorectum,
but only for Schistosoma haematobium (S.  haematobium) in relation
to bladder cancer is the evidence sufficiently robust to claim causality
(IARC, 1994b, 2012a). Infection occurs via exposure to contaminated
fresh water and is most frequent in parts of Africa (mainly along the
Nile River) and the Middle East. On release from freshwater snails,
a free-​living form of S. haematobium can enter a human host through
the skin, eventually migrating to live in the veins that drain the bladder.
Eggs are released and pass in urine back into water and then to the snail.
Infection can be ubiquitous in endemic regions and begins in child-
hood. Many infections are asymptomatic. However, egg deposition in
the bladder can cause significant inflammatory responses leading to
oxidative stress and nitric oxide–​induced genotoxicity, resulting in the
development of an estimated 7,000 cases of bladder cancer worldwide
in 2012 (Table 24–2), mainly squamous cell carcinoma (Bedwani et al.,
1998). Tobacco smoking is a cofactor of S. haematobium infection in
bladder cancer. Formerly a disease of rural areas, urban schistosomia-
sis from man-​made reservoir and irrigation systems is an increasing
problem in many countries. Despite large-​scale pharmacological inter-
ventions, particularly using praziquantel, evidence for the impact of
repeated treatment for schistosomiasis on the prevention and control of
bladder cancer remains limited (IARC, 1994b, 2012a).
The liver flukes Opisthorchis viverrini (O. viverrini) and Clonorchis
sinensis (C.  sinensis) are food-​borne trematode worms of the same
genus, but different species. It is estimated that about 45 million peo-
ple are infected, primarily in China, Thailand, Vietnam, Laos, Korea,
and Cambodia (IARC, 1994b, 2012a). C.  sinensis is approximately
three times more frequent than O. viverrini. In endemic areas they are
an important cause of cholangiocarcinoma, resulting in approximately
1300 cases each year (Table 24–2). Infection in humans is via con-
sumption of contaminated undercooked or raw freshwater fish that are
used as traditional snacks or sauces. Other fish-​eating mammals can
be affected, and domestic dogs and cats are an important reservoir of
infection. On release from snails, the parasites can enter many fish
species, and from there, infect humans. They eventually inhabit the
intrahepatic bile ducts and secrete eggs back into the environment
via feces. As with schistosomiasis, infection is often asymptomatic
and the development of cancer appears to be related to decade-​long
chronic inflammation and the resulting genotoxic oxidative stress.
Cholangiocarcinoma is usually late stage at diagnosis and is rarely
curable. Improvement of sanitation, aquaculture control, and dietary
education could diminish the transmission of liver flukes.
OTHER SUSPECTED CARCINOGENIC AGENTS
A few other infectious agents have been suspected to be carcinogens
in humans, but epidemiological evidence was considered insufficient
by IARC (Table 24–1).
P. falciparum, like HIV, is not carcinogenic per se, but it can
increase the carcinogenicity of other infections, notably EBV. There
are estimated to be globally about 198 million cases of malaria each
year, most caused by one of four species (WHO, 2014). The major-
ity of malaria deaths are associated with P. falciparum, and 90% of
those occur in children < 5 years, primarily in Sub-​Saharan Africa.
The life cycle has several stages and involves both humans and the
Anopheles mosquito. Co-​infection of P. falciparum with EBV seems
to cause dysregulation of the virus, thereby facilitating the develop-
ment of BL (reviewed in IARC, 2014). Numerous ecological studies
link BL to malaria, both geographically (Burkitt, 1962) and over time
and, more recently, case-​control studies among children in Uganda
and Malawi demonstrated increased risks of the tumor with increasing
titers of antibodies against malaria—​indeed the highest risk of BL was
among those with high titers of antibodies against both malaria and
EBV (Carpenter et al., 2008; Mutalima et al., 2008). Clear evidence
for other malaria species and for other cancer sites is lacking (IARC,
2014).
Two cutaneous HPV types, HPV5 and 8 are often detected in squa-
mous cell carcinomas of the skin in Epidermodysplasia verruciformis
patients. HPV5 and 8 belong to the ß-​genus that, together with other
 45
Infectious Agents 455
HPV genera, includes many more HPV types than the mucosal α-​genus
(IARC, 2012a). Cutaneous HPVs are also more ubiquitous in the gen-
eral population than mucosal types and have been found in squamous
cell carcinomas of the skin and its precursor, actinic keratosis, also in
immunocompetent individuals. However, viral DNA is not integrated
within the host genome, is often present at low copy number, and is
not necessary for expression of the malignant phenotype (Tommasino,
2014). Transgenic mice expressing beta-​HPV E6/E7 proteins develop
skin squamous cell carcinomas on ultraviolet (UV) light exposure as
these proteins hamper the repair of UV-​induced DNA damage (Howley
and Pfister, 2015). Finally, contrary to mucosal HPV, a clear identifi-
cation of high-​risk species/​types is lacking for cutaneous HPV types,
whose truly causal role in skin cancer remains uncertain (IARC, 2012a).
An especially interesting possibility is the involvement of the gut
microbiome in the onset of colorectal cancer (CRC), the most frequent
cancer in nonsmokers worldwide. The wide range in gut microbiota
composition and associated metabolic functions among individuals
provides a rationale for proposing the existence of associations with
disease processes, including CRC (Doll and Peto, 1981). A case-​con-
trol study based on 16S rRNA sequencing of fecal samples showed
that CRC cases had decreased microbial diversity compared to con-
trols, lower levels of Clostridia, and significantly increased levels of
Porphyromonas and Fusobacterium (Ahn et al., 2013). The CRC sub-
type associated with Fusobacterium may have molecularly distinct
features (i.e., high degree of CpG island methylation, and high rate of
mutations overall, though not of the TP53 gene) (Tahara et al., 2014).
Of note, CRC occurrence is known to be influenced by host genetics
and factors such as obesity, nutrition, and exercise that also influence
and can be influenced by gut microbiota.
The discovery in human bilis and the biliary tract of Helicobacter
species other than H. pylori raised the possibility of an association of
these bacteria with cancer of the gallbladder and extrabiliary tract, a
group of malignancies whose incidence varies substantially across the
world (de Martel et al., 2009). A case-​control study showed an associa-
tion of extra-​hepatic cholangiocarcinoma with PCR-​detected H.  bilis
but not H. hepaticus or Salmonella typhi in Mexico, a high-​incidence
area for these malignancies (Segura-​Lopez et al., 2015). An association
of seropositivity for H.  pylori with biliary tract cancer was reported
in the Finnish Alpha-​Tocopherol, Beta-​Carotene Cancer Prevention
prospective study (Murphy et al., 2014). On account of the low speci-
ficity of H. pylori serology, these findings may reflect cross-​reactivity
with non-​pylori Helicobacter species, which could contribute to cancer
onset through chronic inflammation and epithelial DNA damage.
Other associations between infections and cancer may emerge in the
future, driven by the discovery of more accurate biomarkers for candi-
date agents and a finer molecular characterization of cancer types into
subsites that may differ from an etiologic point of view.
ACKNOWLEDGMENT
The authors would like to thank Dr. Jin Young Park for her review of
the H. pylori section and Dr. Gary Clifford for suggestions on the HPV
section. Mrs. Susan Gamon provided technical assistance.
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 461
25 Immunologic Factors
ERIC A. ENGELS AND ALLAN HILDESHEIM
OVERVIEW
The immune response is a highly complex system that has developed
to protect individuals from morbidity and mortality induced by exog-
enous exposures, including infections. As summarized in this chapter,
alterations in the immune response, whether due to immunosuppres-
sive or immune stimulatory effects, have important consequences
with respect to cancer risk. The demonstration that individuals with
inherited immunological defects, acquired immunological deficien-
cies, chronic unresolved infections, and autoimmune conditions are at
considerably increased risk for multiple cancers suggests an important
role for the immune response in the development of cancer at various
anatomical sites. Studies that have directly evaluated immunogenetic
and immunological factors and cancer risk are beginning to identify
specific immunological risk factors associated with individual can-
cers. Furthermore, technological advances have made it increasingly
feasible to evaluate specific immunological factors and their relation-
ship to cancer risk, suggesting that additional insights are likely in the
coming years.
OVERVIEW OF THE IMMUNE SYSTEM
The immune system is a highly complex network that has evolved to
recognize and eliminate pathogenic microorganisms such as viruses
and bacteria (non-​self) and altered host cells (altered self), while
simultaneously recognizing self to avoid the destruction of healthy
cells (tolerance) (Paul, 2013). Pathogens are highly variable microor-
ganisms that can quickly cause morbidity and mortality in their host.
To deal with these aspects of pathogenic infections, the immune sys-
tem has evolved to allow for (1)  rapid recognition of and response
to highly conserved motifs present on the surface of pathogens, (2)
de novo generation of responses targeting specific pathogens to which
it is exposed, and (3) long-​lasting memory to protect against reinfec-
tion with pathogens encountered in the past.
Innate Versus Adaptive Immune Responses
The immune system can broadly be classified into two arms: innate and
adaptive. The innate response is designed to recognize key molecules
present on microbial surfaces (danger signals) that do not otherwise
exist on host cells. These responses are non-​specific in that they tar-
get evolutionarily conserved pathogen-​associated molecular patterns
(e.g., lipopolysaccharides in bacteria and double-​stranded ribonucleic
acids in viruses) and do not require prior exposure for recognition to
occur. As pathogen-​infected and otherwise altered host cells often stop
expressing self-​molecules known as human leukocyte antigens (HLA)
on their surface (as a mechanism for evading immune recognition
by the adaptive response described in the following), innate immune
cells have also evolved to target and eliminate such cells. The innate
response is designed to be rapid, to serve as a first line of defense
to limit infections, and to signal and activate the adaptive immune
response.
In contrast to the innate response, the adaptive response is generated
de novo after initial exposure (called priming) by a specific pathogen.
Since there is no a priori knowledge of the pathogens to which an
individual will be exposed, the adaptive immune response has evolved
to allow for real-​time generation of a genetically diverse immune rep-
ertoire through a process of genetic recombination and somatic hyper-
mutation of germline DNA. Cells generated through this process are
able to specifically recognize and target infecting pathogen and altered
host cells.
Cells Types Involved in Immune Response
The two arms of the immune response function through a variety of
cell types. The primary cells involved in the innate immune response
are natural killer (NK) cells, neutrophils, macrophages, and dendritic
cells. NK cells are lymphocytes involved in recognizing and kill-
ing infected or otherwise altered cells that have down-​regulated the
expression of self-​molecules on their surface. Neutrophils and mac-
rophages are phagocytes that engulf and eliminate microbes and
apoptotic/​necrotic cells. Importantly, macrophages and their derived
specialized dendritic cells are involved in cross-​talk between the innate
and adaptive responses and are responsible for processing and present-
ing foreign antigens to effector cells of the adaptive immune response
via cell surface molecules known as HLA.
The primary cells involved in the adaptive immune response are
lymphocytes and their derived cells. Various types of lymphocytes
exist. Cytotoxic (also called CD8 +) T-​lymphocytes are the primary
effector cells responsible for specifically recognizing and killing
infected or otherwise altered cells that express non-​self antigens on
their surface. Helper (also called CD4 +) T-​cells assist in this process
and also contribute to the process of antibody production described
next. B-​lymphocytes mature into plasma cells that produce antibodies
that specifically recognize and bind foreign pathogens. T-​regulatory
(T-​reg) cells are produced to modulate/​downregulate responses so as
to avoid exacerbated, uncontrolled responses that might be detrimental
to the host.
Compartments of the Immune Response
The cells described in the preceding derive from and go through
the process of differentiation, maturation, selection, expansion, and
development of long-​lived memory cells in distinct compartments
of the immune system. The primary lymphoid organs comprise the
bone marrow and the thymus. The bone marrow is the source of
self-​renewing hematopoietic stem cells. It is the site where B-​cells
undergo their initial differentiation from hematopoietic stem cells
into naïve B-​cells, and ultimately where the mature B-​cells return
after having encountered antigens in the secondary lymphoid organs
so that they can serve as a reservoir for fully differentiated plasma
cells in the periphery. Hematopoietic stem cells also leave the bone
marrow and seed the thymus, where they undergo differentiation
into naïve T-​cells. It is in the thymus that T-​cells undergo the initial
process of selection, thus ensuring that those cells most adept at tar-
geting pathogens to which the host has been exposed (high-​affinity
cells) are selected for, while low-​affinity cells and cells that recog-
nize self antigens are selected against. The lymph nodes, spleen, ton-
sils, and mucosal associated lymphoid tissues (MALT, including
the Peyer’s patches of the gastrointestinal tract) are considered
461
462
462 PART III:  THE CAUSES OF CANCER
secondary lymphoid organs. At these sites, antigen presenting cells
(APCs) returning from the periphery interact with naïve B-​and
T-​cells, enabling the process of maturation, selection, and expansion
of those cells most adept at targeting the pathogen at hand (i.e., high-​
affinity B-​and T-​cells), and the development of long-​lived memory
cells. In addition to the selection and expansion of high-​ affinity
B-​and T-​cells, the secondary lymphoid tissues also serve as sites where
B-​cells that recognize self are selected against and where peripheral
tolerance is induced for self-​antigen targeting T-​cells that might have
escaped the negative selection process in the thymus. The spleen also
serves as the site where damaged and dead cells and pathogens from
circulation are cleared.
Effectors of the Immune Response
In addition to direct phagocytosis and killing of infected/​altered cells,
cells of both the innate and adaptive immune system regulate and
modulate the immune response through the production of soluble fac-
tors. These include cytokines (which can further be subdivided into
pro-​inflammatory Th1 cytokines and anti-​inflammatory Th2 cyto-
kines) and chemokines that are produced by T-​cells and other immune
and non-​immune cells. These secreted factors act to both attract
immune cells to the site of infection or tissue damage and to regulate
their own responses (autocrine response) or that of neighboring (para-
crine response) or in some instances more distant cells. Plasma cells
derived from B-​cells produce soluble factors called antibodies, which
are the effectors of the humoral immune response through binding of
foreign pathogens to prevent reinfection and to facilitate phagocytosis
by APCs such as macrophages.
An important feature of the immune response is the ability of den-
dritic cells and other APCs to process and present pieces of proteins
(peptides) of an invading pathogen or altered cell to T-​cells so that
they are activated, and for activated T-​cells to recognize and eliminate
infected cells that present peptides from invading pathogens on their
surface. This process is mediated through Class I and II HLA mole-
cules that are specialized in presenting peptides to the immune system
on the surface of cells. Peptides are presented on the surface of APCs
by both classes of HLA and on the surface of infected non-​immune
cells by Class  I  HLA molecules. Genes that encode for HLA mol-
ecules are highly polymorphic, resulting in diversity across individu-
als in a population with respect to the HLA molecules they produce.
Consequently, this results in varying efficiencies with which different
individuals are able to present and respond to individual pathogens or
altered cells. This has implications for cancer risk, as will be discussed
later in this chapter.
ABNORMALITIES OF THE IMMUNE RESPONSE
As will be described further in this chapter, alterations in this complex
system disturb the careful balance of the immune response and can
lead to disease states. On the one hand, immunosuppression, whether
inherited or acquired, can lead to increased susceptibility to infections
that can cause cancer and reduced ability to target transformed cancer
cells for destruction. On the other, states that lead to chronic immune
stimulation, such as autoimmunity due to an inability to distinguish
self from non-​self, or hyper-​reactivity to external stimulants (as in
allergic states), typically result in chronic inflammation and may result
in increased risk of cancer development. More subtly, among individ-
uals with an otherwise healthy immune system, naturally occurring
variability in one’s ability to recognize and eliminate specific patho-
gens might predispose to specific cancers caused by infectious agents.
In the remainder of this chapter, we summarize the primary deter-
minants of the immune response that should be considered when eval-
uating the link between immunity and cancer, discuss inherited and
acquired immune variation associated with cancer development, and
briefly touch on the role of the immune response in determining prog-
nosis after a cancer diagnosis and the promise of new immune-​based
therapies for some cancers.
DETERMINANTS OF THE IMMUNE RESPONSE
Age
It is known that the immune response varies considerably by age. The
immune response of newborns is distinct from that of adults (Dowling
and Levy, 2014). Given the limited exposure to antigens in utero,
B-​and T-​cells in early life are largely naïve and there is a relative
deficit of memory cells. Infants are therefore highly reliant on the
innate immune response (and passively transferred immunoglobulins
from the mother) for protection against pathogen exposure. Innate
and adaptive immune response in early life also differs from that of
adults with respect to the magnitude and types of responses observed.
Responses tend to be skewed toward a more anti-​inflammatory state
(Th2 response), and the reactivity of immune cells tends to be more
modest than those in adults. This attenuated response in early life is
understandable, as it avoids rejection of maternal and self antigens
during fetal development/​early life and permits colonization of the
skin and gut by commensal micro-​organisms. Nonetheless, these same
characteristics make young children more susceptible to pathogenic
infections and lead to an immune response among infected young chil-
dren that is less robust, thereby increasing the chances of the infection
becoming chronic (hepatitis B virus/​HBV, cytomegalovirus/​CMV) or
progressing to clinical disease (human immunodeficiency virus/​HIV)
(Prendergast et al., 2012).
These differences in response in childhood versus adult life have
potential implications for cancer risk, since exposures occurring early
in life lead to long-​term immunological responses that are distinct from
what is observed when the same exposure first occurs in adulthood.
One example of this is the higher predisposition to chronic infection
and liver disease in newborns infected with HBV (Prendergast et al.,
2012). Another is the higher risk of Hodgkin’s lymphoma (HL) follow-
ing adolescent infection with the Epstein-​Barr virus (EBV) (Hjalgrim
et al., 2000). This latter association is thought to be explained by the
strong lymphoproliferative state (often leading to clinical infectious
mononucleosis) induced by first infection with EBV in adolescence,
once the immune system has matured.
In adolescence, the well-​known phenomenon of thymus involution
occurs (Sauce and Appay, 2011). This is the earliest manifestation of
the process of immunosenescence that occurs with aging. With this
involution, production of new populations of naïve T-​cells is drasti-
cally reduced, and in the ensuing years the pool of naïve T-​cells dimin-
ishes and is increasingly replaced by memory T-​cells. The smaller pool
of naïve cells leads to a diminished ability to adequately respond to
new pathogens at older ages.
Additional changes in both the innate and adaptive immune response
occur later in life, including reduced NK cell cytotoxicity, reduced
number and function of APCs, and decreased naïve and memory
B-​cells (Fulop and Montgomery, 2014; Kogut et al., 2012; Nikolich-​
Zugich, 2014; Shaw et al., 2013). Decreases in the class switch recom-
bination process of B-​cells that generates protective antibodies and
memory B-​cells is also observed. At the same time, the redirection of
responses from adaptive to innate immune responses leads to a dys-
regulated state characterized by increased levels of inflammatory mol-
ecules. These changes increase susceptibility to new infections, reduce
the ability to control existing chronic infections, and result in reduced
responses to vaccination. These changes have also been hypothesized
to affect cancer risk through an inability to efficiently detect and target
transformed cells (decreased immunosurveillance).
Like those seen in early life, characteristics of the immune response
in late adult life likely have important implications for cancer develop-
ment. However, it has been difficult to tease apart effects on cancer risk
of immune aging from those of other age-​related phenomenon.
Sex
The effect of sex on immune response is more modest and less well
understood. The female excess for the majority of autoimmune condi-
tions is suggestive of sex differences in the underlying immunological
 463
Immunologic Factors 463
conditions that predispose to these diseases (Whitacre, 2001). Also,
in many instances women have been found to develop a more robust
immune response following vaccination compared to men, again
suggesting sex differences in immune response (Klein et  al., 2010).
These differences are supported by hormonal differences across the
sexes. In fact, hormonal receptors have been shown to be expressed
on immune cell subsets of the innate and adaptive immune response
(Gabriel and Arck, 2014)  and estrogens, progesterone, and tes-
tosterone have distinct effects on cells expressing their receptors
(Nalbandian and Kovats, 2005; Tan et  al., 2015; Trigunaite et  al.,
2015). This may explain, in part, why females typically have elevated
levels of T-​helper cells, and higher plasma levels of various cytokines
and immunoglobulins compared to men. It is interesting to note that
men with Klinefelter’s syndrome, a condition in which men are born
with an extra X chromosome, have elevated serum levels of immu-
noglobulins and various cytokines, and androgen treatment results in
reductions in levels of these same markers, suggesting that the lack
of testosterone in patients with Klinefelter’s syndrome enhances cel-
lular and humoral immunity and that androgen replacement treatment
may reverse this effect (Kocar et  al., 2000). Finally, immunological
alterations observed in pregnancy, during the course of the menstrual
cycle, and among women using exogenous hormones further support
the role of hormonal profile as a mediator of the immune response
(Klein et al., 2010).
Host Genetics
Another intrinsic factor that influences the immune response is
genetics. The link between genetic mutations and primary immuno-
deficiency disorders is proof-​of-​principle of the important role that
genetics plays in determining the immune response (see further dis-
cussion later in this chapter). In contrast to the single-​gene, high-​pen-
etrance model observed for these rare conditions, the effect of genetic
factors on immune response more broadly is understood to be com-
plex and polygenic, making them more difficult to study. Nonetheless,
progress has been made in recent years in elucidating the underlying
genetic underpinnings of the immune response. For example, stud-
ies that have evaluated common genetic polymorphisms and autoim-
mune disease risk, particularly in the genome-​wide association study
(GWAS) era, have uncovered various gene polymorphisms associated
with modest risk for specific autoimmune conditions (Hu and Daly,
2012). In some instances, initial findings from GWAS have led to fol-
low-​up efforts that have identified functional variants associated with
specific autoimmune conditions and/​or patterns in the genetic associa-
tions seen across autoimmune diseases suggestive of common or dis-
tinct biological causal pathways. GWAS conducted within carefully
controlled vaccination studies have provided another fruitful approach
to identify genetic determinants of immune response (Kennedy et al.,
2012, 2014). While more difficult to study due to the absence of an
outcome with a strong immunological phenotype (as seen for auto-
immune conditions) and the lack of tight experimental control (as
seen in vaccination studies), evaluation of healthy individuals have in
some instances pointed to specific genes associated with variability
in the levels of specific immunological factors, including antibodies
and cytokines (Dehghan et al., 2011; Liao et al., 2012; Rubicz et al.,
2013). Taken together, studies to date confirm the role of genetics as a
determinant of immune response in health and disease states and not
unexpectedly suggest that effects are highly polygenic. Despite this
progress, the fact that the effect of single genes on immune response is
typically small and the association between individual immune param-
eters and cancer are likely modest poses a challenge for studies aimed
to uncover the effect of genes that regulate the immune response on
risk of cancer.
Medications That Cause Immunosuppression
Immunosuppressive medications are utilized in the therapy of auto-
immune or allergic diseases, where they are used to decrease the
intensity and destructiveness of disease activity, and in transplanta-
tion, where they are used to prevent or treat graft rejection (in solid
organ transplantation) or graft-​versus-​host disease (in hematopoietic
stem cell transplantation). The adaptive immune system, specifically
T-​cell immunity, is the primary target of these therapies, and while
the clinical intent is to achieve a narrow effect (e.g., abrogation of a
specific autoimmune disease process), the effects are generally broad
and non-​specific. Immunosuppressive medications are often admin-
istered in combinations for prolonged periods (typically for months
or years), although the intensity of immunosuppression typically var-
ies over time in concert with dosing to achieve the desired clinical
effects.
Several classes of medications used in this setting have broad
effects on adaptive immunity, especially when used in combination,
including calcineurin inhibitors (e.g., cyclosporine and tacrolimus),
antimetabolites (e.g., azathioprine, methotrexate, and mycophenolate
mofetil), and inhibitors of the mammalian target of rapamycin (mTOR
inhibitors, e.g., sirolimus) (Halloran, 2004). Intravenous administra-
tion of antibodies against T-​cells or B-​cells (e.g., rituximab targeted
at B-​cells) induces pronounced short-​term deficits in these arms of the
immune system.
Additional classes of medications have varying effects on the
immune system. Fludarabine, used to treat chronic lymphocytic leu-
kemia and other low-​grade lymphomas, causes a marked depletion of
T-​cells (Cheson, 1995). Antibodies against tumor necrosis factor alpha
(e.g., infliximab and etanercept) are used in the treatment of several
autoimmune diseases, including rheumatoid arthritis and Crohn’s dis-
ease. Corticosteroids are widely used in the short-​term treatment of
common ailments such as asthma, or in combination with other medi-
cations for long-​term immunosuppression in transplantation or treat-
ment of autoimmune diseases.
Many of these immunosuppressive medications have somewhat
non-​specific and overlapping effects on the adaptive immune system,
and because they are often administered in combination, it is diffi-
cult to determine whether they differ with respect to their effects on
cancer risk. Also, it can be challenging to separate the effects of the
medications from the underlying disease processes for which they are
the treatment. Indeed, cancer risk may be increased due to the effects
of chronic inflammation and immune activation seen in autoimmune
diseases, graft rejection, or graft-​versus-​host-​disease.
In addition, it is apparent that several immunosuppressive medi-
cations have indirect effects other than immunosuppression that
modulate cancer risk. For instance, calcineurin inhibitors and anti-
metabolites cause DNA damage or impair DNA repair (IARC,
2012a, 2012b). Also, calcineurin inhibitors upregulate expression of
transforming growth factor beta-​1 (TGF-​beta1) and vascular endo-
thelial growth factor (VEGF), which may promote the development
of cancer (Basu et al., 2008; Hojo et al., 1999). In contrast, mTOR
inibitors may be relatively protective, by blocking the mTOR path-
way (a central pathway in cellular metabolism and proliferation)
and downregulating the VEGF pathway (Gentzler et al., 2012; Guba
et al., 2002).
HIV Infection and AIDS
Human immunodeficiency virus type 1 (HIV) is a retrovirus that
causes lifelong chronic infection. HIV is acquired through exposures
to blood or other bodily fluids, and most people become infected
through sexual contact or the use of injection drugs. HIV infection
typically results in progressive immunosuppression, which, when
it becomes severe enough, is classified as acquired immunodefi-
ciency syndrome (AIDS). HIV infects and destroys CD4-​positive
T-​cells, and the major manifestation of AIDS is a profound deficit
in T-​cell immunity (Castro et al., 1992). The concentration of CD4-​
positive T-​cells in peripheral blood (i.e., CD4 count) is a commonly
used clinical measure of immune function in HIV-​infected people.
Chronic polyclonal B-​cell activation is also present, along with defi-
cits in adaptive B-​cell function (Moir and Fauci, 2009). Some of the
46

464 PART III:  THE CAUSES OF CANCER

immune abnormalities may result from chronic antigenic stimulation
in response to the virus, or from increased permeability of the gas-
trointestinal tract and bacterial translocation (Brenchley et al., 2006).
Since 1996, combinations of medications targeted at HIV (i.e., highly
active antiretroviral therapy [HAART]) have increasingly allowed
for the suppression of HIV replication and substantial reconstitution
of the immune system (Althoff et al., 2012; Palella et al., 1998). In
many cases, however, immune reconstitution is incomplete, and some
degree of chronic immune deficit and inflammation appears to persist
(Lederman et al., 2013).
Autoimmune and Allergic Conditions
Autoimmune diseases are characterized by a chronic immuno-
logic response directed at self antigens, leading to progressive tis-
sue destruction (Mackay and Rose, 2006). Many such diseases are
described, each defined by a constellation of specific clinical findings
and immunological markers. T-​cell infiltrates are commonly present in
the targeted tissues, and polyclonal B-​cell activation may also occur.
Patients with these diseases are treated chronically with a variety of
immunosuppressive medications, which vary according to the condi-
tion, although the targeted level of immunosuppression is usually less
intense than in transplantation.
Common allergic conditions include asthma, hay fever, and eczema,
and they are sometimes grouped together as manifestations of “atopy”
(Nelson and Blauvelt, 2012). These conditions are characterized by
hypersensitivity to environmental exposures (i.e., allergens) involv-
ing the production of IgE, degranulation of mast cells, and elevated
levels of eosinophils in affected tissues and the circulation. Onset is
frequently during childhood. The incidence of allergic conditions is
rising over time, perhaps due to improved hygiene and reduced expo-
sure to microbes in early life (Wills-​Karp et al., 2001). Immune-​modu-
lating medications used to treat these conditions include systemic and
inhaled corticosteroids (for asthma and hay fever), topical corticoste-
roids (eczema), and antihistamines (hay fever). Because of the low
doses, short treatment courses, or localized administration of these
medications, patients with allergic conditions can be considered to be
only minimally immunocompromised.
IMMUNE VARIATION AND CANCER
Inherited Conditions
Inherited Immunodeficiency Disorders and Cancer
Primary immunodeficiency disorders (PID) comprise a diverse set of
conditions characterized by inherited defects that affect the immune
system. Over 200 forms of PID have been identified to date (Al-​Herz
et al., 2014; Ochs and Smith, 2014). Most PIDs are exceedingly rare.
Approximately half have been reported in ≤ 10 unrelated individu-
als, making their study and characterization of cancer risk difficult.
Causal attribution, when trying to understand increased cancer risk
observed for these diseases, is also complicated by the fact that the
underlying molecular defects involved in PID affect critical cellular
processes that have pleiotropic effects, including immune deficien-
cies, autoimmunity, inflammation, DNA repair, and chromosomal
stability. Nonetheless, these single-​ gene diseases provide impor-
tant clues to the biological mechanisms linking immune response
to cancer.
PIDs are broadly categorized based on the component of the
immune system that is primarily involved (Al-​Herz et  al., 2014).
Specifically, PIDs are currently classified based on the following
groupings: (1) combined immunodeficiency disorders (CIDs) (with or
without syndromic features) in which both B-​and T-​cell functions are
altered, (2) diseases with predominant antibody deficiencies, (3) dis-
eases of immune dysregulation, (4) defects of phagocyte number and/​
or function, (5)  defects in innate immunity, (6)  autoinflammatory
disorders, and (7)  complement deficiencies. It should be noted that
because of the complex nature of these conditions, some PIDs fit the
criteria for more than one category.
Approximately two dozen PIDs have an elevated risk of malignancy
as one of their associated features (Al-​Herz et al., 2014), and 14–​16
of these PIDs (depending on how conditions are grouped) have been
reported in > 10 unrelated individuals (Table 25–1). Because immu-
nological deficiencies characterized by these PIDs invariably lead
to increased susceptibility to infections, much of the cancer excess
observed occurs among infection-​associated cancers, primarily EBV-​
associated lymphomas. Furthermore, for several PIDs associated with
cancer development (e.g., ataxia telangiectasia, Nijmegen breakage

Table 25–1.  Primary Immunodeficiency Diseases Associated with Cancer

International Union of Immunological

Condition Societies Classification* Associated Cancers

Ataxia telangiectasia (AT) Combined Immunodeficiency Disorders with Lymphoma, leukemia, breast, stomach,
Syndromic Features liver, thyroid
Wiskott-​Aldrich syndrome (WAS) Combined Immunodeficiency Disorders with Lymphoma
Syndromic Features
Nijmegen breakage syndrome (NBS) Combined Immunodeficiency Disorders with Lymphoma
Syndromic Features
Bloom syndrome (BS) Combined Immunodeficiency Disorders with Lymphoma, breast, colon, skin
Syndromic Features
Cartilage hair hypoplasia Combined Immunodeficiency Disorders with Lymphoma
Syndromic Features
Immunodeficiency with centromeric instability and Combined Immunodeficiency Disorders with Lymphoma
facial anomalies (ICF) Syndromic Features
X-​linked lymphoproliferative disease (XLP) Combined Immunodeficiency Disorders Lymphoma
Class-​switch recombination (CSR)/​CD40 ligand Combined Immunodeficiency Disorders Lymphoma, biliary tract, liver, pancreas
deficiency
Hyper-​IgE syndrome (HIES)/​DOCK8 deficiency Combined Immunodeficiency Disorders Lymphoma, HPV-​associated cancers
MST1 deficiency Combined Immunodeficiency Disorders Lymphoma
Common variable immunodeficiency disorders (CVID) Predominantly Antibody Deficiencies Lymphoma, breast, melanoma, stomach
Autoimmune lymphoproliferative sydrome (ALPS) Diseases of Immune Dysregulation Lymphoma
EVER1/​2 deficiencies Defects of Innate Immunity Non-​melanoma skin
Severe congenital neutropenia (SCN)—​ELA2/​HAX1 Congenital Defects of Phagocyte Number Leukemia
deficiencies and/​or Function

* Conditions can be classified into > 1 IUIS classification group. Herein each condition is classified into a single group hierarchically based on the order in which they are listed in
the table.
 465
Immunologic Factors 465
syndrome, and Bloom syndrome), the underlying genetic defect leads
to immunological deficiency via DNA repair defects that affect the
normal process of recombination and hypermutation observed in B
and T cells as part of their mechanism to induce immunological diver-
sity. The observed increase in cancers for these conditions might there-
fore also be related to these defects in DNA repair mechanism.
While EBV-​associated lymphomas of B-​cell origin (primarily NHL,
but also HL) account for the majority of cancer excess observed in
PID, excesses in T-​ cell lymphomas (for Nijmegen breakage syn-
drome), non-​EBV lymphomas (for X-​linked lymphoproliferative dis-
ease), and leukemias (for ataxia telangiectasia, Nijmegen breakage
syndrome, and severe congenital neutropenia) have been reported. In
addition, solid tumors have been noted in excess of expectation for
several PIDs. Examples include breast cancer in ataxia telangiectasia
and common variable immunodeficiency; gastric cancer in common
variable immunodeficiency; liver, pancreas, and gallbladder cancers
in CD40 ligand deficiencies; HPV-​associated non-​melanoma skin can-
cers in epidermodysplasia verucciformis; and various solid tumors in
Bloom syndrome.
To follow, we describe individual PIDs that are reported to be asso-
ciated with increased risk of cancer, and summarize the breadth and
magnitude of the associations observed. It should be stressed that, in
many instances, the absolute and relative risk estimates presented are
based on modest size studies, given the rarity of the conditions being
considered, and that these estimates are therefore imprecise.
Combined Immunodeficiencies Associated with
Syndromic Features. Ataxia telangiectasia (AT) is an autoso-
mal recessive multisystem disease associated with progressive neu-
rodegeneration (ataxia), oculocutaneous telangiectasia, and variable
degrees of immune deficiency. AT is caused by mutations in the ATM
gene, which is known to be involved in numerous cellular functions,
including DNA repair. AT patients are predisposed to infections, par-
ticularly upper and lower respiratory infections. Immunodeficiency
observed in AT patients is highly variable, but involves both antibody
production (hypogammaglobulinemia) believed to be due to a defect
in B-​cell differentiation and cellular immunity resultant from faulty
development of the thymus. AT is estimated to occur at a frequency
ranging from 1:40,000 to 1:80,000 live births and occurs with approx-
imately equal frequency in males and females (Yel et al., 2014). AT
patients typically have a life span of about two decades.
Predisposition to malignancies is a hallmark of AT. Approximately
a quarter of AT patients develop malignancies, typically in the first
decade of life. While lymphomas predominate, solid tumors are also
observed, and an excess of breast cancer among women has been
reported. In a study of 279 patients with AT from a French national reg-
istry (Suarez et al., 2015), 69 (24.7%) developed cancer. Cumulative
incidence of cancer was 10.4% at 10 years and increased to 38% at
40 years. The majority of cancers were lymphomas, accounting for
55% of tumors. These non-​Hodgkin’s lymphomas (NHL) were pre-
dominantly of B-​cell origin (26 of 38), half of which were EBV-​asso-
ciated. At ages 0–​14, the observed incidence of NHL, HL, and acute
leukemia (AL) was 5667, 540, and 49 times higher than expectation,
respectively. Solid tumors were observed among nine AT patients, and
included breast, gastric, liver, and thyroid cancers, as well as a glioma
diagnosed after treatment for HL. An excess of breast cancer mortal-
ity was also noted in a separate study (Reiman et al., 2011), where a
standardized mortality ratio of 31 was reported among 141 women
with AT.
Wiskott-​Aldrich syndrome (WAS) is an X-​linked condition char-
acterized by low platelet count (thrombocytopenia), reduced platelet
size, bloody diarrhea, and eczema. WAS is caused by mutations in the
WAS gene, which is known to play an important role in cytoskeletal
remodeling following T-​cell receptor (TCR) binding and immune syn-
apse formation. WAS patients are predisposed to infections, including
respiratory and ear infections. Immunodeficiency observed in WAS
patients involves both B-​cells and T-​cells, but varies, typically depend-
ing on the WAS mutation observed and its effect on protein expression.
While B-​and T-​cell circulating levels in infancy might be normal, their
function is altered and levels tend to decline with increasing age during
childhood. NK cell function is also altered in WAS. Autoimmune dis-
eases are commonly observed in WAS patients. WAS is a rare condi-
tion diagnosed in 1 to 10 per million men. Life expectancy is typically
15–​20 years (Shin et al., 2012).
A predisposition to malignancies is seen in WAS, particularly lym-
phomas. In one series of 154 patients, cancer was observed in 13%
of cases (average age: 9.5 years), over 70% of which were lympho-
mas (Sullivan et al., 1994). In a more recent series of 50 patients, can-
cers were observed in a comparable proportion of cases (10%), were
restricted to lymphomas, and occurred preferentially among patients
with no WAS protein expression (Imai et al., 2004).
In addition to AT, other PIDs caused by mutations in genes that lead
to chromosomal instability have been reported to be associated with
excess cancer risk. These include most notably NBS (an autosomal
recessive condition caused by NBS1 gene mutations) and Bloom syn-
drome (an autosomal recessive condition caused by BLS gene muta-
tions), although other rarer conditions have also been suggested to be
associated with increased risk of malignancies (Wegner et al., 2014). It
has been reported that over 50% of individuals with NBS and Bloom
syndrome develop cancer, typically before age 20–​25. Greater than
90% of malignancies seen in NBS are lymphomas of B-​and T-​cell
types (Gladkowska-​ Dura et  al., 2008). It has been estimated that
NBS patients have a 50-​fold increased risk of early onset cancer and
> 1000-​fold increased risk of lymphomas (Wegner et al., 2014). Bloom
syndrome patients have also been shown to have an excess risk of lym-
phomas, but in contrast to NBS, a large fraction of cancer diagnosed
in Bloom syndrome (particularly those diagnosed in adulthood) are
carcinomas. Among carcinomas, colon, skin, and breast cancers pre-
dominate (German, 1997).
Other immunodeficiencies with syndromic features that are associ-
ated with an excess risk of cancer include cartilage hair hypoplasia
(an autosomal recessive condition caused by mutations in the DRMRP
gene), a disease reported to be associated with a 7-​fold increased risk
of cancer overall and a 90-​fold increased risk of NHL (Makitie, 2014);
and immunodeficiency with centromeric instability and facial anoma-
lies (ICF; an autosomal recessive condition caused by mutations in
DNMT3B-​ICF1 or ZBTB24-​ICF2 genes) (Hansen et al., 2014).
Other Combined Immunodeficiencies. X-​linked lym-
phoproliferative disease (XLP) is a condition that is characterized by
an exquisite susceptibility to EBV infection. Approximately 80% of
cases are attributable to mutations in the gene SH2D1A, whose pro-
tein affects multiple intracellular signaling pathways that are involved
in the interaction of various immune effector cells after activation,
including T-​cells and NK cells. XLP caused by this gene are referred
to as XLP-​1 to distinguish it from other XLP that are not caused by
SH2D1A. XLP-​1 is estimated to occur with an incidence of 1–​3 per
million males; prognosis is poor, with approximately 70% of cases
dying before the age of 10 years, many from fulminant EBV infection
(Schuster and Latour, 2014).
Approximately 30% of affected males develop lymphomas, with
an average age at diagnosis of 4–​6 years (Schuster and Kreth, 2000;
Schuster and Latour, 2014). The vast majority (90%) of lymphomas
are of B-​cell origin, and most occur at extranodal sites. The risk of
lymphoma in XLP has been estimated to be about 200 times higher
than general population rates. Interestingly, the likelihood of develop-
ing lymphoma in XLP is similar in EBV-​infected and EBV-​uninfected
individuals, suggesting that lymphoma risk in XLP is not EBV specific
(Sumegi et al., 2000).
Class-​switch recombination (CSR) deficiencies (previously called
X-​linked hyper-​IgM syndrome) include CD40 ligand deficiencies that
are X-​linked conditions characterized by low levels of serum IgG,
IgA, and IgE and normal or elevated levels of IgM (Notarangelo et al.,
2006; Notarangelo et al., 2014). Patients with this condition typically
present with recurrent upper and lower respiratory tract infection.
Neutropenia is a common finding, contributing to the predisposition
to bacterial infections. As noted by its name, this condition is caused
in CD40 ligand mutations that impair the ability of B-​cells to undergo
T-​cell-​mediated class switching from IgM-​producing cells to those
that produce other immunoglobulin classes. This condition is rare,
46
466 PART III:  THE CAUSES OF CANCER
usually detected in infancy, and estimated to occur in about 1:500,000
male births per year (Winkelstein et  al., 2003). Affected individuals
typically survive into their forties. An interesting feature of this condi-
tion, in addition to its predisposition of lymphomas (Filipovich et al.,
1994), is the reported elevation in incidence of liver, pancreas, and
biliary tract cancers (Hayward et al., 1997).
Other combined immunodeficiency conditions that are associated
with an excess risk of cancer include hyper-​IgE syndrome (HIES; an
autosomal recessive condition caused by mutations in the DOCK8
gene), a disease reported to cause cancer in close to 20% of affected
individuals (half of whom develop hematological malignancies)
(Aydin et  al., 2015); and MST1 (caused by mutations in the SKT4
gene), a disease thought to involve increased lymphoma risk but for
whom too few cases have been evaluated to permit definitive state-
ments regarding cancer risk (Al-​Herz et al., 2014).
Other Primary Immunodeficiency Disorders (PIDS).  plastic syndrome (MDS) or acute myeloid leukemia (AML) of 36%
Combined variable immunodeficiency (CVID) is a heterogeneous
condition that is characterized by marked reductions in serum immu-
noglobulin levels (hypogammaglobulinemia), impaired antibody
responses, and recurrent bacterial infections (Hammarstrom, 2014).
A substantial proportion of cases develop inflammatory and autoim-
mune conditions. While abnormalities in B-​cell responses are the
primary immunological features of CVID, evidence has accumu-
lated to suggest the presence of T-​cell abnormalities as well (Ramesh
et  al., 2015). The underlying molecular basis for CVID is unknown
for the vast majority of cases, and most cases are sporadic in nature.
Nonetheless, some specific autosomal recessive gene mutations have
been linked to CVID (including ICOS, CD19, CD20, CD21, CD81,
LRBA, BAFF receptor, CXCR4, NFKB2, and PIK3CD), and a recent
GWAS revealed a potentially important role for copy number varia-
tions (CNVs) in this condition (Orange et al., 2011). It is estimated that
between 1:25,000 and 1:50,000 individuals develop CVID, making it
one of the more common PIDs (Resnick et al., 2012). CVID occurs
with approximately equal frequency in males and females. Diagnosis
occurs, on average, around age 25–​30 years; about 25%–​30% are diag-
nosed before the age of 20 years.
Registry-​based studies of several hundred cases each have reported
cancer in up to 15% of cases in the most recent report (Resnick et al.,
2012). A  large fraction of cancers are lymphomas, primarily B-​cell
NHL. It has been estimated that individuals with CVID have a 6-​to
18-​fold increase in risk of NHL compared to the general population
(Mellemkjaer et al., 2002; Quinti et al., 2007). Elevations in other can-
cers have also been reported, including gastric, breast, and melanoma
(Resnick et  al., 2012). With respect to gastric cancer, earlier reports
suggested a 50-​fold increase in risk, but the observed increase in risk
is more modest in the latest report, suggesting changes with increased
follow-​up or in more recent years (Mellemkjaer et  al., 2002; Quinti
et al., 2007; Resnick et al., 2012).
Autoimmune lymphoproliferative syndrome (ALPS) is a condition
characterized by chronic lymphadenopathy and splenomegaly of early
onset, autoimmune phenomenon, and expanded populations of T-​cells
expressing specific T-​cell receptors α/​β and CD4/​CD8 double-​negative
T-​cells (Fleisher et al., 2014). ALPS is typically inherited in an auto-
somal dominant fashion, although autosomal recessive and recessive
forms of the disease have been reported less frequently. The majority
of the conditions diagnosed to date are caused by mutations in the FAS
gene (ALPS-​FAS). As a result, cases have an inability to respond to
cell death signals. ALPS occurs in both males and females. The condi-
tion is rare and no incidence figures are available. It has been estimated
that risk of NHL is elevated 14-​fold in ALPS-​FAS and that of HL 51-​
fold compared to general population rates of similar age (Straus et al.,
2001).
Epidermodysplasia verruciformis is a very rare autosomal reces-
sive condition, usually detected in early life, that is characterized by
an exquisite and specific predisposition to cutaneous HPV infections.
This condition is caused by underlying mutations in EVER1/​2 genes
(also known as TMC6/​8), which are involved in maintenance of zinc
balance within epithelial and T-​cells, which when altered predispose
to uncontrolled cutaneous HPV infections (Lazarczyk et  al., 2009).
Early reports suggested that a third of cases developed squamous
cell carcinomas of the skin over a period of decades, particularly in
sun-​exposed areas, but more recent studies with long follow-​up time
suggest that virtually all cases are prone to the development of these
cancers (Majewski et al., 1997).
Severe congenital neutropenia (SCN) is a condition (usually
detected in infancy) characterized by maturation arrest of myelopoi-
esis, resulting in reduced neutrophil counts, predisposition to recurrent
bacterial and fungal infections, and decreased mineral bone density.
The disease can be inherited in either an autosomal dominant or
recessive pattern, depending on the specific gene mutation involved.
Mutations in ELA2 and HAX1, both involved in the process of apopto-
sis, have been shown to be causal for the dominant and recessive forms
of this disease, respectively. Follow-​up of 374 cases with SCN treated
with granulocyte colony stimulating factor (G-​CSF) therapy from an
international registry demonstrated a cumulative risk of myelodys-
by 12 years after initiation of treatment (which occurred on average
at age 3 years) (Rosenberg et  al., 2006). Of note, dose of G-​CSF
treatment was positively associated with risk of MDS/​AML, with a
1.2-​fold increase in risk per doubling of treatment dose. This suggests
the possible existence of a group of individuals at risk of cancer that
can be defined by non-​responsiveness to standard therapy.
Common Genetic Polymorphisms
In addition to the rare and highly penetrant mutations that give rise to
PIDs, more common polymorphisms in immune response genes with
low penetrance are likely to contribute to cancer risk. As mentioned
earlier, these effects are likely to be polygenic and of modest effect
size, making them more difficult to study than the link between single
gene mutations involved in PIDs and cancer. Despite these theoretical
difficulties, past candidate-​based studies have shown consistent evi-
dence for association between some immune response genes and vari-
ous cancers, particularly cancers caused by viral infections and those
of hematopoietic origin.
In particular, consistent associations with cancer have been
reported for HLA genes. These associations are biologically plausible
since, as described earlier in this chapter, these are genes involved in
the presentation of foreign antigens to the adaptive arm of the immune
response and in innate responses mediated through HLA binding.
Studies have shown specific associations between HLA alleles and
haplotypes for several cancers, including cervical cancer (caused by
HPV) (Chen and Gyllensten, 2015; Hildesheim and Wang, 2002),
nasopharyngeal carcinoma (caused by EBV) (Su et  al., 2013; Tang
et al., 2012), hepatocellular carcinoma (frequently caused by HBV or
HCV) (Jiang et al., 2013; Kumar et al., 2011; Li et al., 2012; Lin et al.,
2010; Lopez-​Vazquez et  al., 2004; Xin et  al., 2011), HL (approxi-
mately one-​third EBV-​associated) (Cozen et al., 2014; Hjalgrim et al.,
2010; Huang et al., 2012; Urayama et al., 2012), and NHL (Skibola
et  al., 2012; Smedby et  al., 2011; Vijai et  al., 2015; Wang et  al.,
2010a) among others. Findings from candidate gene studies of HLA
genes are now beginning to be confirmed by large, agnostic GWAS,
where polymorphisms in the MHC region of chromosome 6 (where
HLA resides) have often provided the strongest evidence for asso-
ciation with individual cancers. Furthermore, when HLA alleles are
inferred or directly measured in these GWAS, the SNP associations
are often in strong LD with known HLA alleles previously reported
to be associated with the respective cancer being investigated. As
expected, the specific HLA genes and alleles associated with different
cancers vary, since presentation of peptides to the immune system
by HLA molecules is antigen-​specific. Figure 25–1 summarizes key
findings from GWAS for hematopoietic and/​or infection-​associated
cancers with strong evidence for associations within the MHC region
(Su et al., 2013).
While the specific HLA alleles associated with different cancers
vary, some patterns are beginning to emerge that provide useful clues
to the underlying mechanisms of observed associations. First, HLA
associations have been most consistent for cancers of hematopoietic
origin and/​or those caused by viral infections. Of note, associations
with HLA have not been noted for gastric cancer, a cancer linked to
 467

Immunologic Factors 467

70
Non-HLA HLA Class I Non-HLA Class I/II HLA Class II Non-HLA

Nasopharyngeal carcinoma
EBV-positive Hodgkin’s lymphoma
60
Hodgkin’s lymphoma
EBV-negative Hodgkin’s lymphoma
Nodular sclerosis Hodgkin’s lymphoma
Follicular lymphoma
Chronic lymphocytic leukemia
50 Lymphoma
Hepatocellular carcinoma
HCV-related hepatocellular carcinoma
HBV-related hepatocellular carcinoma
Cervical cancer
–Log10 (P value)

40 Lung cancer
Lung adenocarcinoma
Testicular germ cell tumor
Prostate cancer
Multiple cancers

30

20

10

0
29M 30M 31M 32M 33M 34M
Position in MHC Region (MB)
Figure 25–1.  Plot of strongest GWAS associations within the major histocompatibility complex (MHC) across anatomic sites. Source: Adapted from Su
et al., Front Oncol (2013).

H. pylori infection. This makes sense since H. pylori is an extracel-
lular bacterial pathogen and the immune response to such pathogens
is driven by B-​rather than T-​cell responses, where HLA presenta-
tion is not required. Second, while the strong linkage disequilibrium
patterns in the MHC region make it difficult to disentangle specific
HLA alleles/​haplotypes that drive observed association, there is some
indication that the strongest effects observed for lymphomas are with
HLA Class II rather than Class I genes. Again, this makes sense since
Class II HLA molecules are only expressed in cells from the immune
lineage. One exception to this general pattern is observed for HL,
where EBV(-​) HL appears to have a stronger Class II effect, while
EBV(+) HL has a stronger Class  I  effect (Figure 25–2) (Urayama
et al., 2012). Third, for cancers caused by viruses, evidence is accu-
mulating to suggest that HLA Class I genes are most important for
EBV-​associated cancers, while HLA Class II genes are most impor-
tant for other viral-​associated cancers. Thus, the HLA Class I asso-
ciations are stronger than Class  II associations for EBV(+) HL
and for NPC, while HLA Class  II associations are stronger than
Class  I  associations for cervical cancers and HCC (whether HBV
or HCV related). It remains to be seen whether the close to 10%
of gastric cancers associated with EBV infection have HLA associa-
tions and whether they are stronger for HLA Class I or II genes. The
Class I predominance for EBV-​associated cancers is interesting bio-
logically since EBV is the only oncogenic virus that establishes long-​
term latency in B-​cells. Taken together with findings from GWAS for
HIV, another virus that infects lymphocytes and for which strong
HLA Class I associations have been reported for progression to AIDS
(Martin and Carrington, 2013), this observation suggests that viral

Extended Class I Class I Class III Class II

30
EBV-positive HL
25 EBV-negative HL
–Log10 (P value)

20

15

10

5
Figure  25–2. Hodgkin’s lymphoma GWAS findings
0 within the major histocompatibility complex (MHC) by
27 28 29 30 31 32 33 tumor EBV status. Source:  Adapted from Urayama K,
Position in MHC Region (MB) et al., JNCI (2011).
468
468 PART III:  THE CAUSES OF CANCER
tropisms are important determinants of the type of HLA association
observed with the cancers that they cause. Finally, HLA associations
have been reported for other cancers, including non-​viral-​associated
solid tumors and leukemias, but those associations have tended to
be less consistent than those observed for virus-​associated cancers
and lymphomas (Bonamigo et al., 2012; Urayama et al., 2013; Wu
et al., 2014).
Other than for HLA, results from candidate immune gene studies
and cancer risk have been largely conflicting and typically modest in
size, making them difficult to interpret (Cerhan et  al., 2007; Engels
et al., 2007; Hildesheim and Wang, 2002; Hildesheim and Wang, 2012;
Schoof et  al., 2011; Shiels et  al., 2012a; Wang et  al., 2010b; Wang
SS et al., 2011). In recent years, more agnostic approaches have been
applied in large-​scale studies to query the entire genome for associa-
tions with cancer. While these studies have the limitation of identi-
fying markers that might not be causal for disease but rather are in
linkage disequilibrium with the causal gene, they do identify chromo-
somal regions linked to cancer development and provide an indication
for genes in those regions that are potentially causal. A  query of the
NHGRI catalog of published GWAS (EMBL-​EBI: performed on May
16, 2015 @ www.genome.gov; restricting to etiology studies of cancers
and lymphomas with greater than 500 cases and 500 controls) revealed
a total of 584 potential genes linked to one or more of 16 cancers stud-
ied within 122 published reports. Review of these genes in six path-
way databases (KEGG, PID_​NCI, REACTOME, PID_​BIOCARTA,
NETPATH, and INOH) revealed 66 genes (11.3% of total) involved
in the immune response (Table 25–2). Among others, these genes are
involved in inflammatory responses (e.g., CRP, IL13, IL4 genes) and
modulation of responses to soluble immune factors (e.g., IL1RAP,
IRF4, TNFBR2 genes). As expected, the magnitude of associations
observed for individual gene polymorphisms are modest, suggesting
that, at best, they each account for a small proportion of these cancers.
Acquired Conditions
Cancers Associated with HIV Infection and AIDS
The effect of immunosuppression on cancer risk has been best stud-
ied in association with HIV/​AIDS and solid organ transplantation,
because these conditions are relatively common, readily diagnosed
by clinicians, and reportable to state or national registries. The idea
that these immunosuppressed groups would have an elevated risk of
cancer is related to the “immune surveillance hypothesis,” which was
first framed by Burnet in 1957 (Burnet, 1957)  and which has been
further developed and updated more recently (Dunn et al., 2002). This
hypothesis states that an intact immune system can recognize pre-​neo-
plastic or neoplastic cells as foreign due to the expression by those
cells of novel proteins (i.e., neoantigens), and that the immune system
can contain or destroy these cells, thereby preventing the development
of cancer. A corollary of this hypothesis is that people with a weakened
immune system would have increased cancer risk.
The broadest form of the immune surveillance hypothesis appears
to be false, because as described in the following, HIV-​infected people
and transplant recipients do not have an elevated risk for cancer of all
types. Rather, the cancers that are most strongly increased are caused
by viruses. Indeed, the greatly elevated risks for Kaposi sarcoma (KS)
and Merkel cell carcinoma among people with AIDS (Beral et  al.,
1990; Engels et  al., 2002)  were important clues that led to the dis-
covery of the viral causes of these cancers. Thus, the immune system
appears to recognize and contain or clear cells that express viral pro-
teins more readily than for other precancerous or cancerous cells.
Much of the available data on cancer risk in HIV-​infected peo-
ple come from linkage of large population-​based HIV and cancer
registries, particularly from the United States, Europe, and Australia
(Dal Maso et  al., 2003; Engels et  al., 2006b, 2008; Frisch et  al.,
2001; Grulich et  al., 2002, 2007; Newnham et  al., 2005; Shiels
et  al., 2009). Results are typically described in terms of standard-
ized incidence ratios (SIRs) comparing cancer incidence in HIV-​
infected people to that expected based on general population rates
(Table 25–3).
HIV infection is associated with a specific spectrum of cancers
(Dal Maso et al., 2003; Engels et al., 2006b, 2008; Frisch et al., 2001;
Grulich et al., 2002, 2007; Newnham et al., 2005; Shiels et al., 2009).
Because of strongly elevated risks in association with advanced HIV
infection, three cancers are considered to mark the onset of AIDS
when they occur in HIV-​infected people: KS, NHL, and cervical can-
cer (Castro et al., 1992). There is less information on cancer risk in
HIV-​infected people in sub-​Saharan Africa (Mbulaiteye et al., 2006;
Newton et  al., 2001; Tanon et  al., 2012), due to a paucity of relia-
ble data sources, even though the prevalence of HIV is highest in this
region of the world. Nonetheless, there are very strong excesses of the
three AIDS-​defining cancers (KS, NHL, and cervical cancer) in HIV-​
infected people in Africa compared with the general population.
The etiologic contribution of HIV-​induced immunosuppression per
se is variable across cancer types, but the importance of immunosup-
pression is indicated by several lines of evidence. First, many of the
same cancers are elevated in both HIV-​infected people and solid organ
transplant recipients (Tables 25–3 and 25–4, and see further discus-
sion in this chapter) (Grulich et al., 2007). Second, risk for some can-
cers in HIV-​infected people increases as the CD4 count declines and
is higher after the onset of AIDS (Biggar et al., 2007; Engels et al.,
2008; Frisch et al., 2001; Guiguet et al., 2009). Third, the incidence
of some cancers is lower in HIV-​infected people receiving HAART
and has declined over calendar time after the introduction and with the
increasing utilization of HAART (Cancer, 2000; Engels et al., 2006b,
2008; Ledergerber et  al., 1999; Robbins et  al., 2014). Nonetheless,
the incidence of KS and NHL was declining steeply even before the
introduction of HAART (Engels et al., 2006b), and whether this fall
was due to improvements in HIV therapy before 1996 or other factors
is unknown.
KS is one of the most common malignancies in HIV-​infected peo-
ple, and the relative risk associated with HIV infection is profound.
In the calendar period before the availability of HAART (i.e., before
1996), KS risk was elevated more than 50,000-​fold among people with
AIDS in the United States (Engels et  al., 2006b). KS is caused by
Kaposi sarcoma–​associated herpesvirus (KSHV, also known as human
herpesvirus 8). The onset of the HIV epidemic led to an explosive
increase in the incidence of KS in the United States (Shiels MS et al.,
2011). KS is also one of the most common cancers in the general pop-
ulation in sub-​Saharan Africa (Mbulaiteye et al., 2006; Tanon et al.,
2012; Wabinga et al., 2000), due to the high burden of both HIV and
KSHV infection in this region. Among HIV-​infected people, KS risk
increases with the degree of immunosuppression (i.e., at lower CD4
counts) (Biggar et al., 2007; Guiguet et al., 2009). KS incidence has
declined substantially over time in the United States (Engels et  al.,
2006b, 2008; Robbins et al., 2014), presumably due, at least in part,
to improvements in HIV therapy, but risk remains substantially higher
than in the general population.
NHL is also common in HIV-​ infected people (Dal Maso et  al.,
2003; Engels et  al., 2006b, 2008; Frisch et  al., 2001; Grulich
et  al., 2002, 2007; Newnham et  al., 2005; Shiels et  al., 2009).
NHL actually comprises a constellation of distinct entities defined
by histologic features and clinical characteristics. Among the
NHL subtypes that arise in HIV-​ infected people, diffuse large
B-​cell lymphoma (DLBCL) is the most common, and risks of DLBCL,
Burkitt lymphoma, and central nervous system (CNS) NHL are strongly
elevated. Among people with AIDS in the pre-​HAART era, risks were
elevated 60-​to 100-​fold for DLBCL, 50-​to 60-​fold for Burkitt lym-
phoma, and 5000-​fold for CNS NHL (Engels et al., 2006b). The inci-
dence rates of both DLBCL and CNS NHL are lower at higher CD4
counts and in people who have not yet developed AIDS (Biggar et al.,
2007; Engels et al., 2008), and both NHL subtypes have declined over
time with improvements in HIV therapy (Engels et al., 2006b, 2008). In
contrast, associations with Burkitt lymphoma are less clear-​cut (Biggar
et  al., 2007; Engels et  al., 2006b, 2008). For unknown reasons, asso-
ciations of HIV infection with NHL appear somewhat more modest
in Africa than in developed countries, with relative risks in the range
of 4–​7 (Mbulaiteye et al., 2006; Sitas et al., 2000; Tanon et al., 2012).
Several less common NHL subtypes, including marginal zone, lympho-
plasmacytic, and T-​cell NHLs, are also increased in HIV-​infected people
 469

Table 25–2.  Genes Involved in Immune Response That Have Been Implicated in Cancer from Genome-​Wide Association Studies

Cancers for Which Associations

GENE Symbol Gene Name* Reported References

ADH1C Alcohol dehydrogenase 1C Upper aerodigestive tract cancers McKay et al., 2011
ANK2 Ankyrin 2 Prostate cancer Tao et al., 2012
AR Androgen receptor Prostate cancer Kote-​Jarai et al., 2011
ATF1 Activating transport factor 1 Colorectal cancer Houlston et al., 2010
BMP2 Bone morphogenetic protein 2 Colorectal cancer Peters et al., 2013
CCND1 Cyclin D1 Breast cancer Ahsan et al., 2014; Michailidou et al., 2013;
Turnbull et al., 2010a
CCND2 Cyclin D2 Colorectal cancer Jia et al., 2013; Peters et al., 2013;
Zhang B et al., 2014a
CCNE1 Cyclin E1 Bladder cancer Figueroa et al., 2014b; Rothman et al., 2010
CD180 CD 180 molecule Prostate cancer Tao et al., 2012
CDH1 Cadherin 1 Colorectal cancer Study et al., 2008
CLDN11 Claudin 11 Prostate cancer Kote-​Jarai et al., 2011
CRP C-​reactive protein Lung cancer Amos et al., 2008
CSNK1A1 Casein kinase 1 Esophageal cancer Wu et al., 2011
CYCS Cytochrome C Colorectal cancer Jiao et al., 2012
DAB2 Dab, mitogen-​responsive phosphoprotein, Pancreatic cancer Wu et al., 2012b
homolog 2
DUSP4 Dual specificity phosphatase 4 Colorectal cancer Fernandez-​Rozadilla et al., 2013
EOMES Eomesodermin Hodgkin lymphoma Frampton et al., 2013
ERAP1 Endoplasmic reticulum aminopeptidase 1 Hodgkin lymphoma Urayama et al., 2012
ESR1 Estrogen receptor 1 Breast cancer Couch et al., 2013; Garcia-​Closas et al., 2013;
Long et al., 2012; Siddiq et al., 2012;
Zheng et al., 2009
FGF10 Fibroblast growth factor 10 Prostate cancer Kote-​Jarai et al., 2011
FGFR2 Fibroblast growth factor receptor 2 Breast cancer Ahsan et al., 2014; Elgazzar et al., 2012;
Fletcher et al., 2011; Gaudet et al., 2010;
Hunter et al., 2007; Li et al., 2011; Low
et al., 2013; Michailidou et al., 2013;
Thomas et al., 2009; Turnbull et al., 2010a
GATA3 GATA binding protein 3 Colorectal cancer and Hodgkin lymphoma Cozen et al., 2014; Figueiredo et al., 2014
GNG2 Guanine nucleotide binding protein Lung and non-​melanoma skin cancers Zhang et al., 2013; Zhang R et al., 2014
(G protein) gamma 2
GRHL1 Grainyhead-​Like 1 Prostate cancer Eeles et al., 2013
HLA-​DQB2 Human leukocyte antigen DQ beta 2 Lymphoma Vijai et al., 2013
HLA-​F Human leukocyte antigen F Prostate cancer Tao et al., 2012
IL13 Interleukin 13 Hodgkin’s lymphoma Cozen et al., 2014; Urayama et al., 2012
IL1RAP Interleukin 1 receptor accessory protein Lung cancer Amos et al., 2008
IL4 Interleukin 4 Hodgkin’s lymphoma Cozen et al., 2014
INHBA Inhibin beta A Prostate cancer Tao et al., 2012
IRF4 Interferon regulatory factor 4 Non-​melanoma skin cancer Zhang et al., 2013
ITGA6 Integrin alpha 6 Breast and prostate cancers Eeles et al., 2009; Michailidou et al., 2013
ITPR1 Inositol 1,4,5-​trisphosphate receptor type 1 Breast cancer Michailidou et al., 2013
JUP Junction plakoglobin Esophageal cancer (squamous cell) Wu et al., 2012a
KITLG KIT ligand Testicular germ cell cancer Turnbull et al., 2010b
KLC3 Kinesin light chain 3 Lung cancer Wang et al., 2013
MAP3K1 Mitogen-​activated protein kinase kinase Breast cancer Ahsan et al., 2014; Michailidou et al., 2013;
kinase 1, E3 ubiquitin protein ligase Thomas et al., 2009; Turnbull et al., 2010a
MUC1 Mucin 1, cell surface associated Esophageal and gastric cancers Abnet et al., 2010
MYB V-​Myb avian myeloblastosis viral oncogene Hodgkin lymphoma Frampton et al., 2013
homolog
NLRP1 NLR family pyrin domain containing 1 Non-​small cell lung cancer Yoon et al., 2010
NRG1 Neuregulin 1 Thyroid cancer Gudmundsson et al., 2012
PAG1 Phosphoprotein membrane anchor with Bladder cancer Figueroa et al., 2014b
glycosphingolipid microdomains 1
PARK2 Parkin RBR E3 ubiquitin protein ligase Pancreatic cancer Low et al., 2010
POLR1D Polymerase (RNA) I polypeptide D, 16kDa Large B-​cell lymphoma Kumar et al., 2011b
PRKAA1 Protein kinase, AMP-​activated alpha 1 Gastric cancer Shi et al., 2011
catalytic subunit
PRKACB Protein kinase CAMP-​dependent catalytic Breast cancer (male) Orr et al., 2012
beta
PRKAR2B Protein kinase CAMP-​dependent regulatory Bladder cancer Figueroa et al., 2014a
type II beta
PTPN2 Protein tyrosine phosphatase non-​receptor Esophageal cancer (squamous cell) Wu et al., 2012a
type 2
RUNX1 Runt-​related transcription factor 1 Esophageal cancer Wu et al., 2011
(continued)
470

470 PART III:  THE CAUSES OF CANCER

Table 25–2. Continued

Cancers for Which Associations

GENE Symbol Gene Name* Reported References

SIAH2 Siah E3 ubiquitin protein ligase 2 Breast cancer Elgazzar et al., 2012
SKAP1 Src kinase–​associated phosphoprotein 1 Ovarian cancer Goode et al., 2010; Pharoah et al., 2013
SKIL SKI-​like proto-​oncogene Prostate cancer Kote-​Jarai et al., 2011
SLC22A1 Solute carrier family 22 (organic cation Prostate cancer Eeles et al., 2009; Schumacher et al., 2011
transporter) member 1
SMAD3 SMAD family member 3 Mothers Against Lung cancer Zhang R et al., 2014
Decapentaplegic Homolog 3
SMAD7 SMAD family member 7 Mothers Against Colorectal cancer Broderick et al., 2007; Peters et al., 2012;
Decapentaplegic Homolog 7 Peters et al., 2013; Tenesa et al., 2008;
Tomlinson et al., 2008; Zhang B et al.,
2014a; Zhang B et al., 2014b
SYK Spleen tyrosine kinase Prostate cancer Tao et al., 2012
SYNJ2 Synaptojanin 2 Colorectal cancer Jiao et al., 2012
TCF3 Transcription factor 3 Hodgkin’s lymphoma Cozen et al., 2014
TCF7L2 Transcription factor 7-​like 2 (T-​cell specific Breast and colorectal cancers Couch et al., 2013; Michailidou et al., 2013;
HMG-​box) Zhang B et al., 2014a
TERT Telomerase reverse transcriptase Breast, lung, prostate, and testicular germ Garcia-​Closas et al., 2013; Hu et al., 2011;
cell cancers Kote-​Jarai et al., 2011; Lan et al., 2012;
Michailidou et al., 2013; Purrington et al.,
2014; Turnbull et al., 2010b
TET2 Tet methylcytosine dioxygenase 2 Breast cancer Michailidou et al., 2013
TFF2 Trefoil factor 2 Pancreatic cancer Wu et al., 2012b
TGFBR2 Transforming growth factor beta receptor II Breast cancer Michailidou et al., 2013
(70/​80kDa)
TNFRSF19 Tumor necrosis factor receptor superfamily Lung cancer Hu et al., 2011
member 19
TNRC6B Trinucleotide repeat containing 6B Prostate cancer Amin Al et al., 2013; Sun et al., 2009;
Tao et al., 2012
TUBA1C Tubulin alpha 1C Prostate cancer Kote-​Jarai et al., 2011

* From GeneCards Human Gene Database.

(Gibson et  al., 2014b), and the risk of multiple myeloma is elevated
(Clifford et al., 2005; Dal Maso et al., 2003; Engels et al., 2006b, 2008;
Frisch et al., 2001; Grulich et al., 2002, 2007; Newnham et al., 2005;
Shiels et al., 2009).
Epstein-​Barr virus (EBV) plays an important role in the etiology of
DLBCL, Burkitt lymphoma, and CNS NHL. EBV genomic material
and viral proteins can be detected in a sizable fraction of DLBCL and
Burkitt lymphoma tumors, and in virtually all CNS NHLs, that arise in
HIV-​infected people (International Agency for Cancer on Research, 1997).
Chronic B-​cell activation also may contribute to the etiology of NHL
among HIV-​infected people (Landgren et al., 2010; Vendrame et al., 2014).
HIV-​infected people have an elevated risk of anogenital cancers
(Chaturvedi et  al., 2009; Dal Maso et  al., 2003; Engels et  al., 2006b,
2008; Frisch et al., 2001; Grulich et al., 2002, 2007; Newnham et al.,
2005; Shiels et al., 2009). Among these cancers, the most common are
cervical and anal cancers, but risk is also increased for vulvar, vag-
inal, and penile cancers (Chaturvedi et  al., 2009). Anogenital cancers
are largely caused by oncogenic subtypes of human papillomavirus
(HPV). HIV-​infected women manifest an elevated prevalence of cervi-
cal HPV infection, which appears at least partly related to decreased
HPV clearance, and there is an increased incidence of cervical atypia
and in situ cervical cancer (De Vuyst et al., 2008). Cervical cancer is
the most common cancer among HIV-​infected women in sub-​Saharan
Africa (Mbulaiteye et al., 2006; Newton et al., 2001; Tanon et al., 2012).
High-​risk sexual behaviors, as well as inadequate screening for cervi-
cal cancer and incomplete follow-​up for treatment of precursor lesions,
likely explain some of the excess risk for cervical cancer among HIV-​
infected women in both developed and developing countries. In the
United States, risk of anal cancer is highest among HIV-​infected homo-
sexual men (reflecting sexual acquisition of anal HPV infection), but all
subgroups of HIV-​infected people manifest an elevated risk compared
with the general population (Chaturvedi et al., 2009).
Among HIV-​ infected people, risk of cervical and anal cancer
increases with immunosuppression (Bertisch et  al., 2013; Guiguet
et  al., 2009). HAART use is associated with decreased persistence
of cervical HPV infection and decreased progression to preneo-
plastic lesions (Minkoff et  al., 2010), and the incidence of cervical
cancer has declined over time among HIV-​infected women in the
United States (Robbins et  al., 2014). For anal cancer, associations
with depressed CD4 counts are apparent over prolonged intervals,
suggesting that HIV-​related immunosuppression affects early stages
on the etiologic pathway from HPV infection to cancer (Bertisch
et al., 2013). Paradoxically, some recent data indicate a rising trend for
anal cancer among HIV-​infected people in the United States (Robbins
et al., 2014). HPV is involved in the etiology of a subset of oropha-
ryngeal cancers, but risk for oropharyngeal cancer is only modestly
elevated among HIV-​infected people (Chaturvedi et al., 2009).
HIV infection is also associated with elevated risk for other less
common malignancies in which viruses are implicated. HL, espe-
cially the mixed cellularity subtype, occurs in substantial excess,
and most tumors manifest evidence of EBV infection (Clifford
et al., 2005; Dal Maso et al., 2003; Engels et al., 2006b, 2008; Frisch
et  al., 2001; Grulich et  al., 2002, 2007; Newnham et  al., 2005;
Shiels et al., 2009). Children with AIDS have a markedly elevated
risk of leiomyosarcoma causally associated with EBV (Simard
et  al., 2012). HIV-​infected people also manifest an increased risk
for liver cancer (specifically hepatocellular carcinoma, caused by
hepatitis B and C viruses), although the contribution of immuno-
suppression is uncertain (Clifford et  al., 2005; Dal Maso et  al.,
2003; Engels et al., 2006b, 2008; Frisch et al., 2001; Grulich et al.,
2002, 2007; Newnham et al., 2005; Shiels et al., 2009). Liver can-
cer risk is highest in subgroups of the HIV population with the
greatest blood-​borne exposure to hepatitis C virus (i.e., injection
drug users, hemophiliacs) (Sahasrabuddhe et  al., 2012). The inci-
dence of liver cancer is increasing among HIV-​infected people in
the United States (Robbins et al., 2014; Sahasrabuddhe et al., 2012),
perhaps due to an increase in the duration of hepatitis B and C
virus infection with prolonged survival. Risk is elevated 13-​fold
 471

Immunologic Factors 471

Table 25–3.  Risk for Selected Cancers in Registry-​Based Cohort Studies of HIV-​Infected People

Frisch et al., Grulich et al., Dal Maso et al., Newnham et al., Engels et al., Engels et al.,
Study 2001 2002 2003 2005 2006b* 2008*

STUDY CHARACTERISTICS
HIV/​AIDS status AIDS HIV or AIDS AIDS HIV or AIDS AIDS HIV without
AIDS
Country US Australia Italy England US US
Calendar years 1980–​1996 1985–​1999 1985–​1998 1985–​2001 1996–​2002 1991–​2002
Number of people 302,834 13,067 12,104 33,190 107,417 57,350
STANDARDIZED INCIDENCE RATIO FOR CANCER (95% CI)
Infection-​related cancers
KS 178 (173–​182) —​ 1750 (1600–​1900) —​ 3640 (3330–​3980) 800 (650–​970)
NHL 73 (70–​75) —​ 350 (320–​390) 43 (39–​46) 23 (21–​25) 5.6 (4.7–​6.6)
Cervix 5.2 (3.8–​6.9) —​ 22 (13–​35) 1.0 (0.2–​2.9) 5.3 (3.6–​7.6) 2.6 (1.6–​3.9)
Anus 23 (17–​30) 37 (18–​68) 34 (12–​74) 23 (14–​37) 20 (14–​26) 8.1 (4.4–​14)
Liver 3.1 (2.0–​4.6) 2.7 (0.6–​8.0) 1.9 (0.4–​5.6) 5.6 (3.0–​9.6) 3.3 (2.0–​5.1) 2.7 (1.4–​4.7)
Hodgkin lymphoma 6.7 (5.3–​8.3) 7.9 (4.4–​13) 16 (12–​22) 5.6 (4.0–​7.7) 14 (11–​17) 4.5 (2.9–​6.6)
Non-​infection-​related cancers
Lung 2.8 (2.4–​3.1) 1.4 (0.8–​2.3) 2.4 (1.5–​3.7) 2.2 (1.6–​3.1) 2.6 (2.1–​3.1) 2.3 (1.8–​2.8)
Kidney 1.2 (0.7–​1.8) 0.8 (0.2–​2.3) 1.1 (0.2–​3.2) 1.1 (0.4–​2.5) 1.8 (1.1–​2.8) —​
Melanoma 1.0 (0.7–​1.5) 1.3 (0.9–​1.9) 0.8 (0.2–​2.4) 0.2 (0–​0.6) 1.0 (0.5–​1.8) —​
Colorectum 0.6 (0.4–​0.9) 0.5 (0.2–​0.9) 1.4 (0.6–​2.6) 0.9 (0.5–​1.5) 1.0 (0.7–​1.4) —​
Prostate 0.5 (0.4–​0.7) 1.1 (0.5–​1.9) 1.2 (0.1–​4.3) 0.9 (0.3–​2.0) 0.5 (0.4–​0.7) —​
Breast 0.5 (0.3–​0.8) 1.1 (0.2–​2.3) 0.7 (0.1–​2.0) 0.8 (0.4–​1.4) 0.8 (0.5–​1.2) —​

Abbreviations: CI = confidence interval; KS = Kaposi sarcoma; NHL = non-​Hodgkin’s lymphoma.

Some estimates were calculated using observed and expected counts calculated from data presented in the cited reports.
*Engels et al. (2006b) also contains additional data for calendar years that overlap with Frisch et al. (2001). Engels et al. (2008) contains additional data on people with AIDS that
overlap with Engels et al. (2006b). The overlapping data are not presented in the table.

for Merkel cell carcinoma (Engels et al., 2002), a rare skin cancer
caused by the Merkel cell polyomavirus. A strongly elevated risk
for conjunctival carcinoma has been noted, especially among HIV-​
infected people in Africa (Newton et  al., 2001), although a viral
etiology is not established.
Lung cancer is one of the most common malignancies in HIV-​
infected people, and risk is elevated approximately 1.5-​to 3-​fold
compared with the general population (Dal Maso et al., 2003; Engels
et  al., 2006b, 2008; Frisch et  al., 2001; Grulich et  al., 2002, 2007;
Newnham et al., 2005; Shiels et al., 2009). All subtypes of lung can-
cer arise in excess (Chaturvedi et al., 2007). To some extent, this ele-
vation reflects the very high frequency of current or former smoking
among HIV-​infected people (estimated to be > 80% in many US stud-
ies) (Kirk et al., 2011), and almost all cases of lung cancer occur in
smokers (Engels et al., 2006a). Importantly, however, the elevation in
lung cancer risk appears to be greater than explained by smoking alone
(Chaturvedi et al., 2007; Engels et al., 2006a; Shiels et al., 2010a; Sigel
et al., 2012). Although lung cancer can occur in HIV-​infected people
in the absence of immunosuppression, risk increases with declining
CD4 counts (Guiguet et al., 2009), and there has been a decline in lung
cancer incidence in recent years that may be due to improved HIV
therapy (Robbins et al., 2014). One hypothesis is that lung cancers in
HIV-​infected people occur due to the synergistic effects of tobacco
and the chronic inflammation that arises from repeated lung infections
(Engels, 2009).
There is a slight increase in the incidence of melanoma demon-
strated in some studies of HIV-​infected people (Table 25–3) (Dal
Maso et  al., 2003; Engels et  al., 2006b, 2008; Frisch et  al., 2001;
Grulich et al., 2002, 2007; Lanoy et al., 2009; Newnham et al., 2005;
Shiels et al., 2009). Based on limited data, there also appears to be a
2-​to 3-​fold elevated risk of basal cell and squamous cell skin can-
cers, with risk for squamous cell skin cancer increasing at lower CD4
counts (Silverberg et al., 2013).
HIV-​infected people do not have an elevated risk for other common
cancers. Indeed, many studies demonstrate a reduced risk for breast
and prostate cancers, and colorectal cancer risk is similar to that in the
general population (Dal Maso et al., 2003; Engels et al., 2006b, 2008;
Frisch et al., 2001; Grulich et al., 2002, 2007; Newnham et al., 2005;
Shiels et al., 2009). The deficit in prostate cancer may partly reflect
lower levels of screening or may instead be due to unknown biological
processes (Marcus et al., 2014; Shiels et al., 2010b).
In the United States (and presumably other countries), the HIV
epidemic has had a measurable impact on the general population
trends for KS, NHL, and anal cancer, due to the very high relative
risks associated with HIV infection (Shiels et al., 2012b; Shiels MS
et al., 2011). HIV led to a marked increase in the incidence of KS
in sub-​Saharan Africa (Wabinga et  al., 2000). HIV infection does
not increase risk for common cancers typically associated with aging
(e.g., prostate, breast, and colorectal cancers), and HIV infection is
not associated with an earlier age at diagnosis for most cancers (Shiels
et al., 2010c). Nonetheless, with improvements in HIV therapy and
greater longevity, the HIV population is aging. Consequently, there
has been a shift over time in the cancer burden from AIDS-​defin-
ing cancers to other cancers, including those that are common in the
general population at older ages (Robbins et al., 2015b; Shiels MS
et al., 2011).
Finally, it is of interest to consider whether antiretroviral medica-
tions used to treat HIV infection may affect cancer risk, especially
since the medications must be used lifelong to suppress viral rep-
lication. It is difficult to discern any adverse effects, since the ben-
efits associated with improved immune function are substantial.
Initial attention regarding carcinogenicity focused of one class of
HIV medications, nucleoside reverse transcriptase inhibitors, which
can cause DNA damage in vitro (Olivero, 2007). Perhaps the best
data on the effects of these drugs come from assessment of HIV-​unin-
fected children who were exposed to zidovudine in utero; these stud-
ies, although limited in the number of individuals evaluated and the
length of follow-​up, have not identified a clear increase in cancer risk
(Benhammou et al., 2008; Hanson et al., 1999). More recently, cohort
studies have compared cancer risk associated with the use of two
broad classes of antiretroviral medications:  protease inhibitors and
non-​nucleoside reverse transcriptase inhibitors (Bruyand et al., 2015;
Chao et al., 2012). An increased risk of anal cancer has been observed
for HIV-​infected patients treated with protease inhibitors, but this
association does not have a ready biological explanation (Bruyand
et al., 2015; Chao et al., 2012).
472

472 PART III:  THE CAUSES OF CANCER

Cancers Associated with Solid Organ Transplantation
Solid organ transplantation is a life-​saving procedure for patients
with end-​stage organ disease, most commonly of the kidney, liver,
heart, or lung. Recipients of these organs must receive lifelong
immunosuppressive therapy to prevent immune rejection of their
donor organ. Immunosuppression is maintained with combinations
of medications, which commonly include a calcineurin inhibitor.
Immunosuppression is most intense in the 1–​2  years immediately
after transplantation, due to the use of induction therapy with T-​cell
depleting or modulating antibodies, as well as high doses of oral
immunosuppressive agents. In the absence of organ rejection, medi-
cations are subsequently tapered to simplify the medication regimen
and lower medication doses over a period of several years. Rejection
of the donor organ is treated with increases in immunosuppressive
therapy.
Because transplant immunosuppression mainly targets T-​cell func-
tion, the spectrum of cancer in transplant recipients resembles that
seen in HIV-​infected patients (Tables 25–3 and 25–4) (Adami et al.,
2003; Collett et  al., 2010; Engels et  al., 2011; Grulich et  al., 2007;
Vajdic et  al., 2006; Villeneuve et  al., 2007). However, solid organ
transplant recipients are at increased risk for several cancers not asso-
ciated with HIV infection, which may partly reflect the effects of
end-​stage organ disease, other comorbid medical conditions, or direct
carcinogenic effects of immunosuppressive medications. A  simple
marker of immune status, such as the CD4 count measured in periph-
eral blood, is not available for transplant recipients. As a result, the
argument that immunosuppression itself is responsible for an increase
in cancer risk is mainly based on the similarity in the cancer risks
between HIV-​infected people and transplant recipients, the known
etiologic contribution of viruses, and the absence of other obvious
explanations.
Other than skin cancers (discussed later in the chapter), NHL is
the most common malignancy that arises in solid organ transplant
recipients (Adami et  al., 2003; Collett et  al., 2010; Engels et  al.,
2011; Grulich et al., 2007; Madeleine et al., 2013; Vajdic et al., 2006;
Villeneuve et al., 2007). An increased risk for NHL was first described
in kidney transplant recipients in 1973 (Hoover and Fraumeni, 1973),
which was one of the first clues that this malignancy is caused by
immunosuppression. In the setting of transplantation, NHL is now
considered part of a spectrum of “post-​transplant lymphoprolifera-
tive disorder” (PTLD) (Swerdlow et al., 2008). PTLD ranges from
benign hyperplasia of lymphoid tissue resembling infectious mon-
onucleosis, to aggressive polyclonal proliferation of lymphocytes,
to frank malignancy (including NHL, HL, and multiple myeloma).
PTLD is largely caused by EBV, which can efficiently drive lym-
phocyte proliferation in the absence of effective immune control
(Swerdlow et al., 2008). People who develop primary EBV infection
after transplantation (primarily pediatric transplant recipients) are at
greatest risk of PTLD, due to the lack of preexisting immunity to
EBV (Opelz et al., 2009).
NHL exhibits a biphasic onset after transplantation (Clarke et al.,
2013; Engels et  al., 2011; van Leeuwen et  al., 2009). Risk is very
high in the first year after transplant and is associated with primary
EBV infection and use of intensive induction immunosuppression
(mainly with T-​cell-​depleting antibodies) (Gibson et  al., 2014a; van
Leeuwen et  al., 2009). Risk subsequently falls and then rises again
approximately 3–​5 years after transplantation (Engels et al., 2011; van
Leeuwen et al., 2009). The majority of post-​transplant NHLs manifest
evidence for EBV infection in tumor cells, although a greater fraction
of late-​onset NHLs are EBV negative compared to early-​onset cases
(Swerdlow et al., 2008). DLBCL is the most common NHL subtype
in solid organ transplant recipients, and risk is elevated 14-​fold com-
pared with the general population (Clarke et al., 2013). Risk is strongly
elevated for Burkitt lymphoma and increased for a number of other
less common NHL subtypes as well (Clarke et al., 2013). Transplant
recipients also have an elevated risk of HL and plasma cell neoplasms
(including multiple myeloma), and a large fraction of these cases are
EBV-​positive (Clarke et al., 2013; Engels et al., 2013).
NHL risk is highest in recipients of a heart, lung, intestine, or pan-
creas (Clarke et al., 2013; Engels et al., 2011; Opelz and Dohler, 2004),
which may reflect the variable intensity of immunosuppression across
transplants of different organs, young age of recipients (for intestinal
transplantation), or the exposure of recipients to donor lymphocytes or
EBV delivered with the organ graft (for lung or intestinal transplanta-
tion). Solid organ transplant recipients have a markedly elevated risk
for developing NHL in the transplanted organ (Gibson et  al., 2014a),
which could be caused by chronic immune stimulation against donor
HLA antigens. Nonetheless, the majority of NHLs that arise in transplant

Table 25–4.  Risk for Selected Cancers in Registry-​Based Cohort Studies of Solid Organ Transplant Recipients

Study Adami et al., 2003 Vajdic et al., 2006 Villeneuve et al., 2007 Collett et al., 2010 Engels et al., 2011

STUDY CHARACTERISTICS
Transplanted organs All Kidney Kidney Kidney* All
Country Sweden Australia Canada UK US
Calendar year of transplants 1970–​1997 Pre-​1986–​2003 1981–​1998 1980–​2007 1987–​2008
Number of recipients 5931 10,180 11,155 25,104 175,732
STANDARDIZED INCIDENCE RATIO FOR CANCER (95% CI)
Infection-​related cancers
KS —​ 208 (114–​349) —​ 17 (8.9–​30) 61 (51–​73)
NHL 6.0 (4.4–​8.0) 9.9 (8.4–​12) 8.8 (7.4–​11) 13 (11–​14) 7.5 (7.2–​7.9)
Cervix 2.0 (0.7–​4.7) 2.5 (1.3–​4.3) 1.6 (0.6–​3.4) 2.3 (1.4–​3.5) 1.0 (0.8–​1.4)
Anus 10 (2.8–​26) 2.8 (1.5–​4.6) —​ 10 (6.6–​15) 5.8 (4.7–​7.2)
†
Liver 1.1 (0.3–​2.8) 3.2 (1.5–​5.9) 1.8 (0.6–​4.3) 2.4 (1.5–​3.8) 1.0 (0.8–​1.3)
Hodgkin’s lymphoma 2.2 (0.3–​8.1) 3.8 (1.5–​7.7) 3.6 (1.7–​6.9) 7.4 (5.3–​10) 3.6 (2.9–​4.4)
Non-​infection-​related cancers
Lung 1.7 (1.1–​2.5) 2.5 (2.0–​3.0) 2.1 (1.7–​2.5) 1.4 (1.2–​1.6) 2.0 (1.9–​2.1)
Kidney 4.9 (3.3–​7.1) 7.3 (5.7–​9.2) 7.3 (5.7–​9.2) 7.9 (6.7–​9.3) 4.7 (4.3–​5.0)
Melanoma 1.8 (1.0–​3.0) 2.5 (2.1–​3.1) 1.9 (1.2–​3.0) 2.6 (2.0–​3.3) 2.4 (2.1–​2.6)
Colorectum 2.0 (1.4–​2.7) 1.7 (1.4–​2.1) 1.4 (1.0–​1.8) 1.8 (1.6–​2.1) 1.2 (1.2–​1.3)
Prostate 1.1 (0.7–​1.7) 1.0 (0.7–​1.3) 0.9 (0.6-​1.3) 1.1 (0.9–​1.4) 0.9 (0.9–​1.0)
Breast 1.0 (0.6–​1.5) 1.0 (0.8–​1.3) 1.3 (1.0–​1.7) 1.0 (0.8–​1.2) 0.9 (0.8–​0.9)

Abbreviations: CI = confidence interval; KS = Kaposi sarcoma; NHL = non-​Hodgkin’s lymphoma.

Some estimates were calculated using observed and expected counts calculated from data presented in the cited reports.
*
Collett et al. (2010) also presents cancer risk estimates separately for 12,504 recipients of other organs.
†
The estimate for liver cancer reported in Engels et al. (2011) included prevalent liver cancers in liver recipients. The estimate in the table is instead derived from Koshiol et al. (2014),
which evaluated the same transplant population.
 473
Immunologic Factors 473
recipients are derived from recipient rather than donor lymphocytes
(Kinch et al., 2014). HLA mismatch between the organ donor and recip-
ient is a risk factor for post-​transplant NHL (Hussain et al., 2015), as
is chronic immune activation (Engels et al., 2012; Haque et al., 2011).
As seen in HIV-​infected people, solid organ transplant recipients
also have an elevated risk for KS and HPV-​related anogenital cancers
(Adami et al., 2003; Collett et al., 2010; Engels et al., 2011; Grulich
et  al., 2007; Madeleine et  al., 2013; Vajdic et  al., 2006; Villeneuve
et al., 2007). The elevation in KS risk, while marked, is less than seen
in HIV (Table 25–4), which may reflect a lower prevalence of KSHV
infection. Of interest, some KS tumors are derived from donor cells,
suggesting that KS progenitor cells may be conveyed with transplanta-
tion (Barozzi et al., 2003). Furthermore, case reports document regres-
sion of transplant-​associated KS when patients are switched from a
calcineurin inhibitor-​based regimen to sirolimus (Stallone et al., 2005),
consistent with a strong therapeutic effect arising from blocking the
mTOR pathway in this tumor. Cervical cancer risk is only slightly
increased or (in some transplant populations) not increased (Adami
et  al., 2003; Collett et  al., 2010; Engels et  al., 2011; Grulich et  al.,
2007; Vajdic et al., 2006; Villeneuve et al., 2007); this pattern likely
reflects prevention through effective screening, since risk for in  situ
cervical cancer is elevated (Madeleine et al., 2013).
The contribution of immunosuppression to the development of hepa-
tobiliary cancers in solid organ transplant recipients is uncertain. Liver
recipients have an elevated risk for developing HCC. Of note, HCC
is a common indication for liver transplantation, and misdiagnosis of
some prevalent cancers as incident cases can inflate the risk estimate
(Engels et al., 2011). Nonetheless, the elevated risk is not entirely arti-
factual, and HCC incidence in liver recipients is associated with HBV
and HCV infections as well as diabetes mellitus (Koshiol et al., 2014).
HCC risk is not elevated in other recipients of other types of organs.
Cholangiocarcinoma also arises in excess among transplant recipients
and is associated with the presence of primary sclerosing cholangitis
as an indication for liver transplant and with the use of azathioprine as
maintenance immunosuppressive therapy (Koshiol et al., 2014).
Solid organ transplant recipients have a remarkably elevated risk of
non-​melanoma skin cancers (approximately 20-​to 100-​fold elevation)
(Bannon et al., 2014; Jensen et al., 1999; Lindelof et al., 2000; Moloney
et al., 2006). Although risk is elevated for basal cell carcinoma, risk is
most increased for squamous cell carcinoma, so that there is a reversal
of the usual preponderance of basal cell carcinomas over squamous cell
carcinomas. Risk is much higher than that observed in HIV-​infected
people (Silverberg et  al., 2013), suggesting the presence of distinct
immune-​related pathways or important contributions from non-​immu-
nologic factors. One possibility is that there are direct DNA damaging
effects from immunosuppressive medications, especially azathioprine,
which appears to act synergistically with ultraviolet radiation to dam-
age the skin (Ingvar et  al., 2010; O’Donovan et  al., 2005). Similar
mechanisms may explain the elevated risks for melanoma (Robbins
et  al., 2015a), lip cancer (standardized incidence ratios of 17–​ 53)
(Adami et al., 2003; Collett et al., 2010; Engels et al., 2011; Grulich
et al., 2007; Vajdic et al., 2006; Villeneuve et al., 2007), and Merkel cell
carcinoma (standardized incidence ratio of 24) (Clarke et al., 2015). Of
interest, randomized trials have demonstrated that maintenance immu-
nosuppression with sirolimus (an mTOR pathway inhibitor) reduces
the incidence of non-​melanoma skin cancers in solid organ transplant
recipients, compared with other (mainly calcineurin inhibitor-​based)
regimens (Euvrard et al., 2012; Yanik et al., 2015)
Kidney cancer arises in excess among transplant recipients (Adami
et al., 2003; Collett et al., 2010; Engels et al., 2011; Grulich et al.,
2007; Madeleine et  al., 2013; Vajdic et  al., 2006; Villeneuve et  al.,
2007), which may be due to a complex assortment of factors. Risk of
renal cell carcinoma (RCC) is most increased among kidney recipi-
ents (Collett et al., 2010; Engels et al., 2011), and a large fraction of
RCC cases have a papillary histology, as opposed to the predomi-
nance of clear cell RCCs observed in the general population (Klatte
et al., 2010). The excess of RCCs in kidney recipients is partly due
to the effects of end-​stage renal disease. Patients with end-​stage renal
disease treated with long-​term dialysis can develop acquired poly-
cystic kidney disease, which is associated with the development of
RCC (Hurst et al., 2010; Levine et al., 1991). Most often, a patient’s
native kidneys are left in place at the time of kidney transplantation,
and following transplantation, most RCCs develop in the chronically
damaged native kidneys rather than the donor kidney. Nonetheless,
risk of RCC is also elevated in recipients of organs other than the kid-
ney (Collett et al., 2010; Engels et al., 2011). The occurrence of RCC
in transplant recipients may partly reflect non-​immune side effects
of immunosuppressive medications, since some are nephrotoxic, and
RCC risk is not elevated among HIV-​infected people (Table 25–3).
Furthermore, kidney recipients are at increased risk of cancers of
the renal pelvis and bladder (Adami et al., 2003; Collett et al., 2010;
Engels et al., 2011; Grulich et al., 2007; Madeleine et al., 2013; Vajdic
et al., 2006; Villeneuve et al., 2007), which may be caused by toxic
exposures (e.g., analgesics, herbal remedies) that can lead to renal
failure (Gokmen et al., 2012c, 2013).
Solid organ transplant recipients have an elevated risk of lung can-
cer (Table 25–4), although the increase is less than that seen in HIV-​
infected people, and a contribution due to immunosuppression is not
established. Tobacco use is certainly a major factor (Dickson et al.,
2006; Minai et al., 2008). Lung cancer risk is especially high in lung
recipients (Collett et al., 2010; Engels et al., 2011); many lung recipi-
ents receive only a single donor lung, and lung cancers typically arise
in the end-​stage native lung (Dickson et al., 2006; Minai et al., 2008).
Solid organ transplant recipients have modestly increased risk for
colorectal cancer (Table 25–4) (Adami et  al., 2003; Collett et  al.,
2010; Engels et  al., 2011; Grulich et  al., 2007; Vajdic et  al., 2006;
Villeneuve et al., 2007). Among transplant recipients, risk is most ele-
vated for proximal colon cancer, not increased for distal colon can-
cer, and actually decreased for rectal cancer (Safaeian et  al., 2015).
Although this pattern is unexplained, the absence of a similar eleva-
tion in colon cancer risk among HIV-​infected people argues against
a major contribution from immunosuppression. Indeed, much of the
risk may be related to strong increases in colon cancer among liver
recipients with underlying primary sclerosing cholangitis (a condition
associated with inflammatory bowel disease) and lung recipients with
cystic fibrosis (associated with chronic gastrointestinal malabsorption)
(Safaeian et al., 2015). Colorectal cancer risk is also associated with
use of cyclosporine and azathioprine (Safaeian et al., 2015).
Transplant recipients also have a reduced risk of prostate and
breast cancers (Adami et al., 2003; Collett et al., 2010; Engels et al.,
2011; Grulich et  al., 2007; Vajdic et  al., 2006; Villeneuve et  al.,
2007) (Table 25–4), as seen in HIV-​infected people. Again, the rea-
son for these deficits is unknown, and there may be a biological
explanation. Alternatively, the pattern could reflect the screening of
transplant candidates and the removal of prevalent cancers prior to
transplantation.
In rare instances, a donor cancer is transmitted along with the trans-
planted organ (Desai et al., 2012; Nalesnik et al., 2011; Penn, 1997;
Strauss and Thomas, 2010). Such cancers can be due to the presence
of small tumors of the donor organ that are undetected at the time of
transplantation (e.g., a small renal cell carcinoma in the donor kid-
ney) or due to microscopic metastases of other cancers (e.g., mela-
noma) that are not known to the transplant team. Organ donors are
screened for a remote history or the current presence of an undocu-
mented cancer, and most such individuals are prevented from donating
(Nalesnik et  al., 2011). Transmitted cancers frequently present at a
disseminated stage and behave aggressively, in part due to the presence
of immunosuppression.
Cancers Associated with Hematopoietic
Stem Cell Transplantation
Hematopoietic stem cell transplantation (HSCT) involves the
transplantation of multipotent hematopoietic stem cells from bone
marrow, peripheral blood, or umbilical cord blood. HSCT is most
commonly used as treatment for hematologic malignancies, but is
also sometimes used to treat some non-​malignant hematologic con-
ditions or solid tumors. As part of the procedure, it may be necessary
to ablate the recipient’s own bone marrow, typically with cytotoxic
chemotherapy and/​or high-​dose irradiation used as a conditioning
regimen. The transplant procedure can be autologous (when the
47
474 PART III:  THE CAUSES OF CANCER
patient’s own stem cells are used) or allogeneic (when the stem cells
come from a donor).
A major complication of allogeneic HSCT is graft-​versus-​host dis-
ease (GVHD), in which donor-​derived T-​cells attack the recipient’s
tissues, most notably the skin, gastrointestinal tract, and liver. Acute
GVHD presents in the first few months after HSCT and is a risk fac-
tor for chronic GVHD, which can persist for years. Because severe
GVHD is a major source of morbidity and mortality in HSCT recipi-
ents, allogeneic HSCT recipients are administered GVHD prophylaxis
with immunosuppressive medications in the months immediately fol-
lowing transplantation. Occurrence of GVHD prompts intensification
of these medications and the instigation of prolonged immunosuppres-
sive therapy. The immunosuppressive medication regimens resemble
those used in solid organ transplant recipients (e.g., prophylaxis with
a calcineurin inhibitor, and treatment of acute GVHD with pulsed ste-
roids). One notable difference is that, in the absence of GVHD, HSCT
recipients can often be weaned from immunosuppressive medications
over a period of several years, whereas cessation of immunosuppres-
sive therapy is not possible for solid organ recipients. Autologous
HSCT is not associated with GVHD and so does not require the
administration of long-​term immunosuppressive therapy.
As in solid organ transplantation, PTLD is an important compli-
cation of allogeneic HSCT. PTLD typically develops in the first few
years post-​ transplantation (Landgren et  al., 2009). EBV infection
plays an important role in driving lymphocyte proliferation (Zutter
et  al., 1988). In contrast to what is observed following solid organ
transplantation, the majority of PTLDs in HSCT recipients are derived
from donor lymphocytes (Zutter et al., 1988). While some PTLD cases
are polyclonal in nature, many cases can be classified as monomorphic
NHL or HL (Landgren et al., 2009; Rowlings et al., 1999; Swerdlow
et al., 2008). Broad depletion of T-​cells utilized to prevent GVHD is a
strong risk factor for PTLD (Landgren et al., 2009).
HSCT recipients are also at elevated risk of developing solid tumors
(Rizzo et al., 2009). Most notably, allogeneic recipients have strongly
increased risk for squamous cell carcinomas of the oral cavity, upper
gastrointestinal tract, and skin (Rizzo et  al., 2009). Chronic GVHD
commonly affects these sites, and chronic GVHD is a risk factor for
these malignancies (Curtis et  al., 2005), suggesting that sustained
inflammation resulting from GVHD contributes to carcinogenesis.
However, as in solid organ transplantation, it is difficult to disentangle
whether some increase in risk for these cancers results from directly
carcinogenic effects of the immunosuppressive medications. Radiation
therapy given as part of the therapy for the primary cancers that are
the indication for HSCT, and the HSCT conditioning regimen itself,
are also risk factors for the development of some solid cancers (Rizzo
et al., 2009).
Autoimmune Diseases and Cancer
Patients with certain autoimmune diseases have an increased risk of
NHL, and some of these associations appear to be specific accord-
ing to NHL subtype (Morton et al., 2014). Notably, risk of DLBCL
is elevated in patients with systemic lupus erythematosus, Sjögren
syndrome, and perhaps rheumatoid arthritis (Anderson et  al., 2009;
Ekstrom Smedby et al., 2008; Morton et al., 2014), likely reflecting
the effects of chronic immune activation. Given the parallel with the
immunodeficiency conditions described earlier, it is likely that the
associations are due to etiological links with these conditions or their
treatment. Very strong associations are also described for rarer NHL
subtypes that arise at sites affected by specific autoimmune conditions,
presumably because of chronic localized immune stimulation. Patients
with Sjögren syndrome have 1000-​fold increased risk for developing
marginal zone lymphoma in the salivary glands, the site of chronic
immune damage in this disorder (Ekstrom Smedby et al., 2008). Celiac
disease is associated with a strongly increased risk of T-​cell lympho-
mas, including a 250-​fold elevation in risk of enteropathy-​associated
T-​cell lymphoma of the small intestine (Ekstrom Smedby et al., 2008).
T-​cell lymphoma risk is also increased in patients with psoriasis or
other cutaneous autoimmune diseases (Anderson et al., 2009; Ekstrom
Smedby et  al., 2008), but this perhaps reflects diagnostic confusion
since many T-​cell lymphomas affect the skin.
The medications used to treat autoimmune conditions likely play
a role in the development of some cancers, including NHL. Patients
treated with methotrexate can develop EBV-​ positive lymphomas
resembling cases of PTLD, and the tumors can regress following dis-
continuation of this drug (Kamel et al., 1993), supporting a direct con-
tribution of immunosuppressive therapy. Use of azathioprine or the
related drug 6-​mercaptopurine in patients with inflammatory bowel
disease is associated with an elevated risk of skin cancer (Ariyaratnam
and Subramanian, 2014), either as a result of immunosuppression or
sensitization to ultraviolet radiation. Although there has been concern
that medications that inhibit the action of tumor necrosis alpha might
increase the risk of NHL and other cancers (Brown et al., 2002), most
studies have failed to confirm an association (Lopez-​Olivo et al., 2012;
Nyboe Andersen et al., 2014).
A few autoimmune diseases are associated with an elevated risk of
carcinomas arising in the affected organ, again likely due to chronic
immune-​related damage and inflammation. Inflammatory bowel dis-
ease (including ulcerative colitis and Crohn’s disease) is accompanied
by an elevated risk of colorectal cancer, and the magnitude of risk is
related to the severity, extent, and duration of colonic inflammation
(Beaugerie and Itzkowitz, 2015). Crohn’s disease, which frequently
involves the small intestine, is associated with more than 20-​fold
increased risk of small intestine cancer (Beaugerie and Itzkowitz,
2015; Jess et  al., 2005). Patients with primary sclerosing cholangi-
tis (which is itself associated with ulcerative colitis) have strongly
increased risk of cholangiocarcinoma (Beaugerie and Itzkowitz, 2015;
Claessen et al., 2009).
Finally, some autoimmune diseases are associated with cancer
because of reverse causation (i.e., the cancer or its immediate precur-
sor predisposes to the development of the autoimmune condition).
Examples of such associations include the increased prevalence of der-
matomyositis in patients with many different solid tumors (Kurzrock
and Cohen, 1995)  and of autoimmune hemolytic anemia and idio-
pathic thrombocytopenic purpura in patients with some subtypes of
NHL (Anderson et al., 2009; Visco et al., 2014).
Allergic Conditions and Cancer
It has been challenging to definitively determine whether allergic
disorders affect the risk of cancer. Although numerous studies have
evaluated the relationship between allergic conditions and a number
of different cancers, many of the associations are modest in magni-
tude and vary across studies, making a definitive conclusion difficult
(Turner et al., 2006).
Two opposing mechanisms have been hypothesized to explain
the variable associations observed with allergic conditions. The
immune surveillance hypothesis was mentioned earlier in the
context of HIV infection and transplantation, where it was used
to explain why the risk of some cancers is increased in people
with immunosuppressive conditions. In the context of atopy, this
hypothesis is used to explain a decrease in cancer risk. Specifically,
the immune surveillance hypothesis posits that an allergic immune
response may serve to direct T-​cells to tissues where there is pre-
cancerous damage, which would thereby facilitate the immune
destruction of these lesions. Alternatively, allergic responses may
lead to chronic tissue damage, which would perhaps predict that
atopy would promote the development of cancer. It is unclear
which of these competing hypotheses has a more compelling evi-
dence base in general, and indeed it is possible that allergy may
have differing effects for different cancers.
A methodologic issue in epidemiologic studies of allergic conditions
and cancer is that many such studies rely on participants’ self-​reports
to ascertain the presence of allergic conditions. Because symptoms of
allergic conditions are often mild, and the conditions may be confused
with one another or with non-​allergic conditions, the studies may be
prone to misclassification. Also, subjects may inaccurately recall the
presence of allergic conditions from which they may have suffered in
childhood. When cited in the following, measures of association are
from large well-​designed studies or meta-​analyses.
Several large cohort studies have evaluated cancer risk in association
with asthma or hay fever. Estimates of overall cancer risk vary across
 475
Immunologic Factors 475
studies of people with asthma, from modest protection to slightly
increased risk (i.e., relative risks in the range of 0.7 to 1.1) (Gonzalez-​
Perez et al., 2006; Kallen et al., 1993; Mills et al., 1992; Turner et al.,
2005; Vesterinen et al., 1993). For specific cancer sites, the most con-
sistent association with asthma is the finding of an elevated risk of
lung cancer (relative risks ranging from 1.1 to 1.7) (Gonzalez-​Perez
et al., 2006; Kallen et al., 1993; Mills et al., 1992; Turner et al., 2005;
Vesterinen et al., 1993). Overall cancer risk appears similar in people
with hay fever to people without this condition (Mills et  al., 1992;
Turner et al., 2005).
The association between asthma and lung cancer risk has been
evaluated in numerous case-​control studies in addition to the cohort
studies mentioned in the preceding (Rosenberger et al., 2012; Santillan
et al., 2003). An association between asthma and lung cancer risk has
been observed in studies that adjust for tobacco use (Rosenberger
et al., 2012; Santillan et al., 2003). Proposed biological mechanisms
for an increase in lung cancer among individuals with asthma include
damage to the lung from chronic inflammation, reduced clearance of
inhaled toxins, or increased pulmonary levels of damaging free radi-
cals. Nonetheless, one concern has been that the prevalence of smok-
ing may be higher in people who report a history of asthma than in
people without this history, either because smoking may increase
the risk of asthma or due to confusion in the reports from study par-
ticipants between asthma and chronic obstructive pulmonary disease.
Indeed, the association between asthma and lung cancer risk is weaker
among never-​smokers than in ever-​smokers (Rosenberger et al., 2012),
suggesting that some estimates may suffer from residual confound-
ing by smoking. Furthermore, there is substantial heterogeneity across
studies in the estimated magnitude of the associations of asthma with
lung cancer.
Associations between allergic conditions and risk of brain tumors
have been extensively investigated. Many case-​control studies have
demonstrated protective associations with risk of glioma, for allergic
conditions overall as well as specifically for asthma (odds ratios [OR]
0.6–​0.8), eczema (OR 0.5–​0.9), and hay fever (OR 0.7–​1.0) (Chen
et al., 2011; Zhao et al., 2014). In contrast, associations of serum IgE
levels with subsequent risk of glioma have been borderline and incon-
sistent (Calboli et  al., 2011; Schlehofer et  al., 2011; Schwartzbaum
et al., 2012). Use of antihistamine medications, frequently utilized by
patients in the management of hay fever, are inversely associated with
glioma (McCarthy et al., 2011). Use of antihistamine medications may
simply be a marker for the presence of allergy. Indeed, in one study that
stratified subjects based on the presence of allergic conditions, antihis-
tamine use was not associated with glioma risk overall, and long-​term
use was actually associated with increased risk of high-​grade tumors
(Scheurer et al., 2011). For meningioma, there is some evidence for a
decreased risk in association with eczema (Wang M et al., 2011).
Risk of pancreatic cancer appears reduced in people with allergies,
primarily due to associations with respiratory allergies and hay fever
in particular (OR 0.6–​0.9) (Gandini et  al., 2005; Olson et  al., 2013;
Turner et  al., 2005). In contrast, asthma is not associated with pan-
creatic cancer risk (Gandini et  al., 2005; Olson et  al., 2013; Turner
et al., 2005).
Hay fever is associated with a modestly reduced risk of develop-
ing NHL (OR 0.8), and the association does not appear to vary across
NHL subtypes (Morton et al., 2014). A strong positive association is
observed between eczema and risk of developing mycosis fungoi-
des/​Sézary syndrome (Morton et al., 2014), but as mentioned earlier
regarding psoriasis and other autoimmune diseases that affect the skin,
this association may represent diagnostic confusion between cutane-
ous diseases. Data on the association of atopy with childhood acute
lymphoblastic leukemia are conflicting (Chang et al., 2012; Linabery
et al., 2010).
Despite much epidemiologic research, it is not straightforward
to reach an etiologic conclusion. The effects, even for some of the
most promising protective associations (glioma, pancreatic cancer,
and NHL), are somewhat weak, and the adverse association between
asthma and lung cancer could be due to confounding. Also, it is unclear
why certain allergic conditions would decrease the risk of glioma
and pancreatic cancer, presumably as a result of enhanced immune
surveillance, when risk of these cancers is not strongly increased in
immunosuppressed HIV-​infected people or transplant recipients.
Inflammation and Cancer
Acute inflammation resultant from tissue insults is beneficial and con-
tributes to the elimination of the agent causing the insult and to tissue
repair. However, if the response leads to a chronic inflammatory state,
it can predispose these same tissues to damage that is hypothesized to
be a risk factor for tumor development through several mechanisms,
including increased cellular proliferation and the generation of free
radicals that can lead to DNA damage (Balkwill and Mantovani, 2001;
Coussens and Werb, 2002; Grivennikov et al., 2010). Several lines of
evidence point to a role for inflammation in the development of cancer
at various anatomic sites. Immune infiltrates (e.g., neutrophils, mac-
rophages, and tumor-​infiltrating lymphocytes) are commonly present
at tumor sites and likely play an important part in shaping the tumor
microenvironment. There is also evidence showing that some agents
considered carcinogenic induce chronic inflammation, some inflam-
matory medical conditions predispose to cancer, genes associated
with cancer development code for proteins involved in inflammation
responses, and use of anti-​inflammatory agents reduce cancer risk.
Most infections classified as Class  I  carcinogens by the IARC
induce strong and prolonged inflammatory responses (see Chapter 24).
Helicobacter pylori (causes gastric cancer), hepatitis B and C viruses
(cause liver cancer and NHL), human immunodeficiency virus (predis-
poses to multiple cancers, as described earlier), Schistosoma haemato-
bium (causes bladder cancer), and Opisthorchis viverrini (liver flukes;
causes biliary track cancers) all induce chronic infections that lead to
sustained inflammation at the infection site, which is hypothesized
to partially account for the carcinogenic effects of these infections.
Similarly, several chemicals and particulates classified as Class I car-
cinogens by IARC, including tobacco, asbestos, diesel exhaust, and
formaldehyde (see also Chapters  11 and 16)  induce inflammation,
which may be partly responsible for the chronic tissue effects that lead
to cancer.
Various medical conditions that predispose to cancer development
are also known to induce strong chronic inflammation responses (see
discussion earlier in this chapter). These include liver cirrhosis (asso-
ciated with liver cancer) (El-​Serag and Rudolph, 2007), inflammatory
bowel disease (associated with colorectal and small bowel cancers)
(Beaugerie and Itzkowitz, 2015), gallstones and primary sclerosing
cholangitis (associated with biliary track cancers) (Claessen et  al.,
2009; Maurer et al., 2009), chronic atrophic gastritis (associated with
gastric cancer) (Sipponen and Maaroos, 2015), chronic lung diseases
including chronic obstructive pulmonary disease (associated with lung
cancer) (Brenner et  al., 2011), and diabetes and obesity (associated
with numerous cancers) (Giovannucci et al., 2010) (see Chapter 20).
In some instances, these conditions are a near necessary precondition
for the development of the cancer with which they are associated, add-
ing to the biological plausibility and likely importance of inflamma-
tion in the development of these cancers. For example, 70%–​90% of
liver cancers are associated with liver cirrhosis (El-​Serag and Rudolph,
2007), upward of 80% of gallbladder cancers are preceded by gall-
stones (Hsing et al., 2007), and Helicobacter pylori–​induced chronic
atrophic gastritis and intestinal metaplasia are considered precursors to
gastric cancer (Correa, 1988).
As summarized earlier in this chapter, studies of genetic varia-
tion and cancer also point to a role for genes involved in inflamma-
tion responses and cancer at various sites (Table 25–2). It should be
noted, however, that the magnitude of the effect for genetic variation
in inflammation genes and individual cancers is typically small and
therefore not likely to account for a large proportion of disease.
Finally, evidence has accumulated over the past decade suggest-
ing that regular, long-​term use of aspirin and possibly other non-​
­steroidal anti-​inflammatory drugs (NSAIDs) reduce the risk of some
cancers, most notably colorectal cancer (Thun et al., 2012). NSAIDs
act through various mechanisms, including inhibition of enzymes
(called cyclo-​oxygenases or COX enzymes) involved in the forma-
tion of inflammation-​modulating prostaglandins. While low doses
of NSAIDs (e.g., 75–​100 mg of aspirin daily) recommended for
476
476 PART III:  THE CAUSES OF CANCER
cardioprotection are required to induce their analgesic and antipyretic
effects, considerably higher doses are required to reduce inflamma-
tion (Thun et al., 2012). It was therefore initially uncertain whether
low-​dose aspirin use that has been shown to protect against cardio-
vascular disease would also translate to risk reduction for cancers. In
a pooled analysis of six randomized trials that evaluated daily low-​
dose aspirin, there was evidence that regular use for 3+ years was
associated with a 24% reduction in risk of all cancers (OR = 0.76;
95% CI = 0.66, 0.88) (Rothwell et al., 2012). When individual can-
cers were evaluated in a meta-​analysis of these six randomized trials,
evidence for a protective effect was strongest for colorectal cancer,
where daily aspirin use for 5+ years was associated with a 45% reduc-
tion (OR  =  0.55; 95% CI 0.41–​0.76) (Algra and Rothwell, 2012).
In this same analysis, estimates of risk reduction using data from
observational studies yielded comparable and statistically significant
results (risk reduction ranging from 32%–​49%). This justified the
use of both randomized and observational study data to evaluate the
risk of individual cancers other than colorectal cancer, for which
the randomized trials alone were often underpowered. Evidence for
risk reduction with maximum reported aspirin use that was statisti-
cally significant in meta-​analyses of both observational case-​control
studies and randomized trials was observed for biliary tract (43%–​
65% reduction reported) and esophageal (42%–​ 53% reduction
reported) cancers (Algra and Rothwell, 2012). Statistically signifi-
cant evidence for protection in observational studies alone (with sim-
ilarly trending but non-​significant effects observed for randomized
trials) was also observed for gastric (39% reduction reported) and
breast (15%–​19% reduction reported) cancers. Effects were weaker
or not evident for other cancers.
In general, comparable but more limited risk reductions have been
observed when NSAIDs other than aspirin were evaluated (Rostom
et al., 2007). Evidence for a protective effect has also been stronger
when higher-​dose use or higher-​risk populations (e.g., individuals
with a history of colorectal adenomas) were evaluated (Dube et  al.,
2007). At the time of last review in 2007, the US Preventive Services
Task Force (USPSTF) recommended against the routine use of aspi-
rin and NSAIDs to prevent colorectal cancer in individuals at aver-
age risk for colorectal cancer, in large part due to the competing
risks associated with the risk increases observed for gastrointestinal
bleeding and hemorrhagic stroke (Dube et  al., 2007; Rostom et  al.,
2007). Recommendations are currently undergoing re-​review by the
USPSTF, and a recommendation is being contemplated for low-​dose
aspirin use for the primary prevention of colorectal cancer in adults
ages 50–​59 years who have a 10% or greater 10-​year cardiovascular
disease risk, are not at increased risk for bleeding, have a life expec-
tancy of at least 10  years, and are willing to take low-​dose aspiring
daily for at least 10 years (http://​www.uspreventiveservicestaskforce.
org/​BrowseRec/​Search?s=aspirin).
The multiple lines of evidence linking inflammation to cancer
development have motivated studies to directly assess the asso-
ciation between specific markers of inflammation and cancer risk
(Brenner et al., 2014; Carrick et al., 2015). These studies have not
been straightforward and have been difficult to interpret, however,
for several reasons. First, tumors induce inflammation themselves,
making epidemiologic studies of inflammation and cancer particu-
larly prone to reverse causality. As a result, prevalent case-​control
studies, while useful for initial screening of relevant inflammation
markers, are difficult to interpret, and cohort studies or nested case-​
control studies with pre-​diagnostic specimens are needed to care-
fully account for issues of reverse causality. Second, biologically
relevant inflammation occurs at the tissue level, and measurement of
tissue-​specific inflammation preceding cancer is difficult in the con-
text of epidemiologic studies (Basavaraju et al., 2015; Joshu et al.,
2014; Koshiol and Lin, 2012; Vignozzi and Maggi, 2014). Most
epidemiological studies of inflammation and cancer have opted to
measure circulating levels of inflammation markers, which may or
may not be a good surrogate for inflammation at the tissue level.
Third, levels of inflammatory markers can vary over time (Hardikar
et al., 2014b) and cohort studies with available pre-​diagnostic speci-
mens typically have limited serial sampling, again complicating
efforts to understand the temporal relationship between chronic
inflammation and cancer. Furthermore, the inflammatory response
is highly complex and not yet fully understood. Many cell types
and effector molecules with pleiotropic effects are involved in the
inflammatory response. Fully defining the pattern of inflammatory
response and its relationship with cancer has therefore been diffi-
cult. Until recently, this difficulty has been exacerbated by the ina-
bility to measure the large number of known inflammation response
molecules using small volumes of available specimens in existing
studies. This latter problem has been ameliorated in recent years,
as highly multiplexed, reproducible assays requiring small amounts
of specimen have come online (Chaturvedi et  al., 2011). Finally,
even when significant associations between inflammation markers
and a particular cancer have been observed, it has been difficult to
ascertain whether those associations mediate previously established
risk factors (i.e., causal mediator) for the cancer under study or are
explained by them (i.e., confounding).
Despite the difficulties listed previously, some progress has been
made in evaluating the association between molecular markers of
inflammation and various cancers. The most extensively studied
inflammation biomarker studied to date has been C-​reactive protein
(CRP), an acute-​phase inflammation marker in blood induced by the
pro-​inflammatory cytokine IL-​6 and produced by the liver. CRP is
readily measured and has been convincingly linked to risk of cardi-
ovascular disease (CVD), so it was considered a good candidate to
evaluate in studies of inflammation and cancer. In contrast to CVD,
however, evidence linking CRP levels to cancer risk have been con-
flicting. Nonetheless, suggestive evidence for a positive association
between circulating, pre-​diagnostic CRP levels and cancer risk has
been reported for numerous cancers, including colorectal cancer
(Aleksandrova et al., 2010, 2014b; Ananthakrishnan et al., 2014; Chan
et al., 2011; Guo et al., 2013; Song et al., 2013; Toriola et al., 2013;
Tsilidis et al., 2008), lung cancer (Guo et al., 2013; Shiels et al., 2014,
2015b; Zhou et al., 2012), hepatocellular carcinoma (Aleksandrova
et al., 2014a; Chen et al., 2015), gallbladder cancer (Aleksandrova
et al., 2014a), gastric cancer (Sasazuki et al., 2010), esophageal carci-
noma (Hardikar et al., 2014a), ovarian cancer (Ose et al., 2015; Poole
et  al., 2013; Trabert et  al., 2014) and endometrial cancer (Wang T
et al., 2011). In published meta-​analyses, significant evidence for an
association with CRP were noted for all cancers combined, lung can-
cer, colon cancer, and ovarian cancer. Increases in risk of disease
for the individual cancers evaluated were on the order of 10%–​30%
per unit change in natural logarithm CRP levels (Guo et al., 2013;
Poole et al., 2013; Tsilidis et al., 2008; Zhou et al., 2012). Whether
these associations reflect a causal link and, if so, whether they medi-
ate previously known cancer risk factor associations remain to be
determined.
Additional markers of inflammation have been directly evaluated
for their association with cancer, most notably IL-​6, IL-​8, sTNFRI,
and sTNFRII (Aleksandrova et al., 2014a; Brenner et al., 2014; Chan
et al., 2011; Dossus et al., 2013; Edlefsen et al., 2014; Epplein et al.,
2013; Hardikar et al., 2014a; Heikkila et al., 2008, 2009; Ho et al.,
2014; Il’yasova et al., 2005; Kakourou et al., 2015; Ose et al., 2015;
Poole et al., 2013; Shiels et al., 2014; Song et al., 2013; Trabert et al.,
2014; Vendrame et al., 2014; Wang T et al., 2011; Zhou et al., 2012).
As for CRP, while evidence for an association between these markers
and various cancers have been reported, results have not been entirely
consistent. Finally, some recent studies have utilized highly multi-
plexed assays to assess the role of the inflammation pathway in can-
cer development (Bassig et al., 2015; De Roos et al., 2012; Purdue
et  al., 2013, 2015; Shiels et  al., 2013, 2014, 2015b; Trabert et  al.,
2014). These studies are noteworthy because of their attempt to more
comprehensively evaluate the link between inflammation and can-
cer and to identify the subset of markers with consistent, reproduc-
ible associations. Of note are results from discovery and replication
efforts to evaluate inflammation markers associated with NHL and
lung cancer. Studies of NHL have demonstrated robust and consist-
ent associations with B-​cell activation and pro-​inflammatory markers,
including three soluble receptors (sCD23, sCD27, and sCD30) and a
pro-​inflammatory marker receptor (sTNFRII). Odds ratio estimates
 47

Immunologic Factors 477

comparing upper to lower tertiles for these markers were in the range system (Schumacher and Schreiber, 2015). One potential advantage of
of 2–​3. Studies of lung cancer have identified a set of acute-​phase immunotherapy is that the exquisite specificity of the immune system
markers (CRP and SAA), a pro-​inflammatory marker receptor (sTN- might allow targeting of only tumor cells, thereby minimizing treat-
FRII), and a chemokine (CXCL9/​MIG) that are reproducibly asso- ment toxicity.
ciated with future lung cancer risk. Odds ratio estimates comparing Of note, the cancers that are the most frequent focus in the devel-
upper to lower quartiles were in the range of 1.5–​2.0. For both of opment of immunotherapies are not the same as the cancers that are
these cancers, the associations were evident many years before can- increased in immunosuppressed populations (e.g., virus-​related can-
cer diagnosis for many of the markers, suggestive of a true etiological cers). The reasons for this disjunction are not entirely clear. A major
association rather than reverse causality. focus of immunotherapy has been directed against melanoma, which
is increased, but not strongly, in HIV-​infected people and transplant
recipients. Nonetheless, melanoma has been considered an attractive
CANCER OUTCOMES target based on the large number of neoantigens present in this malig-
nancy (Schumacher and Schreiber, 2015), the prognostic relevance
Immunity, Cancer Stage, and Outcomes of tumor-​infiltrating lymphocytes (Clemente et  al., 1996), and the
observation that, in rare cases, melanoma can regress spontaneously
In comparison to investigations relating immunity with the risk of
(presumably due to the development of an effective immune response)
developing cancer, less is known about how immune function affects
(Nathanson, 1976).
the behavior of cancers or the prognosis of cancer patients follow-
Several approaches to immunotherapy have been utilized across a
ing diagnosis. As noted earlier, inflammatory cell infiltrates contribute
range of cancers. Administration of interferon α-​2b has clinical effi-
prominently to the tumor microenvironment. These inflammatory cells
cacy in stimulating an immune response in the treatment of patients
are thought to reflect both the complex processes leading to the cancer
with metastatic melanoma (Kirkwood et al., 1996). Sipuleucel-​T is a
and the host’s immune response to the tumor (Coussens and Werb,
cellular vaccine used in the treatment of advanced stage prostate can-
2002). Inflammatory cells within tumors may play a role in promoting
cer (Karan et al., 2012); treatment consists of isolation of a sample of
metastases (DeNardo et al., 2008), and some studies have described
the patient’s circulating antigen presenting cells, expansion of these
associations of specific features of these infiltrates with the risk of
cells in the presence of a fusion protein based on prostatic acid phos-
cancer recurrence. For example, the intensity of lymphocyte infiltra-
phatase, then reinfusion of the antigen presenting cells back into the
tion has prognostic relevance for melanomas that have begun to grow
patient. Instillation of the bacterium Bacillus Calmette-​Guérrin into
vertically, as indicated by increased tumor thickness (Clemente et al.,
the bladder stimulates a brisk local immune response, which is used as
1996). Likewise, the presence of CD8 positive T-​cells in colorectal
therapy for bladder cancer (Fuge et al., 2015). Rituximab, a monoclo-
and ovarian cancers is associated with improved survival (Gooden
nal antibody against the B-​cell surface protein CD20, is an important
et al., 2011).
component of therapy of some NHLs and probably acts, at least in
Other limited research has related the presence of immune-​related
part, by instigating an immune response against tumor cells (Perez-​
conditions in cancer patients to stage at cancer diagnosis, which itself
Callejo et al., 2015).
has prognostic significance. However, cancer stage is somewhat com-
A major effort in experimental immunotherapy has been directed
plex to assess, because it reflects not only the aggressiveness of a
toward the treatment of cancer through the administration of tumor-​
malignancy but also the timing of diagnosis, which can be affected
directed T-​cells (Rosenberg and Restifo, 2015). This therapy has
by screening or delays in access to medical care. HIV-​infected people
been most actively pursued for metastatic melanoma. Treatment
have an increased risk of being diagnosed at an advanced stage com-
typically involves surgical excision of a tumor lesion, isolation
pared to HIV-​uninfected people for many cancers (especially for lung
and expansion of specific populations of tumor-​infiltrating T-​cells,
and prostate cancers) (Brock et  al., 2006; Shiels et  al., 2015a), but
and reinfusion of these cells into the patient. While progress has
this may simply be due to delayed diagnosis. Along the same lines,
been made along these lines, the complexity and expense of this
transplant recipients tend to present at earlier stages for many cancers,
approach has limited wider evaluation. Similarly, infusion of EBV-​
which probably reflects increased surveillance (Shiels et al., 2015a).
directed T-​cells has been utilized in the treatment of PTLD (Bollard
Both HIV-​infected patients and transplant recipients are at increased
et al., 2012).
risk for presenting with advanced stage tumors for melanoma and
Recently, substantial success has been reported for immuno-
bladder cancer (Shiels et  al., 2015a), which may be most consistent
therapies targeting checkpoint proteins including the programmed
with an increased aggressiveness related to immunosuppression for
death 1 protein (PD-1) and cytotoxic T-lymphocyte-associated
these two cancers.
antigen 4 (CTLA-4). These molecules, which are expressed on the
There are also limited data relating immune conditions to out-
surface of lymphocytes during the inflammatory process, bind to
comes after cancer diagnosis. HIV-​ infected patients have an
their cognate ligands on other cells, down-regulating the immune
increased risk of dying from their cancer compared to HIV-​unin-
response and thus serving to limit tissue destruction. Some cancer
fected patients, for a range of malignancies including cancers of
cells also express the ligands, thereby inhibiting T-cell response
the colorectum, lung, prostate, breast, and pancreas, and melanoma
against tumor neoantigens. Among patients with metastatic mela-
(Coghill et al., 2015; Marcus et al., 2015). Also, transplant recipi-
noma, lung cancer, and other malignancies, infusion of monoclonal
ents with melanoma are more likely to die from their melanoma
antibodies directed against checkpoint molecules has proven effec-
than melanoma patients in the general population (Robbins et al.,
tive in stimulating anti-tumor immunity and prolonging disease-
2015a). It is possible that some of these differences arise from dif-
free survival (Brahmer et  al., 2012; Hodi et  al., 2010; Topalian
ferences in cancer treatment or from inaccuracies in assigning the
et al., 2012).
cause of death in patients with multiple medical conditions. Among
Finally, for HIV-​infected patients, one approach to treating KS is
patients with glioma, elevated serum levels of IgE (indicating the
simply to administer HAART if the patient is not already receiving
presence of atopy) are associated with improved survival (Wrensch
it, which leads to an improvement in immune status (Bower et  al.,
et al., 2006).
2009). Likewise, reduction in the intensity of immunosuppression (by
reducing the doses or eliminating some of the immunosuppressant
medications) is also used in the treatment of some forms of PTLD
Immunotherapy for Cancer
in transplant recipients (Preiksaitis and Keay, 2001). In addition, the
Substantial laboratory and clinical effort has been devoted to devel- infusion of T-​cells directed against EBV can be used in the treatment
oping effective immunotherapy for the treatment of cancer, espe- of PTLD (Khanna et  al., 1999; Rooney et  al., 1995). Nonetheless,
cially for metastatic cancers (Kirkwood et  al., 2012). This approach these approaches are not uniformly successful by themselves, and
is predicated on the idea that tumor cells frequently express neoan- other forms of directed treatment (e.g., chemotherapy) are often
tigens that could potentially be recognized by the adaptive immune required.
478
478 PART III:  THE CAUSES OF CANCER
FUTURE DIRECTIONS
As summarized in this chapter, immune factors play a role in the devel-
opment of cancers at many, if not most, anatomical sites. However,
the immune response is a highly complex and multifaceted system
that varies over time, making it difficult to study. As a result, much
remains to be learned regarding the specific immunological param-
eters involved in cancer development and the underlying mechanisms
of observed associations. As patterns of immune response become bet-
ter understood and novel technologies for querying the immune sys-
tem become more widely available, it is likely that our understanding
of immunological factors linked to cancer development will increase.
Promising areas for future discoveries include the delineation of spe-
cific components of the immune response linked to cancer (made pos-
sible by “-​omic” technologies), the discovery of new infections linked
to cancer (made possible by the continued study of immunosuppressed
populations), the elucidation of the role of early life immunological
imprinting on cancer risk later in life (made possible by studies that
measure biologically relevant exposures and their immunological
implications in early life), increased understanding of the role of tissue
microenviroment on immunological responses that modulate cancer
risk and prognosis (made possible by systematic tissue banking studies
and novel technologies that can be applied to these collections), and
better delineation of the patterns of immune response over time that
are associated with protection and risk for cancer (made possible by
cohort studies with repeated and appropriate biological sampling). As
we learn more about the immunological components that drive cancer
development and its progression, new avenues and opportunities for
improved primary and secondary prevention and treatment of cancer
by targeting and harnessing the immune response are possible.
ACKNOWLEDGMENTS
The authors would like to acknowledge Qi Yang from the Center for
Genomics Research at the NCI-​LEIDOS in Frederick, Maryland, for
her support with the pathway-​based analysis required for Table 25–2,
David Check for his assistance with the figures, and Sandra Brown for
her assistance with text formatting and referencing.
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486
 487

IV
CANCERS BY TISSUE OF ORIGIN
 489
26 Nasopharyngeal Cancer
ELLEN T. CHANG AND ALLAN HILDESHEIM
OVERVIEW
The main epithelial malignancy arising in the nasopharynx is
nasopharyngeal carcinoma (NPC). Although rare throughout most
of the world, NPC has a unique geographic distribution, with high-​
risk endemic areas in southern China and parts of Southeast Asia,
intermediate incidence rates elsewhere in Southeast Asia, North
Africa, the Arctic, the Middle East, and among Asian and Pacific
Islander migrants, and very low risk in other areas. The great
majority of NPC cases worldwide are non-​keratinizing tumors that
predominate in endemic, high-​incidence areas and comprise up to
half of tumors in low-​incidence populations. The other histologic
subtype of NPC, keratinizing squamous cell carcinoma, accounts
for 40%–​ 50% of cases in low-​ incidence areas. Infection with
Epstein-​Barr virus (EBV) is a necessary but not sufficient cause
of non-​keratinizing NPC, but it is more weakly associated with
keratinizing squamous cell tumors. Tobacco smoking increases
the risk of both subtypes. Other established cofactors for non-​
keratinizing NPC include dietary consumption of salt-​preserved
fish and other preserved foods, and germline polymorphisms in
the human leukocyte antigen (HLA) genes HLA-​A*02:07-​B*46:01
and HLA-​A*11:01, which affect proteins that present antigens to
immune cells. Exposures in childhood are thought to be particu-
larly important in the etiology of non-​keratinizing NPC. In high-​
incidence areas, EBV infection is typically acquired in infancy or
early childhood, inherited polymorphisms in HLA may affect the
immune response to the virus, and in southern China, infants were
traditionally weaned on salt-​preserved fish with a high content
of nitrosamines. Less is known about the etiology of keratinizing
squamous cell NPC, or any histologic subtype of NPC in areas
with low and intermediate incidence rates.
DISEASE BURDEN
NPC is a relatively rare cancer in most areas of the world. While NPC
is not the only malignancy that arises in the nasopharynx, it comprises
the great majority of cases. Thus, data on incidence and mortality rates
for cancers located within the nasopharynx are generally considered
to represent NPC.
Worldwide, approximately 86,700 newly diagnosed cases and
50,800 deaths from NPC occur each year, making it the 24th most
common cancer and the 23rd leading cause of cancer death in the
world (Ferlay et al., 2013). The United States contributes minimally
to this international disease burden, with approximately 2,000 NPC
cases and 800 deaths identified annually. In the United States, NPC
ranks 26th among cancers in terms of incidence and 27th in terms of
deaths.
Over 80% of NPC cases and deaths that occur annually (70,100
and 41,400, respectively) are in Asia, while 10% of cases and 13%
of deaths (8300 and 5500, respectively) occur in Africa (Ferlay et al.,
2013). Even when averaged across all of Asia, NPC ranks only 22nd
in cancer incidence and 20th in cancer mortality. It ranks higher in
Southeast Asia, however, where NPC is the 10th most common cancer
and cause of cancer death, accounting for approximately 25,600 new
diagnoses and 14,200 deaths each year.
TUMOR CLASSIFICATION
NPC is identified using ICD-​O-​3 site codes C110–​C119. Three main
histologic subtypes are currently recognized by the World Health
Organization (WHO):  non-​keratinizing carcinoma (differentiated or
undifferentiated); keratinizing squamous cell carcinoma; and basaloid
squamous cell carcinoma. Non-​keratinizing carcinoma is designated
by the ICD-​O-​3 histology code 8072/​3; keratinizing squamous cell
carcinoma as 8071/​3; and basaloid carcinoma as code 8083/​3. The lat-
ter morphologically resembles squamous cell carcinomas that occur
commonly elsewhere in the head and neck region (Chan et al., 2005).
Other rare malignant epithelial tumors that arise in the nasopharynx,
including adenocarcinoma and salivary-​gland-​type carcinoma, are not
considered in this chapter.
Histologic classification of NPC has changed relatively little since
1978, when WHO characterized the three histologic subtypes of NPC
as squamous cell carcinoma (WHO type 1), non-​keratinizing carci-
noma (WHO type 2), and undifferentiated carcinoma (WHO type
3)  (Shanmugaratnam and Sobin, 1978). A  1991 reclassification by
WHO retained the category of squamous cell carcinoma and com-
bined the other two subtypes into the single category of non-​keratin-
izing carcinoma; the latter was then subclassified as differentiated or
undifferentiated (Shanmugaratnam, 1991). The most recent WHO
classification in 2005 added basaloid squamous cell carcinoma as
an additional, rare (< 0.2%) histologic subtype (Chan et  al., 2005).
Updated classification schemes that consider the molecular profile of
tumors are currently being considered; these may provide more accu-
rate predictions of prognosis (Wang et al., 2011).
As noted earlier, the non-​keratinizing carcinoma subtype predom-
inates in high-​incidence areas. Previous infection with EBV can be
demonstrated in essentially 100% of tumors by in situ hybridization
for EBV-​encoded early RNA tumors (Chan et al., 2005). The samples
that have been characterized histologically and tested for EBV are not
population-​based, yet they have been assumed to be representative
because of the distinctive geographic clustering. In contrast, keratin-
izing squamous cell carcinoma can comprise up to 40%–​50% of NPC
tumors in low-​incidence areas such as the United States (Vaughan
et al., 1996; Wang Y et al., 2013). The reported frequencies of NPC
histologic subtypes vary widely within low-​risk geographic regions.
WHO has attributed this heterogeneity to a combination of unclear
boundaries between the histopathologic categories, sampling error due
to the small size of biopsies, and suboptimal intra-​and inter-​observer
reproducibility of classification (Chan et al., 2005).
PRECANCEROUS OR PRECURSOR LESIONS
In situ NPC in the absence of invasive carcinoma is very rare (Chan
et al., 2005). The scarcity of in situ cancers suggests either that invasive
NPC does not typically develop from in situ cancer, or that progression
to invasive disease is so rapid that the in situ phase generally is not
detected. Three small case series and one case report have described
patients with NPC in situ. These included 11 (Pathmanathan et  al.,
1995), two (Cheung et  al., 1998), one (Pak et  al., 2005), and three
patients (Pak et al., 2002), all of whom were positive for EBV, indi-
cating that EBV infection of the nasopharyngeal epithelium precedes
489
490
490 PART IV:  Cancers by Tissue of Origin
tumor invasiveness. Studies of tumor progression from in situ to inva-
sive cancer have all been small. Two of three patients with untreated
NPC in situ and neither of two patients with radiotherapy-​treated NPC
in situ were reported as subsequently having developed invasive NPC
(Cheung et al., 1998; Pak et al., 2005).
SURVIVAL
Tumor node metastasis (TNM) stage is the strongest established prog-
nostic factor for NPC (Edge et al., 2010; Sobin et al., 2009). Survival
rates vary considerably across centers. For example, at large oncology
centers in Hong Kong and China, recent 5-​year disease-​specific sur-
vival rates were 80%–​85% for all stages, 92%–​100% for stage I, 87%–​
96% for stage II, 79%–​83% for stage III, and 65%–​70% for stage IV
(Lee et al., 2005; Sun et al., 2013). Other centers in Asia have reported
5-​year overall survival rates of 60%–​90% for stage I, 57%–​79% for
stage II, 44%–​77% for stage III, and 17%–​43% for stage IV (Dou
et al., 2014; Leung et al., 2005; Phua et al., 2011, 2013). Some overlap
in the relative survival for stages I and IIA and a large gap between
stages IIA and IIB (Leung et al., 2005) suggest that stage IIA could
potentially be considered along with stage I as early-​stage NPC. In
general, the stage distribution of NPC at diagnosis is skewed toward
more advanced stages due to the non-​specific symptoms and corre-
spondingly late diagnosis of the disease.
Circulating plasma/​serum EBV DNA levels have been shown to
predict NPC survival (Chan et  al., 2002; Lin et  al., 2004; Lo et  al.,
2000; Wang WY et al., 2013). In particular, higher pre-​treatment and
especially post-​treatment circulating EBV DNA levels are signifi-
cantly associated with poorer overall, disease-​specific, progression-​
free, and relapse-​free survival.
DESCRIPTIVE EPIDEMIOLOGY
Demographic Patterns
In high-​incidence areas, the age-​specific incidence rates of NPC
increase monotonically up to around age 45–​59 years, followed by a
plateau or modest decline (Figures 26–1a and 26–1b) (Forman et al.,
2013). This age-​related pattern is consistent with the role of early-​
life exposure to EBV and other risk factors in the development of
NPC in high-​incidence areas. In low-​incidence areas, the age-​specific
NPC incidence rates show a minor peak at around age 15–​19 years,
especially in males, followed by a slight decline and then a mono-
tonic rise from around age 30–​34 to 65–​79 years (Figures 26–1c and
26–1d) (Bray et al., 2008; Forman et al., 2013). The early peak has
been documented in Australia, northern and western Europe, North
America, and low-​risk Asian countries (India and Japan), with some
geographic variation in the timing of the peak and the duration of the
subsequent decline (Bray et  al., 2008). The bimodal pattern could
be consistent with exposures occurring at different times of life. The
early peak may reflect inherited or other early-​life risk factors (per-
haps including EBV infection), whereas the later peak may reflect
long-​term adult environmental exposures. It has been hypothesized
that the bimodal age-​ incidence pattern occurs also in high-​ inci-
dence regions, but that the early peak is obscured by genetic and
epigenetic factors that are associated with increased NPC risk (Bray
et al., 2008).
Across all geographic areas, regardless of background NPC rates,
the age-​adjusted incidence rate of NPC is consistently around two to
three times higher in males than in females, with even higher ratios
in some areas (Figure 26–2) (Forman et  al., 2013). The male pre-
dominance of NPC is largely unexplained by established risk factors
(Edgren et al., 2012).
The distribution of NPC varies substantially by geographic
region and race/​ethnicity, even within countries. For example, in
China a clear gradient runs from north to south, with the highest
rates in southern China (Figures 26–2 and 26–3) (Forman et  al.,
2013). Historically, in the high-​incidence southern Chinese prov-
ince of Guangdong, NPC occurrence was highest in the Tanka boat
people and twice as high in Cantonese speakers as in the Hakka,
Hokkien, and Chiu Chau linguistic/​ethnic groups (Li et al., 1985).
Across Southeast Asia, groups with a higher degree of racial and
social admixture with southern Chinese, and especially with the
ancestors of the Tanka called the Bai-​Yue (also called “proto-​Tai-​
Kadai,” “proto-​Austronesian,” or “proto-​Zhuang”), generally have
higher NPC risk (Wee et  al., 2010). This pattern is observed in
Singapore, for example, where NPC incidence is highest among
Chinese, intermediate among Malays who have historically inter-
married with Chinese, and lowest among Indians, who have rela-
tively little admixture with Chinese (Figure 26–2) (Forman et  al.,
2013; Ho, 1976). In the United States, NPC incidence is highest
among Chinese, followed by Filipinos (who have historical ties to
southern Chinese), and substantially lower among Koreans, non-​
Hispanic whites, Japanese (who, like Koreans, have had traditional
ties mainly with northern China), and Hispanic whites (Figure 26–2)
(Forman et al., 2013).
No clear incidence patterns by county-​level socioeconomic status
are evident for NPC in the United States (SEER, 2015).
GEOGRAPHIC VARIATION
The distinctive international pattern of incidence and mortality rates
of NPC has been described earlier. The rates are highest in southern
China and parts of Southeast Asia, intermediate elsewhere in China
and Southeast Asia, North Africa, the Arctic, and the Middle East,
and lowest (below 1 per 100,000 person-​years) throughout the rest of
the world. Globally, NPC incidence rates vary by more than 200-​fold
between the highest-​and lowest-​incidence regions.
Population-​based cancer registry data show that in 2003–​2007, the
highest NPC incidence rates worldwide were recorded in Zhongshan
City, China, where the age-​standardized incidence rate (per 100,000)
was 26.8 in males (based on 799 cases) and 10.7 in females (based
on 326 cases) (Figures 26–2 and 26–3) (Forman et  al., 2013). The
next highest rates (per 100,000) were reported in Macau, China (15.7
based on 246 cases among males; 6.7 based on 104 cases among
females), and Hong Kong, China (14.4 based on 3245 cases among
males; 4.9 based on 1247 cases among females) (Figures 26–2 and
26–3). Intermediate rates (per 100,000) also prevail in both native
and migrant Asian populations and in the Arctic, North Africa, and
the Middle East, generally ranging from 2–​6 among males and 1–​3
among females (Figure 26–2).
TEMPORAL TRENDS
Reports from high-​risk areas, including Singapore, Taiwan, Hong
Kong, and Guangzhou, have documented declines in NPC incidence
and/​or mortality in recent years, although the rates in some areas
of southern China appear to have changed little over time (Deng
et  al., 2014; Wei et  al., 2010). Specifically, among Chinese males
in Singapore, the annual age-​standardized incidence rate of NPC
(per 100,000) fell from 18.7 in 1988–​1992 to 10.3 in 2003–​2007
(National Registry of Diseases Office, 2009, 2013). Between the late
1970s and 2008, the age-​standardized incidence rate of NPC in Hong
Kong decreased by 66.1% for males and by 73.7% for females (Lau
et al., 2013), while in urban Guangzhou, China, the average annual
percentage change in the NPC incidence rate between 2000 and 2011
was –​3.26% for males and –​5.74% for females (Li et al., 2014). The
decline in Taiwan has been smaller, with age-​standardized NPC inci-
dence rates (per 100,000) decreasing from 9.50 in males and 4.12
in females in 1980–​1984 to 8.59 in males and 2.88 in females in
2000–​2006 (Chiang et  al., 2010). An analysis of national cancer
mortality data in China found comparable declines in NPC mortality
in rural and urban areas between 1987–​1991 and 2007–​2009 (Guo
et al., 2012).
In contrast, age-​standardized NPC incidence rates (per 100,000)
held steady at approximately 28 among males and 11 among females
in Zhongshan, China, between 1970–​ 1974 and 2005–​ 2007 (Wei
 491

Nasopharyngeal Cancer 491
(a) 120 (b) 60
China, Hong Kong China, Hong Kong
China, Zhongshan City China, Zhongshan City

Incidence rate (per 100,000 person-years)

Incidence rate (per 100,000 person-years) Singapore Chinese Singapore Chinese
100 50

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10
Age group (years) Age group (years)

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USA whites USA whites
Scandinavia 0.9 Scandinavia
Incidence rate (per 100,000 person-years)

Japan

Incidence rate (per 100,000 person-years)

Japan
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Figure 26–1.  Age-specific incidence rates of nasopharyngeal carcinoma in high- and low-incidence areas, 2003–2007. (a) Incidence among males in
high-​incidence areas (Hong Kong, China; Zhongshan City, China; and Singapore Chinese).  (b) Incidence among females in high-​incidence areas.  (c)
Incidence among males in low-​incidence areas (United States: National Program of Cancer Registries, 42 states, whites; Scandinavia: Denmark,
Finland, Iceland, Norway, and Sweden; and Japan: Aichi Prefecture, Fukui Prefecture, Hiroshima, Miyagi Prefecture, Nagasaki Prefecture, Niigata
Prefecture, Osaka Prefecture, and Saga Prefecture).  (d) Incidence among females in low-​incidence areas.  Data from Cancer Incidence in Five
Continents, Vol. X (Forman et al., 2013).

et al., 2010), while reported NPC mortality rates (per 100,000) did
not change substantially between 1971–​1973 and 2004–​2005 among
males (7.00 to 7.24, standardized to the 1982 China age structure) or
females (2.96 to 2.54) in Guangxi, China (Deng et al., 2014).
The observed decreases in NPC incidence in several high-​ risk
regions may be due in part to declining dietary consumption of salt-​
preserved fish and increasing consumption of fresh fruits and vegeta-
bles, although reductions in the prevalence of tobacco smoking also
may have contributed. The prevalence of salt-​preserved fish consump-
tion in southern China and elsewhere has decreased in Southeast Asia,
based on limited information derived from epidemiologic studies of
NPC. Up to 48% of adults and 47% of children reportedly consumed
salt-preserved fish in studies conducted in the 1980s and early 1990s.
This has decreased to 4% among adults and 2% among children in
studies conducted in the late 1990s and 2000s (IARC, 2012d). The
once-​common traditional practice of feeding salt-​preserved fish during
weaning and early childhood has become rare (IARC, 2012d). (The
epidemiologic literature on salt-preserved fish consumption in relation
to NPC risk is discussed later.) Changes in NPC screening, diagnosis,
or classification are unlikely to have had an appreciable effect on tem-
poral incidence and mortality trends.
Trends in incidence rates in intermediate-​ risk countries have
been mixed. In Algeria, the age-​standardized incidence rate (per
100,000) among males increased from 4.5 in 1986–​1990 to 7.3 in
1996–​2000 and declined thereafter to 4.8 in 2006–​2010. In contrast,
the incidence rate among females was relatively stable at about 2
per 100,000 from 1986 through 2010 (Hamdi Cherif et  al., 2014).
In intermediate-​risk Shanghai, the NPC incidence rate was stable at
roughly 3 per 100,000 between 1973 and 2005 among adolescent
and young-​adult males, but declined by 2% per year among females
of the same age (from 2.1 to 1.1 per 100,000 between 1973–​1975
and 2003–​2005) (Wu et al., 2012). Reports from low-​risk areas also
have been mixed, with the incidence in some countries reported to
be stable (Lau et al., 2013; Xie et al., 2012) and others (including the
US) declining (Lau et  al., 2013; SEER, 2015). Some authors have
reported a decrease in keratinizing but not non-​keratinizing NPC,
possibly due to reductions in smoking (Arnold et  al., 2013; Sun
et al., 2005). For instance, in studies of Chinese males living in the
Los Angeles and San Francisco/​Oakland regions of California, the
incidence of keratinizing squamous cell NPC decreased significantly
by 71% (95% confidence interval [CI] = –​85, –​45%) between 1992
and 2002, whereas the incidence of non-​keratinizing NPC increased
492

30
Males
Females

25

Incidence rate (per 100,000 person-years)

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Figure 26–2.  Age-​standardized (to world

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Harbin City: 1.3

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Macau: 15.7
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Figure 26–3.  Age-​standardized (to world
standard population) incidence rates per
100,000 of nasopharyngeal carcinoma
among males in China, 2003–​2007. Map
shows the north-​to-​south gradient in inci-
dence within China. Data from Cancer
Incidence in Five Continents, Vol. X
(Forman et al., 2013).
 493
Nasopharyngeal Cancer 493
nonsignificantly (+ 56%, 95% CI = –​36, 277%) and the incidence of
undifferentiated NPC was fairly stable (+12%, 95% CI = –​43, 120%)
(Sun et al., 2005). Overall, given the sharper declines in high-​inci-
dence areas, these global patterns have resulted in a narrowing of the
international variation in NPC incidence and mortality.
MIGRANT STUDIES
Migrant studies suggest that a combination of environmental, cultural,
and heritable genetic factors contribute to NPC risk. Early studies
showed that individuals with low-​risk North American or European
parents who were born in high-​risk regions had a significantly higher
risk of NPC than would be expected from their parentage. For exam-
ple, between 1955–​1964, five of 273 white male decedents with NPC
in California had been born in China or the Philippines, more than
40 times the 0.11 expected based on controls with cancer of the oro-
pharynx, hypopharynx, or pharynx, not otherwise specified (Buell,
1973). Similarly, the age-​standardized annual incidence rate of NPC
among males of French origin born in the Maghreb (Northwest Africa)
was 1.7 per 100,000, compared with 0.3 per 100,000 for French males
born in France (Jeannel et al., 1993).
The increased risk of NPC among migrants from high- to lower-
risk host countries remains higher in first-​generation migrants. In
Sweden, compared with native-​born Swedes, standardized incidence
ratios (SIRs) for NPC were significantly elevated among first-​gen-
eration immigrants born in Southeast Asia (SIR = 35.60 for males,
24.63 for females), North Africa (SIR = 12.45 for males, 34.73 for
females), and Asian Arab countries (SIR = 4.92 for males, 10.95 for
females) (Mousavi and Hemminki, 2015). In Israel, the odds ratio
(OR) of NPC comparing individuals under 30 years of age born in
Africa to African parents versus those born in Israel to Israel-​born
parents was 3.51 (95% CI = 1.21–​10.1), and that for Israel-​born indi-
viduals with a mother born in Africa was 4.44 (95% CI = 1.67–​11.8)
(Parkin and Iscovich, 1997). Age-​standardized NPC incidence rates
among Chinese migrants were shown to decline with increasing dis-
tance from China. Progressively lower rates were observed among
Chinese in Singapore, Hawaii, and California (Yu and Hussain, 2009).
Nevertheless, in the United States from 2008–​2012, the age-​adjusted
incidence rates of NPC among all Asians and Pacific Islanders (3.58
and 1.23 per 100,000 among males and females, respectively) were
five to six times higher than rates among non-​Hispanic whites (SEER,
2015). When interpreting these results, it should be noted that Asians
and Pacific Islanders in the United States include migrants from high-​,
intermediate-​, and low-​incidence areas in Asia, as well as US-​born
Asian and Pacific Islander Americans.
ETIOLOGIC FACTORS
Epstein-​Barr Virus
EBV is a ubiquitous herpesvirus that infects nearly all humans, usually
during childhood, and persists latently for life (Klein et al., 2010). In
areas with high NPC incidence, EBV infection typically occurs during
infancy or early childhood, and over 90% of the population is infected
by age 8 years (Kangro et al., 1994; Xiong et al., 2014). In low-​inci-
dence areas, primary EBV infection usually occurs later and is less
pervasive. For example, between 2003 and 2010, only 50% of the US
population was seropositive for EBV at ages 6–​8  years and 69% at
ages 15–​17 years (Balfour et al., 2013).
EBV was first classified by the International Agency for Research
on Cancer (IARC) as a human carcinogen in 1997, based largely on
the evidence regarding NPC (IARC, 1997). At the time, evidence of
the etiologic involvement of EBV in NPC had been accumulating for
more than three decades (Old et al., 1966), and it continues to expand
(IARC, 2012b). However, the incidence of NPC is much lower than
the prevalence of EBV infection in all countries, indicating the impor-
tance of cofactors, especially for non-​keratinized tumors.
The detection of clonally identical EBV DNA, RNA, and/​or gene
products in the malignant cells of virtually all non-​keratinizing NPC
tumors establishes the presence of EBV in the initial NPC progen-
itor cell (Niedobitek, 2000; Raab-​Traub and Flynn, 1986). Clonal
EBV is also detected in rare cases of NPC in situ in the absence of
invasive NPC, as described earlier (Cheung et al., 1998; Pak et al.,
2002, 2005; Pathmanathan et  al., 1995). The genomic diversity of
EBV in NPC biopsies has only recently begun to be appreciated,
and no specific viral strains or sequence variants have yet been con-
sistently associated with NPC risk or clinical characteristics. Whole-​
genome sequencing of nine EBV genomes derived from NPC tumor
biopsy specimens from Hong Kong, compared with a reference
EBV genome, revealed more than 1,700 sequence variations, repre-
senting greater sequence diversity than previously captured (Kwok
et al., 2012, 2014). Further sequencing in large studies will be nec-
essary to determine whether any such variations play a role in NPC
development.
Retrospective studies in the 1970s established that NPC patients
have higher levels of several antibodies against EBV antigens,
including immunoglobulin G (IgG) and IgA against the viral capsid
antigen (VCA), early antigen (EA), and latent viral nuclear antigens
1 and 2 (EBNA1 and EBNA2), and neutralizing antibodies against
EBV-​specific DNase, compared with controls (de-​The et al., 1978;
Henderson et  al., 1977; Lin et  al., 1977). Subsequent prospective
studies demonstrated increases in these antibody titers several years
before NPC development (Zeng et al., 1982, 1983, 1985). A land-
mark prospective cohort study by Chien et al. (2001), with 131,981
person-​years of follow-​up for 9699 men in Taiwan, revealed that the
cumulative incidence of NPC per 100,000 person-​years was 11.2 for
subjects with negative serological test results for anti-​VCA IgA and
anti-​DNase neutralizing antibodies, 45.0 for those who were posi-
tive for one marker, and 371.0 for those who were positive for both
markers. The relative risk (RR) was 32.8 (95% CI = 7.3–​147.2) for
two versus no markers, and increased with longer duration of fol-
low-​up. Consequently, anti-​VCA IgA, anti-​EA IgA, and anti-​EBV
DNase antibodies form the basis of long-​ standing immunofluo-
rescence-​based screening tests for NPC in high-​risk populations.
Circulating cell-​free EBV DNA is a valuable biomarker for NPC
detection and prognosis. Its value for NPC screening in unaffected
persons, however, is probably limited (Chan et  al., 2013; Ji et  al.,
2014).
A recent study in Taiwan demonstrates the value of screening for
NPC in high-​incidence groups using enzyme-​linked immunosorbent
assay (ELISA) kits for IgA against VCA and EBNA1 (Coghill et al.,
2014). The study measured pre-​diagnostic serum levels of ELISA-​
based IgA antibodies against several EBV peptides in 21 NPC cases
and 84 controls from high-​risk multiplex NPC families. The detec-
tion of anti-​EBNA1 IgA had 80% sensitivity to identify future cases,
although specificity was only 60%; thus, a more specific screening
test is still needed. The enrollment phase of a cluster randomized
controlled trial in two cities in southern China demonstrated the
feasibility of mass screening for NPC using ELISA-​based sero-
logic testing for anti-​VCA and EBNA1 IgA, followed by fiberoptic
endoscopy and/​or biopsy for individuals with a positive screening
test result (Liu et al., 2013). Of 28,688 participants, 862 (3.0%) were
classified as having a high-​risk serologic screening result. Thirty-​
eight subjects in this group (4.4% of all 862 high-​risk subjects;
5.8% of those who underwent fiberoptic endoscopy and 43.7% of
those who underwent biopsy) were found to have NPC, including 29
(76.3%) with no symptoms at the time of screening and 27 (71.1%)
with clinical stage I or II disease. These initial results suggest that
EBV-​based screening for NPC in high-​incidence areas could reduce
mortality through early detection and treatment. Longer follow-​up
of the randomized communities is needed to establish screening effi-
cacy (Hildesheim, 2013).
A few studies have investigated interactions between EBV and other
NPC risk factors. Positive interactions between cigarette smoking and
anti-​EBV antibody titers were found in some (Hsu et  al., 2009; Lin
et al., 1979; Xu et al., 2012) but not all (Chang et al., 2012) studies.
Cigarette smoke extract has been shown to promote EBV activation
in vitro (Xu et al., 2012), suggesting that tobacco smoke may increase
NPC risk by inducing EBV reactivation.
49
494 PART IV:  Cancers by Tissue of Origin
In addition to the probable role of earlier age of primary EBV infec-
tion, host cofactors are likely to modulate the association between
EBV and NPC. Genetic susceptibility to both EBV infection and
NPC is suggested by greater EBV IgA seroreactivity in unaffected
first-​degree relatives of NPC cases than in general community mem-
bers. Two-​to six-​fold differences in the seroprevalence or serore-
activity of anti-​VCA and/​or anti-​EBNA IgA have been reported in
Taiwan (Pickard et al., 2004), southern China (Qin et al., 2011a), and
Indonesia (Hutajulu et  al., 2012). Shared environmental risk factors
probably also contribute to these findings, as spouses of multiplex
NPC cases in Taiwan and of sporadic (but not multiplex) NPC cases
in southern China had a significantly higher seroprevalence of anti-​
EBV IgA than community controls (Pickard et al., 2004; Qin et al.,
2011a). Further insight into host susceptibility to EBV infection and
NPC development comes from evidence of a functional deficit in the
CD8+ T-​cell immune response to EBNA1 in NPC cases (Fogg et al.,
2009). Specifically, EBNA1-​ specific CD8+ T-​ cells were detected
in 10 of 14 healthy donors, with confirmation of HLA class  I  pres-
entation of EBNA1 epitopes to CD8+ T-​cells in six of six donors.
By contrast, only three of 22 patients with EBV-​associated NPC had
detectable EBNA1-​specific CD8+ T-​cells (P = 0.0003 versus healthy
donors), and a functional deficit in the EBNA1-​specific response was
evidenced by rescue of that response via short-​term peptide and cyto-
kine stimulation in eight of 14 patients. Meanwhile, the frequency of
the LMP2-​specific CD8+ T-​cell response did not differ significantly
between NPC patients and controls, indicating a specific deficit in the
immune response to EBNA1.
Infections Other Than EBV
High-​risk human papillomavirus (HPV) DNA has been detected in a
minority of NPC tumors, especially in low-​incidence regions. HPV
appears not to play an important etiologic role in high-​incidence areas
(Dogan et al., 2014; Giannoudis et al., 1995; Hording et al., 1994; Lin
Z et  al., 2014). HPV-​positive tumors in the nasopharynx may actu-
ally be oropharyngeal carcinomas that have been misclassified, since
tumors of the oropharynx have a strong etiologic link with HPV (see
Chapter 29) and can extend into the nasopharynx. In a histopathologic
study of 45 non-​keratinizing NPC tumor specimens in the United
States, four (9%) were positive for HPV. Records on three of these
cases included information on stage at diagnosis. All three involved
tumor extension into the oropharynx (Singhi et al., 2012). In contrast,
only four (12%) of 34 HPV-​negative NPCs with information on stage
had oropharyngeal involvement.
Registry studies suggest that NPC risk may be doubled among indi-
viduals with AIDS, but excess risk is not observed among patients who
receive immunosuppressive therapy following solid organ transplant.
The SIR for AIDS patients in the United States was identical (2.4) for
both keratinizing and non-​keratinizing tumors (Shebl et al., 2010). No
increase in risk was observed among recipients of solid organ trans-
plants in the United States (SIR = 0.96, 95% CI = 0.42–​1.90) (Engels
et al., 2011). Since the incidence rate of NPC did not increase appreci-
ably after the 1980s as a consequence of the AIDS epidemic, it seems
unlikely that alterations in immune control of EBV infection in adult-
hood play a major role in the development of NPC.
Multiple studies of prior chronic ear, nose, throat, and lower respi-
ratory tract conditions, including allergic rhinitis (Chung et al., 2014;
Lin KT et  al., 2015), rhinitis or rhinosinusitis (Hung et  al., 2013;
Yu et al., 1990; Yuan et al., 2000a), otitis media (Huang WY et al.,
2012; Yu et al., 1990; Yuan et al., 2000a), and nasal polyps (Yu et al.,
1990; Yuan et al., 2000a), have reported positive associations on the
order of a two-​fold or greater increase in NPC risk. Repeated benign
inflammation and infection of the respiratory tract may increase the
susceptibility of the nasopharyngeal mucosa to NPC development.
Some nasopharyngeal flora also may contribute to the local forma-
tion of carcinogenic N-​nitroso compounds through the reduction of
nitrates (Charriere et  al., 1991). Recall bias and prodromal symp-
toms have been difficult to rule out as potential explanations for these
findings.
Dietary Consumption of Salt-​Preserved
Fish and Other Foods
Dietary consumption of Chinese-​style salt-preserved fish is classified
by the IARC as carcinogenic to humans based on sufficient evidence
regarding NPC (IARC, 1993, 2012d). Chinese-​style salt-preserved
fish is prepared by salting, brining (soaking in salted water), dry-​salt-
ing (mixing with dry salt and allowing the resulting brine to drain
away), pickle curing (mixing with salt and storing in the resulting
brine), or a combination of these methods. Salting may result in partial
decomposition of the fish. After a few days of salting, fish are dried in
the sun for 1–​7 days and then are stored for 4–​5 months before being
consumed.
Evidence that consumption of Chinese-​ style salt-preserved fish
increases NPC risk emerged in the 1960s and 1970s, when Ho noted
that the Tanka boat people were at increased risk of NPC and hypoth-
esized that salt-​preserved fish, a staple of the Tanka diet, might account
for the excess risk, especially when coupled with a deficiency of fresh
fruits and vegetables (Ho, 1967; Ho et al., 1978). Chinese-​style salt-
preserved fish has traditionally been a popular dietary staple through-
out high-​risk regions in southern China and Southeast Asia (IARC,
1993, 2012d). Consumption of salt-​preserved foods in the traditional
diet in other geographic regions, such as North Africa and the Arctic,
also may contribute to the NPC incidence rates in these areas. The
mechanism by which consumption of Chinese-​style salt-preserved fish
causes NPC is not established, but may involve exposure to carcino-
genic N-​nitroso compounds and/​or reactivation of latent EBV infec-
tion (IARC, 1993, 2012d).
Nearly all case-​control studies of salt-​preserved fish in relation to
NPC risk have been conducted in Chinese populations. No cohort
studies of the association have yet been published. Among the nearly
20 case-​control studies of Chinese populations, the OR for NPC asso-
ciated with weekly versus no consumption or rare consumption of
salt-​preserved fish has generally ranged from 1.1 to 4, while that for
daily consumption ranges from 1.8 to 20, with positive trends by fre-
quency of consumption (Guo et al., 2009; Henderson and Louie, 1978;
IARC, 2012d; Jia et al., 2010; Xu et al., 2012; Yu et al., 1986, 1988,
1989; Yuan et al., 2000b; Zheng X et al., 1994). A small case-​control
study of Alaska natives (based on 13 NPC cases and matched controls
with questionnaire data) also found a positive association with salt-
preserved fish consumption in childhood (Lanier et al., 1980).
Findings have not been consistent regarding whether consump-
tion of salt-​ preserved fish during weaning and childhood confers
greater risk than exposure in adulthood. Some studies support this
hypothesis (Ning et al., 1990; Yu et al., 1986), whereas others do not
(Armstrong et al., 1998; Yu et al., 1988, 1989; Zheng X et al., 1994).
Consumption of salt-​preserved fish during weaning might be expected
to increase NPC risk as a result of food regurgitation into the nasophar-
ynx. Differences in risk by age at first exposure are highly correlated
with dietary patterns throughout life. A case-​control study of NPC in
Taiwan estimated dietary intake of nitrosamines and their precursors
from a variety of foods, and found positive associations with consump-
tion of nitrite and nitrosamines from foods other than soybean products
during childhood and weaning, but not adulthood (Ward et al., 2000).
ORs for the highest versus lowest quartile of consumption of non-​soy-
bean nitrosamines, as reported by subjects’ mothers, were 3.9 (95%
CI = 1.4–​10.4) for intake during weaning, 2.6 (95% CI = 1.0–​7.0) at
age 3 years, and 2.2 (95% CI = 0.8–​5.6) at age 10 years. In light of the
generally decreasing population-​level consumption of salt-preserved
fish, especially in early life (IARC, 2012d), future studies may lack
sufficient exposure heterogeneity to resolve the question of whether
risk varies by age at first exposure.
Some evidence suggests that the strength of the association between
NPC and consumption of salt-​preserved fish has declined over time
(IARC, 2012d). This pattern could reflect a shift toward commercially
produced products and away from home preparation (Ward et  al.,
2000) or a decrease in the amount of fish consumed. Increasing eco-
nomic development, growing awareness of the potential carcinogenic-
ity of salt-​preserved fish, and a societal shift toward a more Western
dietary pattern may have resulted in secular changes in the association
 495
Nasopharyngeal Cancer 495
between salt-​preserved fish consumption and NPC risk (Zhai et  al.,
2014). However, detailed temporal patterns in salt-preserved fish pro-
duction and consumption have not been well documented. Any meta-​
analysis or pooled analysis of salt-​preserved fish consumption would
be challenged by the between-​study heterogeneity resulting from such
time trends, as well as regional variation in fish-​preparation methods
and consequent nitrosamine levels.
Consumption of other preserved food items that are high in nitro-
samines also has been shown to be associated with increased risk of
NPC in diverse geographic regions, although with less strength and
consistency (Armstrong et  al., 1998; Fachiroh et  al., 2012; Farrow
et  al., 1998; Feng et  al., 2007; Jeannel et  al., 1990; Jia et  al., 2010;
Ning et al., 1990; Xu et al., 2012; Yu et al., 1988; Yuan et al., 2000b).
For example, in a US study, total preserved meat intake was calculated
based on intake of bacon, ham, sausage, liverwurst, and hot dogs; this
variable was found to be associated with increased risk of non-​keratin-
izing NPC (OR for highest vs. lowest quartile = 4.59, 95% CI = 0.78–​
27.01, Ptrend = 0.04), but not squamous cell NPC (Ptrend = 0.58) (Farrow
et al., 1998). In North Africa, preserved foods include quaddid (dried
mutton stored in oil), harissa (a spicy condiment containing red pep-
per, olive oil, garlic, caraway, and salt), toklia (a basic stewing prepa-
ration containing red and black pepper, garlic, oil, caraway, salt, and
coriander), khelii (salted, spicy, dried meat cooked and preserved in
a mixture of oil and melted bovine greases), rancid butter, and rancid
sheep fat. Some of these, particularly quaddid, rancid butter, and ran-
cid sheep fat, have been found to be associated with increased risk of
NPC, with ORs on the order of 2–​3 for frequent consumption (Feng
et al., 2007; Jeannel et al., 1990). A meta-​analysis of six case-​control
studies in China, Southeast Asia, and North Africa reported a two-​fold
increase (meta-​OR = 2.04, 95% CI = 1.43–​2.92) in NPC risk associated
with high versus low consumption of preserved vegetables, despite
difference in food preservation and consumption levels across studies
(Gallicchio et  al., 2006). In contrast, frequent consumption of fresh
fruits and/​or vegetables has been associated with a lower risk of NPC
in several studies from high-​, intermediate-​, and low-​incidence regions
(Armstrong et al., 1998; Jia et al., 2010; Liu et al., 2012; Polesel et al.,
2013; Ward et  al., 2000; Yu et  al., 1989; Yuan et  al., 2000b). In the
meta-​analysis by Gallicchio et  al. described earlier, high versus low
dietary intake of all non-​preserved vegetables was associated with
36% lower risk of NPC (meta-​OR  =  0.64, 95% CI  =  0.48–​0.85),
based on five contributing case-​control studies. Stronger inverse asso-
ciations were observed with consumption of green leafy vegetables
(OR  =  0.55, 95% CI  =  0.32–​0.96) and non-​starchy roots and tubers
(OR = 0.55, 95% CI = 0.34–​0.88). Hypothesized mechanisms for the
apparent protective effect of fresh fruits and vegetables against NPC
include prevention of oxidation and nitrosamine formation.
Tobacco and Other Smoke
The IARC classifies the evidence as sufficient that tobacco smoking
causes cancer of the nasopharynx in humans (IARC, 2004b, 2012d).
In recent case-​control studies, the OR for NPC among current or ever
versus never cigarette smokers has ranged from approximately 1.2 to
3.0, with generally positive (albeit not always monotonic) exposure–​
response trends for intensity, duration, and pack-​years of smoking
(Fachiroh et al., 2012; Feng et al., 2009; Ji et al., 2011; Polesel et al.,
2011; Xu et al., 2012). A meta-​analysis of 28 case-​control studies and
four prospective cohort studies published between 1979 and 2011
reported a meta-​RR of 1.60 (95% CI = 1.38–​1.87) for ever versus never
smoking (Xue et al., 2013). Higher risk was observed for those with
greater cumulative smoking, whether measured as pack-​years (meta-​
RR for ≥ 30 = 2.93, 95% CI = 1.87–​4.61), cigarettes per day (meta-​RR
for higher exposure, with variable cut-​points by study  =  1.98, 95%
CI = 1.31–​2.98), or years of smoking (meta-​RR for longer duration,
with variable cut-​points by study = 2.26, 95% CI = 1.32–​3.84). Risk
was not associated with earlier age at initiation (meta-​RR for earliest
group, with variable cutpoints by study = 1.17, 95% CI = 0.78–​1.75).
Colinearity of the various measures of smoking makes it difficult
to measure their independent associations with risk. Results were
significantly heterogeneous, with a higher point estimate in low-​inci-
dence populations (meta-​RR = 1.76, 95% CI = 1.47–​2.10) than high-​
incidence populations (meta-​RR  =  1.29, 95% CI  =  1.05–​1.58). The
association also was stronger for squamous cell NPC (meta-​RR = 2.20;
95% CI = 1.63–​1.98) than for undifferentiated NPC (RR = 1.27, 95%
CI = 0.98–​1.66). Exposure to passive smoking during childhood was
not significantly associated with NPC risk (meta-​OR based on five
studies = 1.29, 95% CI = 0.80–​2.09). Three studies detected signifi-
cant positive associations (Armstrong et al., 2000; Nesic et al., 2010;
Yuan et al., 2000a), whereas two did not (Cheng et al., 1999; Yu et al.,
1990). The relatively modest association with active tobacco smoking
translates to an attributable fraction for NPC that is roughly one-​tenth
that for lung cancer and other respiratory tract malignancies, and an
even smaller absolute contribution (IARC, 2004b, 2012d).
Studies of the association between exposure to domestic wood fire
and NPC risk have yielded inconsistent results. Case-​control studies
in Malaysia and southern China reported OR estimates between 2.1
and 5.4 for exposure to domestic wood fire (Armstrong et al., 1978;
Guo et  al., 2009; Zheng YM et  al., 1994), whereas other studies in
Hong Kong (Yu et al., 1986), southern China (Yu et al., 1990, 1988),
and North Africa (Feng et  al., 2009) found no significant associa-
tion. The associations reported with burning incense or anti-​mosquito
coils also have been mixed, with some positive (Geser et  al., 1978;
Shanmugaratnam and Sobin, 1978; West et al., 1993) and some null
(Yu et al., 1990, 1986, 1988). One study in North Africa found a pos-
itive association of NPC risk with cannabis smoking (OR for ≥ 2,000
exposures versus none = 3.25, 95% CI = 1.24–​8.50) and with hav-
ing had a non-​ventilated kitchen during childhood (OR = 1.64, 95%
CI = 1.09–​2.48), but not with use of a water pipe (OR = 0.49, 95% CI
= 0.20–​1.23) (Feng et al., 2009). Ever use of snuff in this study was
associated with increased risk of differentiated NPC (OR = 30.2, 95%
CI = 1.67–​546) but not undifferentiated NPC (OR = 0.97, 95% CI =
0.59–​1.58).
Chewing of betel quid—​a mixture of areca nut, betel leaf, and other
ingredients, with or without tobacco—​is common in India and many
parts of Asia, and is classified by the IARC as a cause of cancers of the
oral cavity and esophagus in humans (IARC, 2004a, 2012d). However,
whether use of betel quid causes NPC is unclear, due to potential con-
founding by tobacco smoking. In a community-​based cohort of 19,719
men in Taiwan, NPC mortality was higher among those who smoked
and chewed betel quid (RR = 4.2, 95% CI = 1.5–​11.4; 8 deaths) than
those who only smoked (RR  =  1.3, 95% CI  =  0.6–​3.0; 18 deaths),
compared with those who did neither (9 deaths) (Wen et  al., 2005).
A case-​control study of NPC high-​risk families in Taiwan found that
≥ 20 years of betel nut use was associated with increased NPC risk in
families with late-​onset NPC at or after age 40 years (OR versus never
use = 2.44, 95% CI = 1.16–​5.13), but not early-​onset NPC (OR = 0.71,
95% CI  =  0.27–​1.84) (Yang et  al., 2005). By contrast, use of betel
nut or betel quid was not associated with NPC risk after multivari-
ate adjustment in case-​control studies in the Philippines (OR = 0.56,
95% CI = 0.18–​1.8) (West et al., 1993) and Thailand (OR = 1.34, 95%
CI = 0.64–​2.83) (Fachiroh et al., 2012)
Alcohol
The results of studies of alcohol consumption and risk of NPC have
been inconsistent; both positive (Armstrong et al., 1998; Ruan et al.,
2010; Vaughan et  al., 1996) and null findings (Chen et  al., 1990;
Cheng et al., 1999; Fachiroh et al., 2012; Ji et al., 2011; Sriamporn
et  al., 1992; Xu et  al., 2012; Zheng X et  al., 1994) have been
reported from case-​control studies. A meta-​analysis of 11 case-​con-
trol studies of variable quality reported a meta-​OR of 1.33 (95%
CI = 1.09–​1.62) for the highest versus lowest category of alcohol
intake, based on variable definitions of high and low intake among
studies (Chen et  al., 2009). The association was only marginally
statistically non-significant in studies that controlled for smoking
(meta-​OR = 1.26, 95% CI = 0.99–​1.62). Among the six studies that
considered at least three categories of alcohol intake frequency, a J-​
shaped trend was evident, with NPC risk decreasing up to 15 drinks
496
496 PART IV:  Cancers by Tissue of Origin
per week and increasing thereafter. Data were insufficient to stratify
analyses by NPC histologic type, which may contribute to the het-
erogeneity of results.
Tea and Traditional Herbal Medicine
An inverse association between tea consumption and NPC risk has
been reported in several case-​control studies in China and Taiwan (Hsu
et al., 2012a; Ruan et al., 2010; Xu et al., 2012), with OR estimates
ranging from 0.4 to 0.6 for any consumption, and significant inverse
relationships with frequency of consumption. No prospective studies
have yet replicated these findings. Chinese herbal tea and Cantonese
slow-​cooked soup, which are forms of traditional Chinese medicine,
were both inversely associated with NPC risk in two case-​control stud-
ies (although exposure–​response trends were not evident for herbal
tea) (Jia et al., 2010; Xu et al., 2012), but a positive association with
herbal tea was detected in another study (Zheng YM et al., 1994). In
general, traditional herbal medicines are inconsistently associated with
NPC risk, conferring a two-​to four-​fold increase in risk in some stud-
ies (Hildesheim et al., 1992; Shanmugaratnam et al., 1978; West et al.,
1993; Zheng X et al., 1994), but not others (Jia et al., 2010; Yu et al.,
1986, 1990).
Occupational Exposures
The two occupational exposures classified by the IARC as causally
related to NPC in humans are formaldehyde (IARC, 2006, 2012c) and
wood dust (IARC, 1995, 2012a). The association between occupa-
tional exposure to formaldehyde and risk of NPC has been investigated
mainly in low-​incidence regions. The main evidence comes from a
retrospective cohort mortality study of 25,619 workers at 10 US form-
aldehyde production or usage plants, where an excess of NPC mortal-
ity was detected based on seven NPC deaths among all workers (six
among formaldehyde-​exposed workers) from pre-​1966 through 1979.
The standardized mortality ratio [SMR] comparing all workers to US
rates was (3.18 [p < 0.05] [Blair et al., 1986]). In further follow-​up,
eight NPC deaths were identified among the exposed workers by 1994
(SMR = 2.10, 95% CI = 1.05–​4.21) (Hauptmann et  al., 2004), and
nine through 2004. One case identified in the longest follow-​up was
shown by secondary sources to be oropharyngeal cancer. Exclusion
of this case reduced the SMR through 2004 to 1.84 (95% CI = 0.84–​
3.49) (Beane Freeman et  al., 2013). Statistically significant positive
exposure–​response trends by peak exposure and cumulative exposure
were detected in follow-​up through 1994 (Hauptmann et  al., 2004),
but these were no longer statistically significant in the analysis through
2004 (Beane Freeman et al., 2013). Five NPC deaths, all in the highest
category of peak exposure, occurred at a single plant. At the remaining
nine plants, the SMR for NPC was below 1.0 (McLaughlin and Tarone,
2014) and exposure–​response trends were in a positive direction but
not significant (Beane Freeman et al., 2013).
No excess of NPC was observed in recent cohort or nested case-​con-
trol studies of formaldehyde-​exposed workers in Finland, England, and
Wales, or in studies from the United States published after the 2006
IARC monograph on formaldehyde (Coggon et al., 2014; Hauptmann
et al., 2009; Meyers et al., 2013; Siew et al., 2012). A meta-​analysis of
six case-​control studies and seven cohort studies found a marginally
non-significant excess risk of NPC in case-​control studies (overall meta-​
OR = 1.22, 95% CI = 1.00–​1.50). Adjustment for smoking reduced the
meta-​OR estimate to 1.10 (95% CI = 0.80–​1.51). Conflicting results
were observed among cohort studies that excluded (meta-​SMR = 0.72,
95% CI = 0.40–​1.28) or included (meta-​SMR = 1.60 [95% CI not
reported]) the anomalous US plant (Bachand et al., 2010).
Evidence regarding the association between formaldehyde and
risk of NPC in high-​incidence areas (i.e., predominantly non-​keratin-
izing NPC) is sparse. However, one study conducted in Taiwan that
collected extensive occupational history information found evidence
for an association between formaldehyde exposure and NPC risk that
was stronger among individuals seropositive for any of various anti-​
EBV antibodies associated with NPC (96% of cases, 29% of controls)
(Hildesheim et al., 2001), a pattern that lends biological plausibility to
the association.
A two-​fold or greater increased risk of NPC among woodwork-
ers and other individuals potentially exposed to wood dust has been
reported in several studies conducted in both high-​and low-​incidence
regions (Armstrong et  al., 2000; Demers et  al., 1995; Hildesheim
et al., 2001; Sriamporn et al., 1992; Vaughan and Davis, 1991). Other
studies did not find an association (Siew et al., 2012; Stellman et al.,
1998; Vaughan et al., 2000). Two cohort studies of woodworkers have
reported results for NPC. One was a pooled study of 28,704 work-
ers from five studies in the United Kingdom and United States that
detected an SMR of 2.4 (95% CI = 1.1–​4.5) based on nine NPC deaths
(7 among furniture workers [SMR = 2.9, 95% CI = 1.2–​5.9] and two
among plywood workers [SMR = 4.6, 95% CI = 0.6–​16.4]) (Demers
et al., 1995). In this study, an excess of NPC was observed among those
with either definite or possible exposure to wood dust, first employ-
ment prior to 1950, and 30 or more years since first employment. An
analysis based on 45,399 men (12.5% of the American Cancer Society
Cancer Prevention Study II) found no excess of NPC mortality among
men who self-​ reported employment in a wood-​ related occupation
(RR = 1.44, 95% CI = 0.19–​10.9) or occupational exposure to wood
dust (RR = 0.44, 95% CI = 0.06–​3.29) (Stellman et al., 1998). In each
case the result was based on only one NPC death.
The NPC case-​ control study with the most detailed informa-
tion about wood dust exposure detected positive exposure–​response
trends with increasing duration of exposure (OR for > 10 years versus
none = 2.2, 95% CI = 0.93–​5.3, Ptrend = 0.03 excluding the 10 years
before diagnosis or interview) and cumulative exposure (OR for ≥
25 intensity-​years versus none = 2.4, 95% CI = 1.2–​5.1, Ptrend = 0.02)
(Hildesheim et al., 2001). In this study, which was based in Taiwan,
associations with wood dust exposure (as with formaldehyde) were
stronger among individuals seropositive for EBV antibodies associ-
ated with NPC risk.
Several studies in China found that NPC risk was increased by
about three-​fold among textile workers, with some evidence of posi-
tive exposure–​response trends, potentially due to cotton dust exposure
(Li et al., 2006; Ng, 1986; Zheng et al., 1992). However, some con-
tradictory results have been reported (Yu et al., 1990). Other occupa-
tional exposures, including industrial heat and combustion products
(Armstrong et al., 2000; Yu et al., 1990), solvents (Guo et al., 2009;
Hildesheim et al., 2001), and pesticides (Li et al., 2006; West et al.,
1993; Zhu et al., 2002; Zou et al., 2000), have not consistently been
associated with NPC risk.
HOST FACTORS
Immune Suppression
Some evidence suggests that immune suppression in adulthood is not
likely to play a major role in the development of NPC. The absence
of a large increase in NPC risk among AIDS patients (Shebl et  al.,
2010) and solid organ transplant recipients (Engels et al., 2011), men-
tioned earlier, supports this hypothesis, as do null studies of cancer
in patients with primary immunodeficiency disorders (Rezaei et  al.,
2011; Salavoura et al., 2008), although the statistical power of the lat-
ter was low. The strong association between NPC and genetic variants
in the HLA region suggests that certain aspects of immune function do
affect NPC risk. Except for the null studies of cancer in patients with
primary immunodeficiency disorders (Rezaei et al., 2011; Salavoura
et  al., 2008), these data suggest that defects in immune function in
childhood, when EBV infection first occurs, may be more important
than immunodeficiency in adulthood.
Familial Aggregation
Epidemiologic studies have demonstrated a 4-​to 20-​fold increased risk
of NPC associated with a first-​degree family history of the disease,
thereby establishing strong familial susceptibility (Friborg et al., 2005;
Hsu et al., 2011; Ji et al., 2011; Jia et al., 2004; Zeng and Jia, 2002).
A cohort study of the entire population born in Greenland (73,222 per-
sons), followed from 1973 to 2002, used population-​based registry
 497
Nasopharyngeal Cancer 497
linkages to identify relatives and their cancer diagnoses (Friborg et al.,
2005). This study reported an RR of 8.0 (95% CI = 4.1–​14.0) for NPC
among first-​degree relatives, with no significant differences in risk by
age and sex of the relative and index case or type of relation. In low-​
incidence regions, the number of NPC cases with a family history of
NPC is small, precluding robust analyses of the risk of familial NPC in
such areas (Vaughan et al., 1996). Nevertheless, familial aggregation of
NPC has been documented in high-​, intermediate-​, and low-​incidence
populations (Bei et al., 2012; Zeng and Jia, 2002), especially in south-
ern China, where one family of 109 relatives across four generations
has had 15 members affected by NPC (Zhang and Zhang, 1999).
The risk of malignancies other than NPC does not generally appear
to be elevated in NPC families (Jia et al., 2004; Yu et al., 2009), nor
have studies observed an excess of NPC in any of the known inherited
cancer syndromes (Garber and Offit, 2005). These observations argue
against a familial syndrome that includes NPC as well as other cancers.
However, some studies, including the Greenland cohort study, suggest
that risk of other virus-​associated malignancies, such as cancers of
the salivary glands and uterine cervix, is increased in NPC families
(Albeck et al., 1993; Friborg et al., 2005). A complex segregation anal-
ysis of 1903 Cantonese pedigrees in southern China concluded that
the observed pattern of inheritance was better explained by multiple
genetic and environmental risk factors than by a major susceptibility
gene (Jia et al., 2005).
Four familial linkage studies of NPC have been conducted in
affected siblings or extended pedigrees to map shared regions of the
genome that may confer disease susceptibility (Feng et al., 2002; Hu
et al., 2008; Lu et al., 1990; Xiong et al., 2004). These studies found
disparate results that included (a)  a putative susceptibility locus at
6p22 based on 30 affected siblings from southern China and Southeast
Asia (Lu et al., 1990); (b) a locus at 4p12–​p15 that further narrowed
to the promoter region of a novel gene, LOC344967, based on 20 mul-
tiplex families from southern China (Feng et  al., 2002; Jiang et  al.,
2006); (c)  a locus at 3p21.31–​21.2 based on 18 high-​risk southern
Chinese families (Xiong et al., 2004); and (d) a locus at 5p13.1 based
on 15 multiplex southern Chinese families (Hu et al., 2008). Further
sequencing in combination with functional characterization, along
with replication studies, are needed to better understand these findings
and to resolve whether the observed differences are due to chance or
variation in methods, populations, or disease subtypes.
Human Leukocyte Antigen Genes
Studies of HLA associations in the 1970s formed the basis of the long-​
standing hypothesis that HLA-​mediated variation in the ability to pres-
ent EBV antigens to immune cells may influence NPC risk (Simons
et al., 1975). In particular, a two-​to three-​fold increase in NPC risk
was associated with HLA-​A2-​B46 and B17 in Asians (Simons et al.,
1974, 1978), whereas a 30%–​50% decrease in risk of NPC was asso-
ciated with HLA-​A11, B13, and A2, in Asians and whites (Burt et al.,
1994, 1996; Chan et al., 1983; Simons et al., 1978), The former poly-
morphisms were postulated to confer decreased ability to present EBV-​
antigen-​presenting capability to cytotoxic T-​cells, whereas the latter
were hypothesized to increase antigen-​presenting ability. The appar-
ent inconsistency of the positive association with HLA-​A2 in Asian
populations and the inverse association in Caucasian populations was
reconciled once four-​digit HLA typing by PCR was introduced; the
HLA-​A2 association in Asians is driven by HLA-​A*02:07, whereas
that in Caucasian populations is driven by HLA-​A*02:01 (Hildesheim
et al., 2002). Of note, HLA-​A*02:07, which is almost exclusively pres-
ent in East Asians, also has been shown to be associated with increased
risk of EBV-​positive classical Hodgkin lymphoma, another EBV-​asso-
ciated malignancy, in Chinese subjects (Huang X et  al., 2012). The
role of HLA-​A*02:07 in the development of EBV-​related tumors may
be related to the less effective cytotoxic T-​cell response to EBV LMP2
in individuals carrying HLA-​A*02:07 than in those carrying other
HLA-​A*02 alleles (Lee et al., 1997).
Although more than 100 candidate-​gene association studies have
reported associations between HLA alleles or haplotypes and NPC
risk, the high density of genes (> 150 genes) and strong linkage dis-
equilibrium in the HLA region have made it challenging to identify
specific causal variants (Su et al., 2013). Relatively consistent findings
are positive associations with HLA-​A*02:07 (in linkage disequilibrium
with HLA-​B*46:01) and HLA-​B*58:01 (in linkage disequilibrium with
HLA-​A*33:03) and an inverse association with HLA-​A*11:01 (in link-
age disequilibrium with HLA-​B*13) (Bei et al., 2012; Goldsmith et al.,
2002; Hildesheim and Wang, 2012). Other HLA class I genes (HLA-​
C, -​E, -​G, and others) and class II genes (HLA-​DR, -​DP, and -​DQ) are
less well studied and are not consistently associated with NPC risk.
Metabolism and Biotransformation Genes
Compelling evidence that diet and tobacco smoking affect NPC risk
makes it plausible that genetic variation in phase I and II biotransfor-
mation genes, including those in the glutathione-​S-​transferase (GST),
cytochrome P450 (CYP), and N-​ acetyltransferase (NAT) families,
could contribute to NPC risk by influencing the metabolism of nitro-
samines and other environmental carcinogens. Several meta-​analy-
ses of up to 15 case-​control studies of the GSTM1 and GSTT1 null
polymorphisms, which result in reduced detoxifying enzyme levels,
have consistently demonstrated an increased risk of NPC in associa-
tion with the GSTM1 null genotype (meta-​ORs = 1.42–​1.54), and most
also showed a positive association with the GSTT1 null genotype
(meta-​ORs  =  1.12–​2.27) (Jin et  al., 2014; Murthy et  al., 2013; Sun
et al., 2012; Wei et al., 2013; Zhuo X et al., 2009). In the largest of
these meta-​analyses (Wei et  al., 2013), 12 of 14 included studies of
GSTM1 and 9 of 10 studies of GSTT1 were conducted in Asians, such
that results in Asians (OR  =  1.53, 95% CI  =  1.24–​1.88 for GSTM1
null; OR  =  2.28, 95% CI  =  1.48–​3.50 for GSTT1 null) were nearly
identical to the overall findings (OR = 1.54, 95% CI = 1.28–​1.86 and
OR = 2.25, 95% CI = 1.50–​3.36, respectively).
Likewise, genetic polymorphisms in CYP2E1 that may result in
increased metabolic activation of xenobiotic carcinogens have been
associated with at least a doubling of NPC risk for homozygous vari-
ants in several studies (Hildesheim et al., 1995, 1997; Jia et al., 2009;
Kongruttanachok et  al., 2001; Yang et  al., 2005). Results are variable
with respect to potential interactions with smoking. A Taiwan case-​con-
trol study with 364 NPC cases and 320 controls found that the increased
risk associated with the homozygous CYP2E1 RsaI c2 allele (rs2031920)
was restricted to non-​smokers (RR = 9.3, 95% CI = 2.7–​32) and was
not detected among smokers (RR = 1.1 for all smokers; RR = 0.96 for
smokers of > 30 years’ duration) (Hildesheim et al., 1997). However, a
case-​control study in Guangdong, China, with 755 cases and 755 con-
trols found that significant positive associations with seven CYP2E1 sin-
gle-​nucleotide polymorphisms (SNPs) (not including rs2031920) and
two CYP2E1 haplotypes were detectable only among smokers aged <
46 years (ORs for SNPs = 1.88–​2.99, P = 0.0140–​0.0001; ORs for hap-
lotypes = 1.65 and 2.58, P = 0.026 and 0.007, respectively) (Jia et al.,
2009). Studies of other CYP and NAT genes are limited in number, with-
out consistent results (Bendjemana et al., 2006; Cheng et al., 2003; Jiang
et al., 2004; Lee et al., 1998; Tiwawech et al., 2006).
DNA Repair and Tumor Suppressor Genes
Genetic variants in DNA repair genes might modify any protective
effects against DNA damage caused by environmental carcinogens
or EBV. A meta-​analysis of up to five case-​control studies of coding
SNPs in the X-​ray repair cross-​complementing group 1 gene (XRCC1),
which is involved in the repair of DNA single-​strand breaks, found
a positive association with the Arg99Gln genotype (OR = 1.30, 95%
CI = 1.01–​1.69 for Gln/​Gln versus Arg/​Arg, based on 1,049 cases and
1,066 controls), but no association with Arg194Trp (OR = 1.79, 95%
CI = 0.50–​6.40 for Trp/​Trp versus Arg/​Arg) or Arg280His (OR = 0.98,
95% CI = 0.50–​1.94 for His/​His versus Arg/​Arg) (Huang et al., 2011).
Other reports of significant associations with genetic variation in
nibrin (NBS1), a protein involved in double-​strand break repair (Zheng
et al., 2011), and with a member of the RAD51 protein family, which
also is involved in repairing DNA double-​strand breaks (Qin et  al.,
2011b), require independent confirmation. The latter study found no
significant association with most haplotypes of 88 DNA repair genes
498

498 PART IV:  Cancers by Tissue of Origin

(including XRCC1) in a case-​control study of 755 NPC cases and 755 findings were found to be driven largely by HLA-​A*11:01, and less so
controls, perhaps indicating that any influence of DNA repair gene by HLA-​A*02:07.
polymorphisms is moderate at most. A meta-​analysis of four NPC GWAS confirmed many of the asso-
In two meta-​analyses of a genetic variant in codon 72 of the TP53 ciations summarized in the preceding and identified a novel associa-
tumor-​suppressor gene (rs1042522, Arg72Pro), which is involved in tion between genetic variation in the CLPTM1L/​TERT region and NPC
cell cycle arrest in response to DNA damage, those with the homozy- risk, suggesting that factors involved in telomere length maintenance
gous Pro/​Pro genotype were found to have a two-​fold increased risk could be involved in NPC pathogenesis (Bei et al., 2016).
of NPC compared with Arg/​Arg carriers (Cai et  al., 2014; Zhuo XL
et  al., 2009). The larger meta-​analysis (Cai et  al., 2014), based on a
total of seven studies with 1133 cases and 1678 controls, detected this OPPORTUNITIES FOR PREVENTION
association in both Asians (OR = 1.79, 95% CI = 1.40–​2.30) and whites
(OR = 2.72, 95% CI = 1.44–​5.12), although it was stronger in the latter. The recently declining incidence rates of NPC worldwide, particu-
larly in high-​risk areas, demonstrate an important role of modifiable
Genome-​Wide Association Studies environmental or behavioral risk factors for NPC that could be targets
Five genome-​wide association studies (GWAS) with information on for prevention. Tobacco control policies and dietary modifications to
400,000–​600,000 SNPs in hundreds of NPC cases and controls have decrease intake of salt-​preserved foods and increase consumption of
been conducted to identify susceptibility loci for NPC. Collectively, fresh fruits and vegetables are important for the prevention of NPC
these studies have provided strong confirmation of previous HLA find- as well as other cancers. However, they may not prevent a large pro-
ings, but do not confirm other genes previously found in candidate-​ portion of future cases, given the fairly modest risk associations and
SNP studies to be associated with NPC risk. indications that salt-preserved fish consumption has already declined
The first NPC GWAS, which included an initial sample set of in high-​risk regions (Lau et  al., 2013). Development of a vaccine
111 Malaysian Chinese NPC cases and 260 controls, along with a against EBV could provide a basis for more widespread prevention of
validation set of 168 cases and 252 controls, identified a significant NPC and other EBV-​associated malignancies that sum to as many as
association with rs2212020 in the integrin α-​9 gene at 3p21 (OR = 200,000 new cancer cases each year, but substantial barriers stand in
2.24, Pcombined = 8.27 × 10–​7) (Ng et al., 2009). the way of such an advance (Cohen et al., 2011, 2013).
A Taiwan-​based GWAS with a discovery set of 277 NPC cases Secondary NPC prevention through EBV-​based screening, leading
and 285 controls and two validation sets with a combined 635 cases to early disease detection and curative treatment, also could reduce
and 1640 controls identified two significant susceptibility loci in the NPC mortality in high-​risk populations. Although promising early
HLA-​A region at 6p21.3 (rs2517713, OR = 1.88, Pcombined = 3.9 × 10–​20; results using ELISA to test for anti-​EBV IgA antibodies have emerged
rs2975042, OR = 1.86, Pcombined = 1.6 × 10–​19), and an independent asso- from the Taiwan multiplex family study (Coghill et al., 2014) and the
ciation with rs29232 in the gamma aminobutyric b receptor (GABBR1) preliminary phase of the southern Chinese screening trial described
gene at the same locus (OR = 1.67, Pcombined = 8.97 × 10–​17, Presidual < 5 × earlier (Liu et al., 2013), a beneficial effect has yet to be demonstrated
10–​4 after adjustment for the HLA-​A SNPs) (Tse et al., 2009). A fol- in a randomized, controlled prospective screening trial.
low-​up study using PCR-​based genotyping for the HLA-​A gene and
for 12 significant GWAS-​identified SNPs in 6p21 found that most of
FUTURE RESEARCH DIRECTIONS
the associations detected in the GWAS were due to previously identi-
fied HLA-​A associations, with the possible exception of the association
Although EBV contributes to virtually all non-​keratinizing NPC cases,
with rs29232 (GABBR1) (Hsu et al., 2012b).
it is unclear why this ubiquitous virus causes NPC in a small fraction
A subsequent GWAS with 1583 southern Chinese NPC cases and
of those infected. Early age at primary EBV infection appears to have
1894 controls in the discovery phase, plus 3507 cases and 3063 cases in
an important etiologic influence. Although several cofactors for NPC
the validation phase, identified three new susceptibility loci: rs9510787
have been established (Table 26–1), at present the majority of cases are
in the tumor necrosis factor receptor superfamily, member 19, on 13q12
(OR = 1.20, Pcombined = 1.53 × 10–​9); rs6774494 in the myelodysplasia 1
and ecotropic viral insertion site 1 fusion proteins on 3q26 (OR = 0.84, Table 26–1.  Known and Suspected Risk Factors for Nasopharyngeal
Pcombined = 1.34 × 10–​8); and rs1412829 in the cyclin-​dependent kinase Carcinoma (See Text for Details).
inhibitors 2A and 2B clusters on 9p21 (OR = 0.78, Pcombined = 4.84 ×
10–​7) (Bei et al., 2010). This study also confirmed the importance of the Risk Factor Level of Evidence
HLA region in NPC by identifying significant loci in HLA-​A, HLA-​B/​C,
and HLA-​DQ/​DR (rs2860580, OR  =  0.58, Pcombined  =  4.88 × 10–​67; Epstein-​Barr virus infection Strong
rs2894207, OR = 0.61, 95% CI = 0.57–​0.66, Pcombined = 3.42 × 10–​33; Chinese-​style salt-preserved fish Strong
rs28421666, OR = 0.67, Pcombined = 2.49 × 10–​18). Family history Strong
The etiologic relevance of the HLA class I region was once again Certain HLA-​A and HLA-​B alleles Strong
highlighted by the results of a GWAS of 567 southern Chinese NPC Tobacco smoke Strong to moderate
cases and 476 controls for discovery and 346 cases and 629 controls Formaldehyde Moderate
for replication, in which significant associations were identified with Preserved foods other than salt-preserved Moderate
glutamine at HLA-​A amino acid site 62 (Pcombined = 7.38 × 10–​29), leu- fish
cine at HLA-​B amino acid site 116 (Pcombined = 6.51 × 10–​19), and tryp- Chronic respiratory tract conditions Moderate
tophan at HLA-​C amino acid site 156 (Pcombined  =  6.84 × 10–​8) (Tang Wood dust Moderate
et  al., 2012). High-​resolution HLA molecular typing in a combined HIV/​AIDS Moderate
1405 cases and 2650 controls revealed independent associations with Fresh fruits and vegetables (inverse) Moderate
HLA-​A*11:01 (P = 1.7 × 10–​19), HLA-​B*38:02 (P = 7.0 × 10–​11), HLA-​ CYP and GST polymorphisms Moderate
B*55:02 (P = 1.6 × 10–​10), and HLA-​C*12:02 (P = 4.3 × 10–​5), and with Other types of smoke Weak
HLA haplotypes including combinations of these alleles. Alcohol Weak
A fifth GWAS conducted with 184 Malaysian Chinese NPC cases Herbal medicines Weak
and 236 controls in the discovery phase and 260 cases and 245 con- Tea (inverse) Weak
trols in the replication phase also confirmed the involvement of HLA-​ Other HLA class I and class II alleles Weak
A in NPC risk, based on a significant association with rs3869062 DNA repair gene polymorphisms Weak
(Pcombined = 1.73 × 10–​9) (Chin et al., 2015). Fine mapping of the HLA-​A CYP = cytochrome P-​450; GST = glutathione-​S-​transferase; HIV/​AIDS = human
region revealed associations with SNPs in the HLA-​A antigen peptide immunodeficiency virus/​acquired immunodeficiency syndrome; HLA = human leukocyte
binding groove, the T-​cell receptor binding site, and other loci; these antigen.
 49
Nasopharyngeal Cancer 499
Box 26–1  EVIDENCE SUPPORTING THE INVOLVEMENT
OF EARLY-LIFE EXPOSURES IN NASOPHARYNGEAL
CARCINOMA DEVELOPMENT
1. Early peak and later plateau/​decline in age-​incidence curve
2. Etiologic role of Epstein-​Barr virus infection, which usually
occurs in early life
3. Possibly stronger association with consumption of Chinese-​style
salt-preserved fish in infancy or childhood than in adulthood
4. Modest or null association with immune suppression in adult-
hood (e.g., HIV/​AIDS, solid organ transplantation), but strong
and consistent association with genetic determinants of immune
function (i.e., HLA alleles)
5. Positive exposure–​response trend with longer duration of smok-
ing, implying earlier initiation
HIV/​AIDS = human immunodeficiency virus/​acquired immunodeficiency
syndrome; HLA = human leukocyte antigen.
not explained by known risk factors such as family history, certain HLA
alleles, Chinese-​ style salt-preserved fish consumption, and tobacco
smoking. It remains to be determined whether most NPC is due to as-​
yet unidentified risk factors, heterogeneity in exposure, or a difference
in host response to a known cause such as EBV. Chance events contrib-
ute to risk, but would not be expected to affect international variation.
A distinctive aspect of NPC that bears further research is the impact of
early-​life exposures on risk. As summarized in Box 26–1, several lines of
epidemiologic evidence point to the involvement of childhood exposures in
NPC development. These include the relatively young average age at onset
in high-​incidence areas, along with the early incidence peak among ado-
lescents and young adults, at least in low-​incidence areas; the fundamental
involvement of EBV infection, which first occurs during early childhood
in the vast majority of people in high-​incidence areas; the stronger RRs
in association with consumption of salt-​preserved fish during infancy and
childhood than adulthood in some studies; the positive association with
cigarette smoking, which generally begins in adolescence (although results
for passive smoking during childhood are equivocal); and the weak or null
associations with immune deficiency in adulthood, countered by strong
associations with genetically determined immune function. Given this col-
lective evidence, the search for novel risk factors for NPC may be most
productive if focused on other early-​life (including heritable) exposures.
Other potentially fruitful avenues for future epidemiologic research
on NPC include investigating how EBV sequence variation influ-
ences NPC risk, delving into the molecular pathways underlying the
involvement of HLA genes in NPC development, and exploring how
the local nasopharyngeal microbiome might affect the risk of malig-
nancy. Measuring the levels of nitrosamines in various foods across
different geographic regions or identifying a valid and accessible
biomarker for nitrosamine consumption would improve the assess-
ment of exposure to key dietary risk factors for NPC. Interactions
among environmental, viral, and genetic risk factors in NPC await
elucidation in large, probably pooled analyses. Shared and distinct
risk factors for keratinizing and non-​keratinizing NPC have not yet
been delineated clearly, and molecular differences between histologi-
cal subtypes also are not well established. Few epidemiologic stud-
ies have been conducted of NPC in intermediate-​incidence regions.
In addition, host and environmental prognostic factors for NPC are
largely unstudied. To reduce the global health burden due to NPC and
other EBV-​related malignancies, progress is needed in the develop-
ment of an EBV vaccine and/​or effective, most likely EBV-​based,
cancer screening strategies.
As southern China and other areas with historically high NPC inci-
dence rates undergo rapid economic development, the ensuing environ-
mental and lifestyle transitions among people living in these regions
will almost certainly lead to changes in the prevalence of risk factors
and their relative importance in the etiology of NPC. A challenge will
be to determine whether any discrepancies in results between older
and newer studies are due to differences in research methods, inherent
exposure characteristics, human behavioral patterns that affect expo-
sure received, the prevalence of interacting exposures, histologic sub-
type distributions, or a combination of these or other factors.
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504 PART IV:  Cancers by Tissue of Origin

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 50
27 Cancer of the Larynx
ANDREW F. OLSHAN AND MIA HASHIBE
OVERVIEW
Cancer of the larynx includes malignant tumors of the glottis, supra-
glottis, subglottis, and laryngeal cartilage. Older treatments for
laryngeal cancer caused significant disfigurement, difficulty with swal-
lowing and speech, and poor quality of life. Newer treatment methods
seek to preserve laryngeal function. Worldwide, an estimated 157,000
new cases and 83,000 deaths from laryngeal cancer occurred in 2012,
accounting for 1.1% of all new cancer cases and 1.0% of all cancer
deaths. The risk of cancer of the larynx is nearly five times higher in
men than women in the United States. Incidence and mortality rates
of these cancers in males are decreasing in most high-​income coun-
tries, and the rates have decreased in all racial and ethnic groups in the
United States.
Active cigarette smoking is the strongest risk factor and explains
the greatest proportion of cases. The association with smoking has
strengthened in both sexes over time, but decreases in smoking prev-
alence have decreased the number of cases in men and women. All
tobacco products are strongly associated with increased risk, especially
when combined with alcohol consumption. Alcohol consumption in
people who have never smoked and several occupational exposures
are more weakly associated than smoking. Dietary patterns and indi-
vidual food groups and nutrients have been associated with lower risk.
Any potential causal role for high-​risk types (e.g., HPV-​16, HPV-​18)
of the human papillomavirus (HPV) is uncertain and is likely to be
small compared to the role of smoking or the association of HPV with
oropharyneal cancer. Potential genetic susceptibility factors have been
identified from candidate gene and genome-​wide association studies
(GWAS). Evidence for molecularly defined subgroups of laryngeal
cancer is rapidly emerging. Molecular profiling indicates many shared
features between cancers of the larynx and other smoking-​related
squamous cell carcinomas.
CLASSIFICATION
Subtypes of laryngeal cancer are classified according to their topogra-
phy. The International Classification of Diseases for Oncology (ICD-​
O-​3) designates codes for cancers of the glottis (C32.0), supraglottis
(C32.1), subglottis (32.2), laryngeal cartilage (C32.3), overlapping
lesion of larynx (C32.8), and larynx NOS (C32.9) (Fritz A, 2000).
Glottic tumors arise from the true vocal cords, including the anterior
and posterior commissures. Supraglottic tumors occur proximal to the
true vocal cords—​specifically the false vocal cords, arytenoids, epi-
glottis, and aryepiglottic folds. Subglottic tumors form below the apex
of the ventricle and extend to the lower border of the cricoid cartilage.
Hypopharyngeal cancers are rare and are often combined with cancers
of the larynx in epidemiologic studies because of their similar clinical
management (Hashibe et  al., 2009). The epidemiologic evidence on
risk factors for cancers of the hypopharynx is limited but is described
later in this chapter under etiologic factors.
Approximately 13,430 new cases of laryngeal cancer were pro-
jected to occur in the United States in 2016 (American Cancer Society,
2016). These cases represent about 1% of all incident cancers in the
United States and 22% of all head and neck cancers. Most laryn-
geal cancers (95%) are squamous cell carcinomas (Surveillance,
Epidemiology, and End Results [SEER], 2015). This proportion did
not change appreciably between 1973 and 2012 in data compiled
by the NCI Surveillance, Epidemiology, and End Results (SEER)
Program (SEER, 2015). Approximately half (51.0%) of laryngeal can-
cers in the United States are glottic, 35.3% supraglottic, 1.9% subglot-
tic, 0.7% involve laryngeal cartilage, and 2.5% overlap the boundaries
of two or more subsites so their point of origin cannot be determined.
For 8.6% of tumors, the anatomic location is not otherwise speci-
fied (NOS). Males have more glottic tumors than females (55.6% vs.
31.8%) and fewer supraglottic tumors (30.7% vs. 54.1%). Among both
sexes, whites have more glottic tumors (51.8%) than blacks (44.2%).
Blacks have a greater proportion of supraglottic tumors (40.6%) than
whites (34.8%).
STAGE AT DIAGNOSIS
Over half (56.2%) of cases reported to SEER registries from 2008 to
2012 with information on stage were classified as localized, 24.5%
as regional, and 18.3% as distant (SEER, 2015). Glottic cancer has
the highest percentage of localized disease (81.5%). The correspond-
ing percentages for other subtypes were 48.1% for tumors of laryn-
geal cartilage, 47.1% for subglottic, 29.7% for supraglottic, 29.7%
for overlapping lesions, and 25.2% for NOS. Of all tumors, 57.7%
among males and 50.2% among females were localized at the time of
diagnosis.
TUMOR PROGRESSION MODELS
In terms of histologic appearance, laryngeal cancers develop through
a series of epithelial mucosal changes. The earliest visible precursor
lesions are keratoses that may appear bilaterally on the vocal cords.
It has been estimated that the annual incidence of laryngeal keratoses
in the United States is 10.2 lesions per 100,000 for males and 2.1 per
100,000 for females (Bouquot and Gnepp, 1991). More than half of
keratotic lesions also contain dysplasia. However, even lesions without
dysplasia have the potential for malignant transformation (Isenberg
et al., 2008). A meta-​analysis of 940 laryngeal lesions with dysplasia
reported that the cumulative incidence of malignant transformation
was 14% (95% CI = 8%, 22%) (Weller et al., 2010). In Weller’s series,
malignant transformation occurred in 10.6% (CI  =  5.1%, 20.7%) of
lesions with mild/​moderate dysplasia and 30.4% (CI = 16.1%, 49.9%)
of lesions with severe dysplasia. The mean time to transformation
was 5.8 years (range = 1.8–​14.4 years). A study of disease progres-
sion among 107 cases at a single institution in relation to sex and age
at diagnosis of dysplasia found no significant trend during the time
period 1993–​2012 (Karatayli-​ozgursoy et al., 2015). Genomic analy-
ses of laryngeal lesions with keratosis and dysplasia have included
very few cases (Bartlett et al., 2012).
Large molecular studies have generally grouped all head and
neck cancers together, rather than reporting results specifically for
laryngeal cancers. However, Makitie and Monni reviewed studies
of genetic alterations in laryngeal cancer based on microsatellite
markers, mutation detection, immunohistochemistry, and compara-
tive genomic hybridization (Makitie and Monni, 2009). They identi-
fied early progression events including allele loss at 3p, 9p21, and
17p13—​loci that contain tumor suppressor genes including FHIT
505
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506 PART IV:  Cancers by Tissue of Origin

(3p), CDKN2A (9p21), and TP53 (17p13). Common amplifications Demographic Patterns
were mapped to 3q, 5p, 8q, 11q13, and 18p; losses were located at
3p, 5q, 8p, 9p, 11q23–​24, 13q, and 18q (Makitie and Monni, 2009). Incidence and Mortality Rates (United States)
These results were generally consistent with a genetic progression Table 27–1 presents US incidence and mortality rates based on the
model for head and neck cancer, based on cytogenetic characteristics NCI SEER registries from 2008 to 2012 (Howlander et  al., 2015).
of cell lines and tumors (Califano et al., 1996). This model proposed Overall, the age-​adjusted invasive laryngeal cancer incidence rates
that multiple genetic alterations accumulate at key loci, affect- per 100,000 are almost five times higher for males (5.8) than females
ing specific events in progression. Loss of heterozygosity (LOH) (1.2); among males, the rates are highest in black men (8.8) and lowest
at 9p21 was thought to be linked to the transition from normal to in Asian/​Pacific Islanders (2.4). For both sexes combined, lower rates
hyperplasia; LOH at 3p21 and 17p13 to progression from hyperpla- (per 100,000) are seen for Hispanics (2.3), American Indians/​Alaskan
sia to dysplasia; LOH at 11q13, 13q21, and 14q32 to the transition Natives (2.3), and Asian/​Pacific Islanders (1.2). In all races combined,
from dysplasia to carcinoma in situ (CIS); and LOH at 6p, 8, 4q27, the incidence rate in US SEER areas was below 1.0 per 100,000 from
10q23 LOH to progression from CIS to carcinoma. Another general age 25 years to 44 years. The incidence rate per 100,000 rose progres-
model of molecular pathogenesis for head and neck cancer included sively with age from 2.3 at ages 45–​49 to 7.7 at ages 55–​59, and to
loss of multiple tumor suppressor genes that affect initiation (TP53), 16.4 at ages 70–​74 years. Mortality rates are considerably lower than
progression (Rb/​INK4/​ARF), and maintenance (Notch) (Rothenberg incidence rates, reflecting the availability of effective treatment. The
and Ellisen, 2012). age-​standardized death rate (per 100,000) is nearly five times higher
One important area of molecular cancer research involves gene-​ in men (1.9) than in women (0.4) in the United States (Table 27–1).
expression profiling of tumors to identify tumor heterogeneity and
subgroups with distinctive prognosis and possibly etiology. A  series Incidence and Mortality Rates (International)
of studies have identified gene expression patterns that differentiate International incidence and mortality data are available through the
normal epithelium from squamous cell carcinoma of the head and registry system of the International Agency for Research on Cancer
neck (Makitie and Monni, 2009). Based on 60 head and neck can- (IARC) and the GLOBOCAN 2012 estimates (Ferlay et  al., 2015).
cers that included 24 laryngeal cancers, Chung identified four sub- Based on 156,877 cases worldwide, the age-​adjusted incidence rate
groups with different prognostic outcomes (Chung et al., 2004). In an was 2.1 per 100,000 in both sexes combined. The incidence rate (per
analysis that did not stratify by tumor site, these subgroups included 100,000) was nearly eight times higher in men (3.9) than women (0.5),
(1) high expression of TGF-​α; (2) mesenchymal signature; (3) normal a larger sex ratio than for any other cancer site. The incidence rate (per
tonsillar epithelial samples positive for cytokeratin-​15 expression; and 100,000) was somewhat higher in economically more developed (2.7)
(4) patients with tobacco exposure. Another gene expression study of than less developed (1.9) regions. The male/​female (M/​F) sex ratio
head and neck cancers by Walter also identified four different gene was slightly higher for less developed (3.5/​0.4 = 8.7) than more devel-
expression profiles, but designated these as basal, mesenchymal, atypi- oped (5.1/​0.6  =  8.5) countries. The highest incidence rates for men
cal, and classical (Walter et al., 2013). The Walter et al. study included (per 100,000) were observed in the Caribbean (7.9) and in Central and
30 laryngeal cases in a total of 138 head and neck cancers. Among Eastern Europe (7.8), Southern Europe (7.2), and Western Asia (6.5).
the laryngeal cancers, 11 (37%) were considered classical, 10 (33%) Lower rates were seen for Middle Africa (1.4) and Western Africa
basal, 5 (17%) atypical, and 4 (13%) mesenchymal. Tumors with (1.4). Globally, the mortality rate (per 100,000) was 10 times higher
the classical signature were obtained from patients with the heaviest in men (2.0) than women (0.2). The M/​F sex ratio for mortality was
smoking history and had elevated expression of genes associated with higher for more developed countries (2.2/​0.2 = 11) than less developed
tobacco smoke exposure. Basal cancers had a similar gene expression countries (2.0/​0.3 = 6.6). As was the case for incidence rates, mortal-
signature as basal cells from normal human airway epithelium, with ity rates (per 100,000) for males were highest in the Caribbean (4.0),
high expression of genes such as COL17A1, TGFA, EGFR, and TP63. Central and Eastern Europe (4.9), and South America (3.0).
Tumors with the atypical signature had a strong HPV-​positive expres-
sion pattern, whereas those with a mesenchymal signature showed Trends in Incidence and Mortality in the United States
elevated expression of genes involved in the epithelial to mesenchy- The incidence and death rates from laryngeal cancer are decreasing
mal transition. Despite the limited sample size, Walter showed a strong among men and women in the United States. The average annual per-
correlation between the head and neck cancer subgroups and subtypes cent change (AAPC) in SEER from 2003 to 2012 showed statistically
of lung squamous cell carcinoma reported elsewhere (Wilkerson et al.,
2010). However, Walter was not able to confirm the association with
survival reported by Chung. Table 27–​1. Incidence and Mortality Rates from Cancer of the Larynx: 
The most comprehensive analysis of the genome of head and US SEER Program (2008–​2012)
neck cancer to date has been reported by The Cancer Genome Atlas
(2015). Their analysis of 279 head and neck tumors identified four Incidencea Mortalityb
gene expression subtypes as reported by Chung et  al. (2004) and
Walter et al. (2013). The proportionate contributions of the smoking-​ Race/​Ethnicity Total Males Females Total Males Females
related “classical” tumors and non-​HPV related “atypical” cancers
were higher for laryngeal cancer than for other head and neck cancers. All Races 3.2 5.8 1.2 1.1 1.9 0.4
Here too the classical subtype was strongly associated with a history White 3.3 5.8 1.2 1.0 1.8 0.4
of heavy smoking and gene alterations of TP53, CDKN2A, 3q, and White Hispanic 2.4 4.7 0.5 0.9 1.7 0.2
oxidative stress genes. White 3.5 6.0 1.4 1.0 1.8 0.4
Non-​Hispanic
Black 4.7 8.8 1.7 1.8 3.6 0.6
Asian/​Pacific 1.2 2.4 0.3 0.4 0.8 0.1
DESCRIPTIVE EPIDEMIOLOGY Islander
American Indian 2.3 4.3 —​ 0.7 1.4 0.2
Disease Burden Alaska Native
Worldwide, an estimated 157,000 new cases and 83,000 deaths from Hispanic 2.3 4.5 0.5 0.8 1.7 0.2
laryngeal cancer occurred in 2012 (Ferlay et al., 2015). These com-
prise 1.1% of all new cases of cancer and 1.0% of all cancer deaths a
Rates per 100,000, age adjusted to the 2000 US population, SEER (2008–​2012), SEER
estimated for that year. The American Cancer Society projects that 18 areas.
b
Rates per 100,000, age adjusted to the 2000 US population, SEER (2008–​2012), US
13,430 new cases and 3620 deaths from laryngeal cancer will occur in Mortality Files.
the United States in 2016 (American Cancer Society, 2016). —​Statistic not shown. Rate based on less than 16 cases.
 507

Cancer of the Larynx 507

significant decreases in incidence (–​ 2.6%) and mortality (–​ 2.2%)
(Figure 27–1) in both sexes combined. This pattern held for every race/​
ethnicity group (Table 27–2), except for a small, non-​significant increase
for American Indians/​Native Alaskans. The largest AAPC decrease in
incidence (–​3.3%) was observed among blacks, followed by Asian/​
Pacific Islanders (–​3.0%) and non-​Hispanic whites (–​2.3%). Similarly,
the largest AAPC decrease in mortality was among blacks (–​3.3%). In
general, larger decreases in incidence were found for females compared
to males (data not shown). For all races, females had a –​3.1% decrease
in incidence compared with males (–​1.9%). For mortality, males had a
slightly larger decrease (–​2.5%) than females for all races combined.
International Trends in Incidence and Mortality
Based on cancer incidence data from Cancer Incidence in Five
Continents, the incidence rates for laryngeal cancer have generally
been declining steadily in men since 1980, as shown for Europe (Figure
27–2), Asia and Oceania (Figure 27–3), and Africa and the Americas
(Figure 27–4) (Australian Cancer Database, 2015; Engholm, 2015;
Ferlay, 2014a, 2014b; Hamdi, 2013; United Kingdom, 2015). Among
women, the incidence rates of laryngeal cancer have also been declin-
ing (Figures 27–5, 27–6, and 27–7, although more modestly than the
rates among men in most locations. Substantial declines have been
observed in India, Thailand, and the United States (whites and blacks).
Survival (United States)
Table 27–3 presents the 5-​year relative survival percentages from
the SEER Program, 2005–​2011. Overall, relative survival was better
for males (61.2%) than for females (56.3%), and for whites (61.2%)
than for blacks (52.9%). Using the SEER Summary Stage 2000 data
(table 2), males had slightly better survival than females for localized
stage tumors (76.8% vs. 71.5%) and distant stage (35.5% vs. 34.3%),
but lower survival for regional stage (43.2% vs. 48.2%). Whites had
better survival for all stages, with the largest difference seen for distant
stage (36.3% vs. 30.5% for blacks).
ETIOLOGIC FACTORS
Tobacco
The causal relationship between tobacco smoking and laryngeal can-
cer is well established (Hashibe et al., 2009; IARC, 2004). Smoking
cigarettes, cigars, or pipes increases risk. The association with ciga-
rette smoking is stronger than for any other cancer except lung cancer
(see Chapter 11 in this volume).
Multiple international cohort and case control studies have shown
dose–​ response relationships between increasing risk of laryngeal
cancer and daily consumption and duration of cigarette smoking.
A pooled analysis of large cohort studies in the United States shows
that the mortality rate from laryngeal cancer among cigarette smok-
ers and the strength of the association between current smoking and
death from laryngeal cancer have increased over time, especially
among women (Carter et  al., 2015). In contrast, tumor registries in
many countries show that the incidence rates from laryngeal cancer in
the general population (including current, former, and never-​smokers)
have decreased among men (Figures 27–2, 27–3, and 27–4) but not
women (Figures 27–5, 27–6, and 27–7), due to the earlier decline in
the prevalence of smoking among men than women.
Pipe and cigar smoking are also associated with increased incidence
and death rates from laryngeal cancer among men. In an analysis of
the American Cancer Society (ACS) cohort Cancer Prevention Study
II (CPS-​II), Henley et al. (2004) reported a strong association between
exclusive pipe smoking by men and mortality from laryngeal can-
cer for both current smokers (HR  =  13.1; 95% CI  =  5.2, 33.1) and

Incidence Mortality
Rate per 100,000 Rate per 100,000
10 10
White
9 Black 9

8 APIb 8
AI/ANc
7 7
Hispanicd
6 6

5 5

4 4

3 3

2 2

1 1

0 0
1975 1980 1985 1990 1995 2000 2005 2012 1975 1980 1985 1990 1995 2000 2005 2012
Year of Diagnosis Year of Death

Figure 27–1.  SEER Incidence and Death Rates: Cancer of the Larynx, Both Sexes.a Source: Incidence data for whites and blacks are from the SEER 9
areas (San Francisco, Connecticut, Detroit, Hawaii, Iowa, New Mexico, Seattle, Utah, Atlanta). Incidence data for Asian/Pacific Islanders, American Indians/
Alaska Natives and Hispanics are from the SEER 13 areas (SEER 9 areas, San Jose-Monterey, Los Angeles, Alaska Native Registry and Rural Georgia).
Mortality data are from US Mortality Files, National Center for Health Statistics, CDC.
a
Rates are age-adjusted to the 2000 US Std Population (19 age groups - Census P25-1103).
Regression lines are calculated using the Joinpoint Regression Program Version 4.2.0. April 2015, National Cancer Institute. Joinpoint analyses for Whites
and Blacks during the 1975-2012 period allow a maximum of 5 joinpoints. Analyses for other ethnic groups during the period 1992-2012 allow a maximum
of 3 joinpoints.
b
API= Asian/Pacific Islander.
c
AI/AN = American Indian/Alaska Native. Rates for American Indian/Alaska native are based on the CHSDA/Contract Health Service Delivery Area)
counties.
d
Hispanic is not mutually exclusive from whites, blacks, Asian/Pacific Islanders, and American Indians/ Alaska Natives. Incidence data for Hispanics
are based on NHIA and exclude cases from the Alaska Native Registry. Mortality data for Hispanics exclude cases from New Hampshire and Oklahoma.
508

508 PART IV:  Cancers by Tissue of Origin

Table 27–​2. Trends in Incidence and Mortality: US SEER Program 14
(2003–​2012)

Incidence Mortality
Race/​Ethnicity AAPCa (%) AAPCb (%)
12
All Races –​2.6 –​2.2
White –​2.4 –​1.9
White Hispanic –​1.8 –​2.5
White Non-​Hispanic –​2.3 –​1.8
Black –​3.3 –​3.3 10
Asian/​Pacific Islander –​3.0 –​1.9
Amer Ind/​Alaska Nat 0.6 –​2.6
Hispanic –​1.8 –​2.5

Rates per 100,000

a
Average annual percent change (AAPC) based on a joinpoint analysis with up to 3 8
joinpoints over the diagnosis years 1992–​2012.
b
The 2003–​2012 mortality AAPCs are based on a Joinpoint analysis using years of death
1992–​2012.

14
4

12
2

10
0
1970 1975 1980 1985 1990 1995 2000 2005 2010

*China Israel *Japan *India

Singapore *Philippines Australia *Thailand
Rates per 100,000

8
*Regional data

Figure 27–​3.  Trends in age standardized incidence rates (ASR) from laryn-

geal cancer (C32) in selected regions of Asia and Oceania (men). Rates
6
have been smoothed using 5-​year average. Source: C15 other database.

former smokers (HR = 5.6; 95% CI = 1.5, 21.2). The association with

4
pipe smoking was stronger for laryngeal cancer than for lung cancer.
By comparison, the HR for lung cancer among current versus never-​
smokers was 5.0 (95% CI = 4.16, 6.01) and for former smokers was
1.70 (95% CI = 1.23, 2.36).
Similar findings were reported for men who exclusively smoked
cigars in the ACS CPS-​II cohort (Shapiro et  al., 2000). The relative
2
risk (RR) estimate for current cigar smokers was (RR = 10.3, 95% CI
= 2.6, 41.0) (Shapiro et al., 2000). A pooled analysis of case control
studies in Europe reported an odds ratio (OR) of 5.60 (95% CI = 1.64,
19.13) for exclusive cigar use, compared to 11.11 for exclusive ciga-
rette use (Hashibe et al., 2007a, 2007b). There were no exclusive pipe
0
1970 1975 1980 1985 1990 1995 2000 2005 2010 smokers in the study population.
International Head and Neck Cancer Consortium (INHANCE)
Denmark Finland *France *Italy investigators performed a pooled analysis of 1026 hypopharyngeal
Norway Slovakia UK: England Sweden cancer cases in relation to cigarette, cigar, and pipe smoking (Wyss
et  al., 2013). Among never-​cigarette-​smokers they found OR esti-
*Regional data mates of 2.51 (95% CI  =  0.90,  –​6.97) comparing current to never-​
cigar-​smokers and 3.90 (95% CI = 1.39, 10.92) for pipe smokers. The
Figure  27–​
2. Trends in age standardized incidence rates (ASR) from OR estimates for larynx cancer were 6.31 (95% CI = 3.09, 12.92) for
laryngeal cancer (C32) in selected regions of Europe (men). Rates have cigar smoking and 3.53 (CI  =  1.48, 8.37) for pipe smoking among
been smoothed using 5-​year average. Source: C15 other database. never-​cigarette-​smokers.
 509

Cancer of the Larynx 509

14 4

3.5
12

3
10

2.5
Rates per 100,000

Rates per 100,000

8

1.5

4
1

2
0.5

0 0
1970 1975 1980 1985 1990 1995 2000 2005 2010 1970 1975 1980 1985 1990 1995 2000 2005 2010

*USA: Black *USA: White Denmark Finland *France *Italy

Norway Slovakia UK: England Sweden
*Regional data
*Regional data
Figure 27–​4.  Trends in age standardized incidence rates (ASR) from laryn-
geal cancer (C32) in the United States (men). Rates have been smoothed Figure  27–​
5. Trends in age standardized incidence rates (ASR) from
using 5-​year average. Source: C15 other database. laryngeal cancer (C32) in selected regions of Europe (women). Rates have
been smoothed using 5-​year average. Source: C15 other database.

Some variation in the strength of the association between smoking
and laryngeal cancer has been reported by anatomic subsite (Olshan,
2010). The INHANCE group, the largest pooling study of laryngeal
cancer (22 international studies), conducted an analysis of tobacco use
using the largest sample of hypopharynx cases (1026 cases) assem-
bled to date (Wyss et  al., 2013). They reported an adjusted OR of
6.48 (CI = 4.94, 8.51) for cancer of the hypopharynx among people
who had ever smoked compared to those who had never smoked. The
adjusted OR for larynx cancer was 8.33 (CI = 7.07, 9.81). All other
head and neck cancer sites had smaller ORs than hypopharynx. A case
control study in Central and Eastern Europe (384 cases) compared the
OR estimates for current versus never smokers for both supraglottic
tumors (OR = 3.23; CI = 1.72, 6.42) and glottic tumors (OR = 2.61;
CI  =  1.67, 4.08) (Hashibe et  al., 2007a). Although the overall point
estimates did not differ, the association with duration of smoking and
pack-​years of smoking was consistently greater for supraglottic than
glottic tumors. The authors estimated that 87% of laryngeal cancers in
Central Europe are due to tobacco use.
Some variation in the strength of the association has also been
reported by type of tobacco (Olshan, 2010). For example, some stud-
ies have reported stronger associations with supraglottic tumors from
smoking black (air-​cured) tobacco compared to blonde (flue-​cured
tobacco) and non-​ filtered cigarettes compared to filter tip, low-​
ventilation cigarettes.
The association between smoking and laryngeal cancer is greater
for women than men in terms of relative risk, but lower in terms of
absolute risk. Carter et al. (2015) reported that the hazard ratio for cur-
rent versus never smoking and death from laryngeal cancer was 107.4
(95% CI = 25.1, 459.4) in women and 15.5 (95% CI = 9.3, 25.8) in
men in a pooled analysis of large cohort studies in the United States,
even though the absolute death rate from laryngeal cancer among
smokers was three times higher in men than women. Freedman et al.
(2007) reported that the hazard ratio associated with smoking was sig-
nificantly larger in women (HR 12.96; 95% CI = 7.81, 21.52) than in
men (5.45; 95% CI = 4.22, 7.05; P for interaction: < .001) for all head
and neck cancers combined in the AARP cohort. A European cohort
study (EPIC), found larger hazard ratios (HR) for female (HR 20.37;
95% CI  =  4.86, 85.5) than male (HR 13.24; 95% CI  =  6.00, 29.20)
current versus never smokers (Agudo et al., 2012). The higher HR in
women than men signifies that the proportion of laryngeal cancers
caused by smoking is higher, even though the absolute risk is lower.
An analysis of pooled data from international case control studies
showed that a history of ever having smoked cigarettes was associ-
ated with a smaller OR in younger adults (≤ 45 years) than in older
510

510 PART IV:  Cancers by Tissue of Origin

4 4

3.5 3.5

3 3

2.5 2.5

Rates per 100,000

Rates per 100,000

2 2

1.5 1.5

1 1

0.5 0.5

0 0
1970 1975 1980 1985 1990 1995 2000 2005 2010 1970 1975 1980 1985 1990 1995 2000 2005 2010
Australia Israel *India Singapore *USA: Black *USA: White
*China *Philippines *Japan *Thailand
*Regional data
*Regional data
Figure  27–​
7. Trends in age standardized incidence rates (ASR) from
Figure 27–​6.  Trends in age standardized incidence rates (ASR) from laryn- laryngeal cancer (C32) in the United States (women). Rates have been
geal cancer (C32) in selected regions of Asia and Oceania (women). Rates smoothed using 5-​year average. Source: C15 other database.
have been smoothed using 5-​year average. Source: C15 other database.

(> 45 years) adults. However, the odds ratios for those under age 45
were larger across pack-​year categories compared to older adults,
although the estimates for the younger group tended to be impre-
cise (Toporcov et  al., 2015). Ramroth et  al. (2011) assessed risk in
relation to self-​reported depth of inhalation in a German case control
study (257 cases) and found significantly lower risk in smokers who
self-​reported light versus deep inhalation (OR = 0.22; CI = 0.09, 0.55).
However, clear dose–​response relationships were seen with the dura-
tion and intensity of smoking, even in those who reported only puffing
lightly on cigarettes.
Several recent international studies have examined the association
with larynx cancer in relation to time since cessation of smoking, and

Table 27–​3.  Five-​Year Relative Survival: US SEER Program (2005–​2011) by Race, Sex, and Stage

5-​Year Relative
Survival % Total Males Females Total Males Females Total Males Females

2011a 60.2 61.2 56.3 61.2 62.2 57.0 52.9 53.7 49.5
All Stagesb 60.6 61.5 56.9 61.6 62.6 57.6 53.3 53.8 51.2
Localized 75.9 76.8 71.5 75.7 76.7 70.9 74.2 74.4 72.9
Regional 44.5 43.2 48.2 45.4 44.0 49.3 40.8 39.8 43.3
Distant 35.2 35.5 34.3 36.3 37.7 34.6 30.5 30.1 31.6
Unstaged 55.7 57.3 49.1 56.8 58.9 47.3 50.7 49.4 —​

a
SEER 18 areas. Period survival estimate for 2011 using conditional survival estimates joined from several 3-​year calendar block cohorts.
b
Stage at diagnosis classified using SEER summary stage 2000.
—​Statistic could not be calculated due to fewer than 25 cases during the time period.
 51
Cancer of the Larynx 511
age at cessation. An Italian case control study reported that 10–​19
years after cessation the OR for laryngeal cancer was 0.33 (CI = 0.23,
0.47) compared to those who continued smoking. The greatest reduc-
tion was seen in smokers who quit by age ≤ 35 years (OR = 0.11; CI =
0.06, 0.23) (Bosetti et al., 2008).
Among those who do not drink alcohol, tobacco smoking is more
strongly associated with laryngeal than with oral cavity cancer. The
International Head and Neck Cancer Consortium (INHANCE) evalu-
ated the separate and joint effects of tobacco and alcohol use, based
on analyses of 2959 cases. The OR for people who reported smok-
ing but not drinking was 6.76 (95% CI = 4.58, 9.96) (Hashibe et al.,
2009). This association was stronger than for cancers of the oral cav-
ity (1.74; CI = 1.10, 2.76) or pharynx (1.91; CI = 1.39, 2.62). A higher
OR [12.83 (95% CI  =  7.95, 20.71)] was observed for people who
reported smoking more than 20 cigarettes per day without alcohol
consumption. The comparable odds ratios for oral cavity and phar-
ynx were lower; 3.13 (95% CI = 1.14,8.59) and 2.83 (95% CI = 1.66,
4.82), respectively.
An INHANCE analysis of passive smoking exposure based on 71
laryngeal cancers among people who have never smoked reported
an elevated but statistically borderline OR for those who were invol-
untarily exposed to tobacco smoke at home or work (OR  =  1.71;
CI = 0.98, 3.00) (Lee et al., 2008). Exposure at home for more than
15 years was associated with an OR of 2.58 (95% CI = 1.20, 5.57).
A Taiwanese cohort study of 176 cases of laryngeal cancer reported
increased risk associated with betel-​quid chewing (Lee et al., 2011).
Individuals who chewed 20 or more quids daily had an adjusted hazard
ratio of 1.7 (95% CI = 1.2, 2.6) compared to non-​users. In an Indian
case control study with 511 cases, Sapkota reported strong associa-
tions between bidi smoking and cancers of the glottis (OR = 6.80; 95%
CI = 4.64, 9.97) and supraglottis (OR = 7.54; 95% CI = 3.84, 14.74)
(Sapkota et al., 2007). Gutkha was the only chewing tobacco product
associated with an elevated OR in the Sapkota study among individuals
with no history of active smoking (OR = 2.55; 95% CI = 0.62, 10.44).
Other smaller Indian studies have also reported an elevated risk for
bidi smoking and use of smokeless tobacco (Jayalekshmi et al., 2013;
Pednekar et al., 2011). Kapil found an OR of 2.37 (95% CI = 1.12,
5.06) for those who chewed betel leaf with tobacco compared to non-​
users (Kapil et al., 2005).
In an analysis based on pooled international studies, Berthiller
reported that having ever smoked marijuana was not associated with
increased risk (OR = 0.98; CI = 0.69, 1.39) (Berthiller et al., 2009).
Neither frequency nor length nor time using marijuana was associated
with laryngeal cancer, except among those with greater than 20 years
of use (OR = 1.42; CI = 0.84, 2.38).
Alcohol
Epidemiologic studies have shown that alcohol consumption in the
absence of tobacco smoking has a weak independent association with
laryngeal cancer (Hashibe et al., 2009). Limited evidence suggests that
supraglottic tumors may be more strongly associated with alcohol than
glottic tumors (Hashibe et al., 2007a). Other features of the association
with alcohol, such as differences between males and females and the
strength of the association for smoking combined with heavy alcohol
consumption, are less well studied.
A recent meta-​ analysis of 41 case control and cohort studies
compared 7059 cases in patients who reported a history of alcohol
consumption with 2575 cases who reported no history of alcohol con-
sumption (Bagnardi et al., 2014). The pooled RR estimates for light
drinkers (< 12.5 grams of alcohol per day), moderate drinkers (≤ 50
g/​day), and heavy drinkers (> 50 g/​day) were 0.87 (95% CI = 0.68,
1.11), 1.44 (95% CI = 1.25, 1.66), and 2.65 (95% CI = 2.19, 3.19),
respectively. Although study-​ specific smoking-​adjusted RRs were
used in the meta-​analysis, residual confounding by tobacco use cannot
be ruled out. Compared to the dose–​response relationship with cancers
of the oral cavity and pharynx, the relationship between the amount
of alcohol consumed and laryngeal cancer risk was less steep and flat-
tened out at consumption above 100g/​day at an RR of about 4.0. This
contrasts with a maximum RR of about 8.0 for cancers of the oral
cavity and pharynx. At light and moderate levels of alcohol consump-
tion, males and females had similar pooled RR estimates; for heavy
drinkers, the RR was higher for men (RR = 2.77; CI = 2.15, 3.57) than
women (RR = 1.55; CI = 0.45, 5.34), although only one study reported
female-​specific results. Results stratified by geographic region showed
similar RR estimates for European and North American studies; RRs
were elevated, but lower for Asian studies, though only four Asian
studies were included.
The INHANCE pooling project also examined the association
between alcohol consumption and laryngeal cancer among indi-
viduals who had never used tobacco (121 cases). Among these, risk
was associated with the amount but not the duration of drinking.
Consumption of more than 5 drinks per day was associated with
an OR of 2.98 (95% CI  =  1.72, 5.17); consumption for more than
40  years was associated with an OR of 1.0 (95% CI  =  0.58, 1.73)
(Hashibe et  al., 2007b). The INHANCE group also examined the
association with different types of alcohol (Purdue et al., 2009). The
OR for participants who reported drinking more than 15 drinks per
week of only beer was 2.7 (95% CI = 1.7, 4.4); 1.9 (95% CI = 0.9, 3.9)
for those reporting only liquor consumption; and 3.9 (95% CI = 1.2,
13.0) for those who consumed only wine. These associations were
weaker for laryngeal cancer than for oral cavity or pharyngeal can-
cer. The separate and joint associations with alcohol and tobacco use
were also examined by INHANCE (Hashibe et al., 2009). The analy-
sis included 2959 cases and found a weakly elevated OR for a history
of alcohol use but no smoking (OR = 1.21; 95% CI = 0.77, 1.92). The
OR for 3 or more drinks per week among individuals who reported
never smoking was 3.16 (95% CI  =  1.23, 8.16). The joint effects
of tobacco and alcohol were greater than additive. The authors esti-
mated that the population-​attributable risk for tobacco and alcohol
consumption was 89% for laryngeal cancer, compared to 64% for
oral cavity and 72% for pharyngeal cancer.
A large analysis (4818 cases) from the INHANCE international
pooling project reported a slightly stronger association for ≥ 5 drinks
per day for persons 45 years of age or older (OR = 2.82; CI = 2.40,
3.25) than persons less than or equal to age 45  years (OR  =  1.81;
CI  =  1.13, 2.90) (Toporcov et  al., 2015). The significance of this is
unclear.
Diet
Studies consistently report an inverse association between greater
consumption of fruits and vegetables and risk of laryngeal cancer
(Lucenteforte et al., 2010). Some studies also suggest increased risk
associated with consumption of meat and eggs. Higher levels of retinol,
total calories, protein, and fat have been associated with an increased
risk in some but not all studies; dairy products have also been reported
to be inversely associated with risk (Lucenteforte et al., 2010).
The World Cancer Research Fund and the American Institute for
Cancer Research (WCRF/​ AICR) have designated the evidence as
“probable” that non-​starchy vegetables, fruits, and foods containing
carotenoids decrease the risk of cancers of the mouth, pharynx, and
larynx combined (WCRF/​AICR, 2007).
Recent case control studies including a case control study in
Uruguay (275 cases) have examined dietary patterns in relation to
laryngeal cancer (De Stefani et al., 2013). Adherence to a dietary pat-
tern classified as “prudent” was associated with reduced risk: (OR =
0.54; 95% CI = 0.36, 0.80), whereas diets described as “starchy plants”
(OR = 1.62; 1.08, 2.41), “Western diet” (OR = 1.84; 1.14, 2.98), or
“drinker” (OR = 2.86; 1.80, 4.56) were associated with increased risk.
An earlier analysis from the same study reported that a high-​fat die-
tary pattern had an OR of 1.47 (95% CI = 0.77, 2.82; and a “healthy”
pattern had a decreased odds (OR = 0.64; 95% CI = 0.24, 1.18) (De
Stefani et al., 2007). A US case control study of 419 cases used factor
analysis to identify dietary patterns and found decreased risk associ-
ated with higher consumption of fruits, vegetables, and lean protein
(highest consumption quartile OR = 0.73; CI = 0.48, 1.10) and an ele-
vated OR for the dietary pattern characterized by fried foods, high-​fat
and processed meats, and sweets (highest consumption quartile OR =
2.12; CI = 1.21, 3.72) (Bradshaw et al., 2012).
512
512 PART IV:  Cancers by Tissue of Origin
The INHANCE pooling project (4073 cases) evaluated different
food groups and reported inverse associations between risk and fruit
intake (highest quartile OR = 0.59; 95% CI = 0.45, 0.79) and white
meat (OR = 0.84; 95% CI = 0.70, 1.00) and increased risk associated
with red meat (OR = 1.50; 95% CI = 0.96, 2.36) and processed meat
(OR = 1.36; 95% CI = 1.06, 1.73) (Chuang et al., 2012). Higher dietary
scores based on high fruit and vegetable and low red meat intake were
associated with a decreased OR (one score unit OR  =  0.89; 95%
CI = 0.82, 0.96).
Studies have also evaluated micronutrients and other dietary
components. The INHANCE pooling study of 1545 cases examined
vitamin C intake and found that the highest quintile of self-​reported
vitamin C intake was associated with reduced odds of laryngeal
cancer (OR = 0.52; 95% CI = 0.40, 0.68) overall, as well as among
current tobacco users (OR = 0.55; 95% CI = 0.4, 0.72) and heavy
drinkers (OR = 0.38; 95% CI = 0.25, 0.59) (Edefonti et al., 2015).
Another INHANCE analysis reported decreased odds ratios for any
vitamin supplementation (OR = 0.68; 95% CI = 0.37, 1.25), vita-
min A supplement use (OR = 0.56; 95% CI = 0.22, 1.24), vitamin
C (OR = 0.70; 95% CI = 0.46, 1.08), and vitamin E (OR = 0.50;
95% CI = 0.10, 2.46) (Li et al., 2013). A recent INHANCE analysis
found that total carotenoid intake was associated with reduced risk
(highest quintile OR = 0.61; 95% CI = 0.50, 0.76) (Leoncini et al.,
2016). Intake of beta-​carotene, beta-​cryptoxanthin, and lutein plus
zeaxanthin also had reduced odds ratios. The inverse association
with lycopene intake was statistically borderline (highest quintile
OR  =  0.83; 95% CI  =  0.68, 1.02). Another INHANCE analysis
showed no association with allium vegetables—​specifically, garlic
or onion consumption (Galeone et  al., 2015). A  large Italian and
Swiss case control study (851 cases) reported elevated odds ratios
for red meat intake (≥ 90 grams a day: OR = 2.34; 95% CI = 1.82,
3.00) (Di Maso et  al., 2013). The same study noted a decreased
OR for consumption of cruciferous vegetables (>1 portion a
week: OR = 0.84; 95% CI = 0.67, 1.05) (Bosetti et al., 2012) and
citrus fruit or citrus juice (> 4 portions per week:  OR  =  0.55;
95% CI  =  0.37,0. 83 (Foschi et  al., 2010). An analysis of dietary
fiber showed about 40%–​60% decreased odds for total soluble,
total insoluble fiber consumption, vegetable fiber, and fruit fiber
(Pelucchi et al., 2003). For total fiber intake, the decrease was simi-
lar for supraglottic and glottic tumors.
Occupation
Cohort and case control studies of occupational populations have
reported several exposures associated with increased risk of laryngeal
cancer (Olshan, 2010). Occupational exposure to asbestos has been
the best studied (Institute of Medicine, 2006), but other researchers
have shown, albeit inconsistently, an elevated risk with man-​made
vitreous fibers, mustard gas, sulfuric acid, solvents, formaldehyde,
wood dust, and nickel refining. A variety of occupations and indus-
tries have also shown to be associated with cancer of the larynx.
These include metal-​related occupations, paint and print workers,
truck drivers, railway workers, butchers, textile workers, plastic and
rubber manufacturing, agriculture, and construction work. The occu-
pational studies are limited by imprecise data on specific exposures
and exposure levels, and in some cases by inability to adjust for
tobacco and alcohol use.
Recent meta-​analyses and several studies of administrative data sets
have reported associations between laryngeal cancer and other expo-
sures, occupations, and industries. A  meta-​analysis of cohort stud-
ies of workers employed in crop-​protection chemical and pesticide
manufacturing reported an overall summary standardized mortality
ratio (SMR) of 1.58 (95% CI = 1.09, 2.31) and an SMR of 1.51 (95%
CI  =  1.01, 2.78) for phenoxy herbicide manufacturing (Jones et  al.,
2009). A US death certificate study reported a statistically insignificant
association with employment as a butcher (OR = 1.19; 95% CI = 0.92,
1.54) (Besson et  al., 2006). An analysis of a large Swedish census
and cancer data set reported elevated standardized incidence ratios
(SIR) for waiters (SIR = 2.70; 95% CI = 1.39, 4.44) and hairdressers
(SIR = 1.78; 95% CI = 1.10, 2.62) (Ji and Hemminki, 2005).
A Dutch case-​control case-​cohort study (216 cases) found weak to
moderately elevated hazard ratios (HR) for asbestos exposure based
on estimates from a job-​exposure matrix (Offermans et  al., 2014).
The HR for the highest cumulative exposure times–​exposure inten-
sity category was 1.51 (95% CI = 0.92, 2.49) and that for the lon-
gest duration of high exposure was 6.36 (95% CI  =  2.18, 18.53).
There was a higher HR for individuals who had ever been exposed
to asbestos for supraglottic cancer (HR = 2.14; 95% CI = 1.13, 4.04)
but not glottic cancer (HR  =  0.94; 95% CI  =  0.61, 1.44); analyses
using other exposure metrics did not show a clear difference by
laryngeal subsite and had wide confidence intervals. An elevated
SMR was found for Chinese male workers in an asbestos factory
using chrysotile (SMR = 4.26; 95% CI = 1.17, 15.52) (Wang, Lin,
et  al., 2013). A  case control study in Central and Eastern Europe
(316 cases; Shangina et al., 2006) found no overall association with
asbestos exposure (OR = 0.86; 95% CI = 0.51, 1.45). A cohort study
of Swedish male construction workers (227 cases) found elevated
rate ratios for those exposed to asbestos (RR = 1.9; 95% CI = 1.2,
3.1) and mineral wool (RR = 1.6; CI = 1.03, 2.4), but no association
with cement dust, asphalt, or stone dust (Purdue et al., 2006). A small
Boston area case control study (118 cases) reported no association
with asbestos exposure (OR =1.04; 95% CI = 0.64, 1.67) (Langevin
et al., 2013).
A meta-​analysis of cohort and case control studies that examined
incidence and mortality from laryngeal cancer in relation to silica dust
exposure reported moderately increased risk (e.g., SIR  =  1.50; 95%
CI  =  0.59, 2.42 in cohort studies; and in case control studies, 1.39;
95% CI = 1.17, 1.67) (Chen and Tse, 2012). In another study, a weak
but statistically insignificant increase in risk was found for uranium
miners exposed to radon and their short-​lived progeny (OR  =  1.13;
95% CI = 0.75, 1.70) (Mohner 2008).
A series of analyses from a German case control study (257 cases)
reported increased odds ratios associated with several occupations
(road construction worker, carpenter, metal production and process-
ing worker, farmer) and exposures (cement dust, and wood dust)
(Dietz et al., 2004; Becher, 2005; Ramroth and Dietz, 2008). Shangina
reported no association with wood dust exposure (OR  =  0.81; 95%
CI = 0.48, 1.37) and non-​significantly increased risk associated with
exposure to soot (OR  =  1.30; 95% CI  =  0.68, 2.48), formaldehyde
(OR  =  1.68; 95% CI  =  0.85, 3.31), and coal dust (OR  =  1.81; 95%
CI = 0.94, 3.47) (Shangina et al., 2006).
Human Papillomavirus
Human papillomavirus virus (HPV), especially the “high-​risk” HPV
subtypes 16 and 18, are established risk factors for cancers of the
oropharynx (see Chapters  24 and 29 in this volume). The associa-
tion between HPV and laryngeal cancer is weaker and the fraction of
cases likely to be smaller for cancers of the larynx (Chaturvedi and
Gillison, 2010). A  recent examination of the prevalence of HPV in
archival samples from laryngeal tumors in selected US states detected
HPV in 20.9% of laryngeal tumor specimens (n = 148) versus 70.1%
of oropharyngeal cancers (Saraiya et al., 2015). Among a series of 91
laryngeal tumors, three cases (3.2%) were found to be HPV positive
by in situ hybridization for “high-​risk” HPV types (16, 18, 31, 33, 35,
39, 45, 51, 52, 56, 58, 66) and P16 immunohistochemistry, whereas six
cases (6.6%) were positive for HPV by p16 immunochemistry (Upile
et  al., 2014). A  German study reported that of 102 laryngeal tumor
samples, three (2.9%) were “HPV-​driven,” that is, they had a pattern of
HPV DNA-​and RNA-​positivity and p16 high expression and low pRB
expression (Halec et al., 2013). The analysis of archival tissue samples
from the NCI’s SEER residual tissue repository (148 cases) found that
21% were HPV positive, and of these, 6% were HPV-​16 positive. They
also found that more women than men were HPV positive (Hernandez
et al., 2014).
Human papillomavirus (HPV) can disrupt the cell cycle through
inactivation of the Rb pathway via the HPV E7 protein and inactivation
of the TP53 pathway through the HPV E6 protein. A large European
case control study (529 hypopharynx/​laryngeal cases) analyzed HPV
16 L1, E6, and E7 seropositivity (Anantharaman et  al., 2013). The
 513
Cancer of the Larynx 513
strongest association was reported for combined HPV 16 E6 and E7
positivity (OR 30.84; 95% CI  =  3.11, 306.0). A  statistically signifi-
cant association was observed for HPV 16 E6 alone (OR = 4.18; 95%
CI = 1.54, 11.32), but not for HPV 16 E7 (OR 1.53; 95% CI = 0.93,
2.51) or HPV 16 L1 (OR = 1.54; 95% CI = 0.81, 2.94). By contrast, for
oropharynx cancer, the comparable odds ratios were 8.60, 132.0, and
897.66. An association between HPV 6 E7 and laryngeal cancer was
also found (OR = 3.25; 95% CI = 1.46, 7.24).
A meta-​analysis of 55 studies (2559 cases) found an overall HPV
prevalence of 28%. High-​risk HPV types were present in 26.6% of
samples and with HPV 16 in 19.8% of samples (LiGao et al., 2013).
Using data from 12 studies with normal laryngeal mucosa compari-
son (control) samples, the authors reported a summary OR of 5.39
(CI = 3.32, 8.73), with larger estimates for high-​risk HPV types (HPV
16, 18, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68; OR = 5.74; CI = 3.05,
10.80), including the most common, HPV 16 (OR = 6.07; CI = 3.44,
10.70).
Other Etiologic Factors
Various other possible risk factors for laryngeal cancer have been
studied. Body size has been examined in several case control and
cohort studies. Gaudet reported an inverse association between
body mass index (BMI) and the incidence of laryngeal cancer in the
INHANCE pooled case control study of 17 studies and 2837 cases
(Gaudet et  al., 2010). A  BMI < 18.5  kg/​m3 was associated with
increased risk (OR  =  1.63; 95% CI  =  1.23, 2.17) whereas a BMI
> 30 was associated with reduced risk (OR = 0.54; 95% CI = 0.45,
0.64). The inverse association with obesity was observed only among
smokers/​drinkers, whereas the increased risk with low BMI persisted
in analyses stratified on tobacco and alcohol use. Lubin also exam-
ined INHANCE data and found a similar association with BMI by
sex (Lubin et al., 2010). Another INHANCE analysis showed a small
decrease in the OR associated with increasing height (Leoncini
et al., 2014).
An analysis of the NIH-​AARP cohort study (211 cases; Etemadi
et  al., 2014)  found an increased but highly imprecise association
between lower BMI (18.5 to < 25.0) and risk of laryngeal cancer
(OR = 2.18; CI = 0.68, 6.98). No association was observed with BMI
≥ 30 (OR = 1.04; 95% CI = 0.70, 1.55). The lowest categories of waist
and hip circumference each had odds ratios below 1.0. Height and
waist-​to-​hip ratio showed no association. A  recent pooling of data
from 20 cohort studies (142 laryngeal cases) found increased risk asso-
ciated with higher BMI (HR = 1.42; CI = 1.19, 1.70, per 5 kg/​m2), but
no associations with height, waist circumference, hip circumference,
or waist-​to-​hip ratio (Gaudet et al., 2015). The differences between the
case control and cohort study findings have been attributed to selection
bias in hospital-​based studies, effects on nutritional status caused by
the cancer itself, and residual confounding by smoking and alcohol
use (Gaudet et al., 2015). Recreational physical activity was examined
in the INHANCE data (612 cases) (Nicolotti et al., 2011). Moderate
levels of activity were associated with decreased risk (OR = 0.81; 95%
CI  =  0.60, 1.11) compared to low or no physical activity. However,
high physical activity was associated with increased risk (OR = 1.73,
95% CI = 1.04, 2.88).
A multi-​center study (240 cases) of markers of oral health reported
an elevated OR for poor oral hygiene (European OR  =  1.95; 95%
CI = 1.02, 3.71; Latin America OR = 1.46; 95% CI = 1.05, 2.04) (Guha
et al., 2007). The INHANCE analysis of education and income (6485
cases) showed that low educational status (no education or completed
first stage of basic education, or at most primary education) compared
to high educational status (vocational or university degree) had an OR
of 1.69 (95% CI = 1.24, 2.32) (Conway et al., 2014).
Analysis of sexual behavior (including the practice of oral sex, num-
ber of lifetime sexual partners, age at sexual debut, history of same-​
sex contact, history of oral-​anal contact) and head and neck cancer
risk using INHANCE pooled data did not show any associations with
laryngeal (940 cases) or hypopharyngeal cancer (251 cases) (Heck
et al., 2010). Cancers of the oropharynx showed elevated odds ratios
for some sexual behavior history factors.
HOST FACTORS
Predisposing Medical Conditions
Most of the recent epidemiologic literature on medical history has
focused on the association between diabetes and the risk of laryngeal
cancer. The results of these studies have been inconsistent. A  study
of discharge data from US Veterans Affairs Hospitals based on 1413
men with diabetes and laryngeal cancer (Atchison et al., 2011) found
decreased risk in veterans with diabetes (RR = 0.76; 95% CI = 0.71,
0.80). The inverse association persisted in analyses examining race
and time since the diagnosis of diabetes. However, an analysis of
the Clinical Practice Research Datalink in the United Kingdom (680
cases) found no association with prescriptions for Metformin (Becker
et al., 2014). No statistically significant association between diabetes
and risk of cancer of the larynx was found in a large Italian/​Swiss
case control study of 782 cases (Bosetti et al., 2012), where the OR
associated with a history of diabetes was slightly but not statistically
significantly elevated (OR = 1.23; 95% CI = 0.86, 1.74).
Several other medical conditions and treatments have also been
studied in relation to laryngeal cancer. A  Swedish cohort study of
patients who underwent gastrectomy for peptic ulcer disease reported
an elevated SIR (2.0; 95% CI  =  1.5, 2.6) (Lagergren and Lindam,
2012). A  South Korean case control study (408 cases) using health
insurance data reported an elevated OR for inhaled corticosteroid use
of any type (OR = 1.60; 95% CI = 0.68, 1.18 (Lee et al., 2013), but not
for specific types or cumulative dose (largest dose: OR = 0.84; 95%
CI = 0.45, 1.55).
Previous studies have inconsistently suggested an association with
gastrointestinal reflux disease (GERD). A  small case control study
(96 cases) reported an adjusted OR of 2.11 (95% CI  =  1.16, 3.85)
for a history of GERD obtained from the medical records (Vaezi
et al., 2006). A European case control study of 183 hypopharyngeal
cancer cases reported that a history of regurgitation or medication
were not associated with risk of hypopharyngeal cancer (regur-
gitation OR  =  0.62; 95% CI  =  0.37, 1.00); medication for regurgi-
tation OR  =  0.62; 95% CI  =  0.24, 1.59) (Macfarlane et  al., 2012).
Heartburn was associated with a decreased hypopharyngeal cancer
risk (OR = 0.64; 95% CI = 0.44, 0.93). No association with larynx
cancer was reported for these factors.
Inherited Susceptibility
Epidemiologic research has shown moderately increased risk of laryn-
geal cancer to be associated with a family history of head and neck
or other cancers (Wang et  al., 2010). An INHANCE analysis (2572
cases) of laryngeal cancer found an OR of 2.07 (95% CI = 1.57, 2.73)
for a family history of head and neck cancer among first-​degree rela-
tives, in analyses adjusted for tobacco and alcohol use (Negri et al.,
2009). A  family history of other head and neck cancers related to
smoking (lung, nasopharynx, nasal cavity, nasal cavity, paranasal
sinuses, esophagus, stomach, pancreas, liver, kidney, urinary bladder,
uterine cervix, myeloid leukemia) in first-​degree relatives was sig-
nificantly associated with laryngeal cancer (OR = 1.27; 95 CI = 1.09,
1.47), whereas a family history of other cancers was not (OR = 1.10;
95% CI = 0.95, 1.22). An Italian/​Swiss case control study (852 cases)
reported associations with family history of cancer among first-​
degree relatives, overall (OR = 2.8; 95% CI = 1.5, 5.1), by age of the
index’s cancer diagnosis (< 60 years: OR = 3.5; 95% CI = 1.4, 8.7; ≥
60 years: OR = 2.2; CI = 1.0, 5.1), sex (male: OR = 3.2; CI = 1.7, 6.0;
females not estimable), and for the cancer site of a specific relative
(colorectal: OR = 1.5; CI = 1.0, 2.3) (Turati et al., 2013).
Epidemiologic studies continue to report candidate gene/​ SNPs
(single nucleotide polymorphisms) associated with laryngeal cancer,
largely including genes previously examined (Wang, Chu, et al., 2013).
A meta-​analysis found no association with the XRCC1 Arg399Gln
SNP (Chen et  al., 2013). An Eastern European multicenter study
(326 cases) examined 37 SNPs in several DNA repair and cell cycle
gene SNPs (XPA, OGG1, APEX, MGMT, CHEK2) and reported asso-
ciations with MGMT and CHEK2 (Hall et al., 2007). A Chinese case
514
514 PART IV:  Cancers by Tissue of Origin
control study (271 cases) reported elevated odds ratios for ERCC1 and
ERCC2 SNPs (Sun, 2015). Another Chinese study reported associa-
tions with genes in the nucleotide excision repair pathway: ERCC1,
XPD, XPB, XPF, XPG, and XPA SNPs (Lu et al., 2014). Haplotypes
of the double-​strand break repair gene, NSB1, were associated with
decreased odds of laryngeal cancer in a combined US and Chinese
study (Park et al., 2010).
A Polish study evaluated smoking-​related loci and found no associa-
tions with laryngeal cancer (Jaworowska et al., 2011). Polymorphisms
in phase 1 and phase 2 metabolic genes combined (COX2, UGT1A1,
UGT1A6, UGT1A7) were associated with risk in a Dutch study (Lacko
et al., 2009). The same study group also reported an elevated OR for
SNP combinations predicted to result in varying epoxide hydrolase,
UGT1A6, UGT1A7, and COX2 activity levels (Lacko et  al., 2013).
A meta-​analysis including 20 studies (2124 cases) found a summary
OR of 1.40 (95% CI = 0.90, 2.16) for the GSTT1 null genotype (Ying
et  al., 2012). A  meta-​analysis including Asian and Caucasian popu-
lations (2809 cases) (Xiao et  al., 2013)  reported a summary OR for
the GSTM1 deletion genotype of 1.44 (95% CI = 1.19, 1.73), with a
larger effect among Asians (OR = 1.89; 95% CI = 1.28, 2.77). Another
meta-​analysis of GSTM1 (2562 cases) (Zhang et al., 2014) reported a
summary OR of 1.22 (95% CI = 1.10, 1.36) and also a strong effect for
Asians (OR = 1.71; 95% CI = 1.34, 2.19; Caucasians: OR = 1.13; 95%
CI = 1.00, 1.27). A meta-​analysis of NAT2 genotypes (7 studies, 980
cases (Ying et al., 2011) found an elevated OR for the NAT slow acety-
lator genotype among Asian studies (OR = 1.99; 95% CI = 1.10, 3.63).
A meta-​analysis of 24 studies (1072 cases) reported no association
between CYP2E1 SNPs and laryngeal cancer (Lu et al., 2011). A meta-​
analysis (1022 cases) reported weak associations for two CYP1A1
SNPs (Zhuo et  al., 2009). An Indian case control study (750 cases)
noted elevated odds ratios for CYP1A1, CYP1B1, and CYP2E1 SNPs
(Maurya et al., 2015). Elevated odds ratios were reported for CYP1B1
(rs1056827) and CYP2E1 (rs3813867) SNPs in a Chinese case control
study (552 cases) (Jin et al., 2014). Another Chinses study (300 cases)
reported elevated odds ratios for CYP2C19 (Feng et al., 2011).
Genes involved in alcohol metabolism have been studied in relation
to laryngeal cancer in several studies. Hashibe reported decreased odds
ratios of laryngeal or hypopharynx cancer (1659 cases) associated with
two alcohol dehydrogenase gene (ADH) SNPs, ADH1B (rs1229984;
OR = 0.71; 95% CI = 0.57, 0.88) and ADH7 (rs1573496; OR = 0.78;
95% CI = 0.65, 0.93) (Hashibe et al., 2008). A case control study from
North Carolina (442 cases) evaluated SNPs of ADH1B, ADH1C, ADH4,
ADH7, ALDH2, and CYP2E1 and found an elevated OR for ADH1B
(rs17028834; OR = 1.5; CI = 1.1, 2.0) (Hakenwerth et al., 2011).
A European case control study (326 cases) examined genes in the
inflammatory pathway and found a decreased OR associated with
a polymorphism of IL8 (rs4073; OR  =  0.70; 95% CI  =  0.50, 0.98)
(Campa et al., 2007). A Brazilian study (237 cases) reported an inverse
association with an SNP involved in folic acid metabolism (SHMT1)
(OR = 0.48; 95% CI = 0.27, 0.86) (Succi et al., 2013). An analysis of
cases (n = 721) and controls from the M. D. Anderson Cancer Center
found an association with an SHTM1 haplotype (OR  =  1.64; 95%
CI = 1.12, 2.40) (Zhang et al., 2005).
There have been few genome-​wide association studies (GWAS) spe-
cifically of laryngeal cancer. A  GWAS of pooled case control studies
(2787 cases) reported associations for laryngeal cancer with ADH1B
(rs1229984; OR  =  0.75; 95% CI  =  0.65, 0.86), ADH7 (rs1573496;
OR  =  0.79; 95% CI  =  0.71, 0.88), ADH1C (rs698; OR  =  1.06; 95%
CI = 0.99, 1.13), ALDH2 (rs4767364; OR = 1.07; 95% CI = 1.00, 1.15),
and a 4q21 variant (rs1494961; OR = 1.08; 95% CI = 1.02, 1.16) (McKay
et  al., 2011). A  Chinese study identified three loci, including FADS1
(rs174549), AIF1 (rs2857595), and TBX5 (rs10492336), with significant
p-​values (x 10–​14 or greater) that could be replicated (Wei et al., 2014).
PREVENTION
Primary Prevention
Alcohol control and tobacco control are discussed in Chapters 12 and
62.1, respectively, in this volume.
Chemoprevention
Because of the association between intake of antioxidant vitamins and
reduced incidence of head and neck cancer in epidemiologic studies,
prevention studies have assessed whether retinoids can reduce the first
occurrence of head and neck cancer and/​or second primary tumors.
Early studies of premalignant oral lesions and head and neck cancers
indicated a possible reduction in risk from 13-​cis-​retinoic acid, but
concern about toxicity and efficacy (overall and long term) limited
the use of this agent (William, 2010). More recent studies, including
larger randomized trials, have not shown a consistent benefit from
α-​tocopherol or β-​carotene. The Alpha-​Tocopherol Beta-​Carotene
Cancer Prevention (ATBC) study (Wright et  al., 2007)  was a pri-
mary prevention randomized trial of daily doses of α-​tocopherol or β-​
carotene given to male smokers. No evidence was observed that either
agent reduced the overall incidence of upper aerodigestive tract cancer.
However, an exploratory analysis found reduced incidence of laryngeal
cancer in subjects treated with β-​carotene (RR = 0.28; 95% CI = 0.10,
0.75). A second randomized trial that administered α-​tocopherol and
β-​carotene supplements to head and neck cancer patients (225 laryn-
geal cases in each trial arm; 82% of all patients in the treatment arm
and 84% of patients in the placebo arm) reported a higher incidence
rate of second tumors in the β-​carotene arm during supplementation
(HR = 2.88; 95% CI = 1.56, 5.31), but a lower rate after the discon-
tinuation of treatment (HR = 0.41; 95% CI = 0.16, 1.03) (Bairati et al.,
2005). A similar pattern was seen following supplementation with α-​
tocopherol. After 8 years, there was no difference between treatment
arms in the rate of second tumors. Earlier studies had not reported a
reduction in the incidence of second primary tumors (Mayne et  al.,
2001; Toma et al., 2003).
Studies have not yet consistently identified a successful approach
for chemoprevention of primary head and neck cancers or second
primary cancers. Most have focused on oral cancer and have not
been designed to examine laryngeal cancer separately. More recent
chemoprevention studies of head and neck cancer have included
molecular risk stratification, as in the Erlotinib Prevention of Oral
Cancer (EPOC) study (William and El-​Naggar, 2015). With the rap-
idly evolving molecular characterization of head and neck tumors,
chemoprevention may offer new opportunities to reduce the risk of
specific subtypes.
Screening and Early Detection
The use of biomarkers such as saliva or blood to detect genetic altera-
tions involved in head and neck cancer, preferably detection at an
early stage, has been explored for at least two decades (Boyle et al.,
1994). The expanding list of genomic alterations in head and neck
cancers now offers additional opportunities for biomarker develop-
ment. A recent proof-​of-​principle study (Wang et al., 2015) evaluated
whether somatic mutations and HPV could be detected in the saliva
and plasma of patients with head and neck cancers. A  96% detec-
tion rate was achieved when both saliva and plasma were used. The
results were best for oral cancers. For laryngeal cancers, mutations
were detected in 70% of patients in saliva samples, 86% in plasma,
and 100% when both saliva and plasma were tested. All except two
of the laryngeal cancer patients had later stage disease. The value of
these biomarkers for detecting early-​stage cancers of the larynx is
uncertain.
FUTURE RESEARCH
Cigarette smoking remains by far the most important cause of laryn-
geal cancer. The decreasing incidence of laryngeal cancer among
men in high-​income countries is encouraging. The incidence rate
among women is expected to decrease soon, consistent with the
delayed reduction in smoking among women. Additional efforts are
needed to prevent the uptake of cigarette smoking and/​or other forms
of tobacco use and to promote cessation. Reductions in other risk
factors are also important. These include heavy alcohol consump-
tion, unhealthy dietary patterns, and certain occupational exposures.
 51
Cancer of the Larynx 515
Large epidemiologic studies are needed to further clarify whether
other factors also affect risk. These include HPV, GERD, diabetes,
and obesity. Ideally, epidemiologic studies can be designed to assess
etiologic heterogeneity between these exposures and the molecular
and topographic subsites of laryngeal cancer. It would be important
to know whether the histological distribution of laryngeal cancer has
changed, given the rise in smoking-​related adenocarcinomas and the
decrease in squamous cell carcinomas observed for lung and laryn-
geal cancers.
Genomic studies of both germline and somatic tumor tissue have
provided intriguing clues in recent years. Further replication and
refinement of this work will require adequately sized studies that allow
laryngeal cancers to be separated from oral cavity and oropharyngeal
cancers. Large studies are also a requirement to characterize molecu-
lar subtypes. Recent research with biomarkers has shown promise for
the detection of head and neck cancers. Further studies are needed
to confirm whether genomic markers can be used for early detection,
markers of prognosis, or therapeutic targets.
Although trials of chemopreventive agents have not as yet been suc-
cessful in preventing the transformation of pre-​malignant lesions into
laryngeal cancer or in reducing the incidence of second tumors, this
may change as new agents are identified and molecular markers are
further characterized.
In summary, cigarette smoking and the use of other combustible
tobacco products are the main cause of laryngeal cancer, accounting
for the majority of cases. As such, research and implementation of
measures to reduce exposure to tobacco products is of utmost impor-
tance to accelerating the decline of this cancer worldwide.
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28 Lung Cancer
MICHAEL J. THUN, S. JANE HENLEY, AND WILLIAM D. TRAVIS
OVERVIEW
Lung cancer is the most common cancer worldwide, ranking first
in men and third in women for new cases and first in both sexes for
deaths. Dynamic global patterns in lung cancer incidence predomi-
nantly reflect past and current patterns of cigarette smoking. Lung
cancer incidence rates in most high-​income countries have decreased
substantially among men, but continue to increase at older ages in
women. More than half of all cases occur in low-​and middle-​income
countries where cigarette smoking remains common, especially among
men. In high-​income countries, strong birth cohort patterns dominate
temporal trends in lung cancer incidence and mortality; these paral-
lel birth cohort patterns in the uptake in cigarette smoking 50 years
earlier. In the United States and the United Kingdom, the average
relative risk (RR) for lung cancer mortality associated with continued
cigarette smoking increased across birth cohorts first among men and
then women. Now, in contemporary cohorts, the relative risk for cur-
rent smokers is about 25 in both sexes. The histologic and topographic
distribution of lung cancer also has changed, corresponding to changes
in cigarette design and composition. Unlike smoking cessation, which
dramatically reduces risk, design changes in cigarettes that dilute the
smoke provide no health benefit. In the United States, active cigarette
smoking accounts for an estimated 95% of lung cancer cases among
smokers and 80% to 85% in the general population; secondhand
smoke causes an estimated 7,300 lung cancer deaths among never
smokers. The International Agency for Research on Cancer (IARC)
has designated at least 7 occupations and 18 exposures other than
active smoking, such as secondhand smoke, radon gas, diesel exhaust,
and particulate air pollution as carcinogenic to humans for lung cancer.
If lung cancer in never smokers were classified as a separate entry, it
would rank among the 10 most common cancers in the United States.
Targeted therapies have improved survival for a subset of lung can-
cer patients with adenocarcinoma and mutations in EGRF or fusions
involving ALK or ROS, although most patients develop resistance to
these agents over time.
INTRODUCTION
Lung cancer occurrence has changed more in the last century than
any other cancer. In high-​income countries, the large increase in lung
cancer mortality rates, first observed among men after World War
I and women after World War II, has dominated cancer death rates for
decades. Similarly, the downturn in lung cancer incidence and mortal-
ity rates among men in most economically developed countries during
the last 10–​25 years has exceeded the decrease in any other cancer.
In contrast, the lung cancer burden in low-​and middle-​income
countries (LMICs) continues to increase rapidly in terms of the num-
ber of cases and deaths, and now accounts for more than half of all
lung cancer cases worldwide. Tobacco smoking remains highly preva-
lent among men in LMICs; exposure to other causes of lung cancer in
occupational and community settings are also much higher in LMICs
than in economically developed countries. Among women in China,
for example, lung cancer incidence is high, despite a low prevalence
of active smoking.
This chapter discusses the epidemiology of primary cancers of the
trachea, bronchus, and lung, commonly referred to as “lung” cancers
(ICD-​10 codes C33–​C34:  ICD-​O-​2/​3 codes C33.9–​C34.9). Our dis-
cussion is limited to carcinomas, which comprise the great majority of
lung cancers. Other primary malignancies that occur in or adjacent to
the lung include carcinoid tumors, accounting for less than 1% of lung
cancers (Chapter 35), pleural mesothelioma (Chapter 16), lymphomas
(Chapters 39, 40), and Kaposi sarcoma (Chapters 24, 25).
We first discuss lung cancer as a global public health problem, con-
sidering how the occurrence of all forms of lung cancer combined
varies by gender, birth cohort, and level of economic development.
We then describe the three main histologic subtypes of lung cancer
with respect to their clinical and epidemiologic features and molecu-
lar pathogenesis. We consider how the changing histologic and topo-
graphic distribution of these subtypes relates to changes in tumor
classification as well as in cigarette design and composition. We then
discuss the known and suspected causes of lung cancer, staging, sur-
vival, prevention strategies including screening, and future research
directions.
DISEASE BURDEN
Lung cancer is the most common cancer worldwide, accounting for an
estimated 1.8 million new cases and 1.6 million deaths in 2012 (Ferlay
et al., 2013). Globally, it ranks first in men and third in women in terms
of incident cases and first in both sexes for cancer deaths. In high-​income
countries, where incidence and mortality rates are decreasing in men of all
ages and in younger women (Peto et al., 2015), it remains the third lead-
ing cause of death from any cause, after heart disease and stroke (Lozano
et  al., 2012). The number of deaths from lung cancer in high-​income
countries exceeds the combined number of deaths from cancers of the
colorectum, breast, and prostate (Torre et  al., 2015). Historically, lung
cancer became the leading cause of cancer deaths in the United States in
the mid-​1950s among men and in 1987 in women (Siegel et al., 2015).
In LMICs, the lung cancer burden is increasing rapidly in men but
not women. This increase is caused by the high prevalence of cigarette
smoking in males, low smoking cessation rates, and population aging.
Massive numbers of young adult males in LMICs are smokers and are
now surviving into middle and older ages when lung cancer becomes
common (see Chapter 11).
DESCRIPTIVE EPIDEMIOLOGY
In most countries, lung cancer occurrence predominantly reflects cur-
rent and lifetime patterns of cigarette smoking. Variations in lung can-
cer incidence and mortality are used as sentinel indicators of the impact
of current and cumulative tobacco smoking in economically developed
countries (Peto et  al., 1992, 2017; Thun et  al., 2012). This approach
is not applicable to all populations, however. For example, women in
China have much higher lung cancer rates than would be expected from
their low lifetime history of active smoking (Jha and Peto, 2014).
Geographic Variation
Figure 28–​1 shows the variation in lung cancer incidence and mor-
tality rates by gender and WHO region, according to Globocan esti-
mates for 2012 (Ferlay et al., 2013). The geographic patterns were
519
520

520 PART IV:  Cancers by Tissue of Origin

Male Female
North America
Micronesia
Eastern Asia
More developed regions
Western Europe
Central and Eastern Europe
Southern Europe
Northern Europe
Australia/New Zealand
Polynesia
World
Western Asia
Less developed regions
Southeast Asia
Caribbean
Southern Africa
South America
Melanesia
Northern Africa
South-Central Asia
Central America
Eastern Africa
Middle Africa
Western Africa
60 40 20 0 20 40 60
Incidence Mortality

Figure 28–​1.  Age-​standardized lung cancer incidence and mortality rates (per 100,000) by gender and WHO geographic region, as estimated for 2012.
Source: Ferlay et al. (2013).

similar for incidence and mortality rates. Lung cancer incidence
rates varied by 25-​fold in men and 34-​fold in women across WHO
regions. In men, the highest incidence rates (per 100,000) were in
Central and Eastern Europe (53.5) and Eastern Asia (50.4), whereas
in women the rates were highest in Northern America (33.8) and
Northern Europe (23.7). Notably low incidence rates (per 100,000)
were observed in Middle and Western Africa for both men (2.0)
and women (1.7). More than half (58%) of cases newly diagnosed
in 2012 occurred in LMICs; about one-​third occurred in China
(Tobacco Atlas, 2015).
Gender-​specific maps of the age-​standardized lung cancer inci-
dence rates (per 100,000) are shown by country in 2012 (Figure 28–​2)
(Ferlay et  al., 2013). (It should be noted that the scale used to dis-
play the rates differs for men and women.) In men, the incidence rates
in 2012 were highest in Central and Eastern Europe and in Eastern
Asia; among women, the rates were highest in Denmark, the United
Kingdom, Canada, and the United States. The geographic patterns of
lung cancer incidence shown here correspond closely to the patterns
of daily cigarette smoking among men and women in 2012, shown in
Chapter 11 (Figure 11–​2).
Lung cancer incidence and mortality rates also vary substantially
within many countries. For example, in the United States, incidence
and mortality rates vary by more than 3-​fold among states (American
Cancer Society, 2016). Researchers have used the regional variation to
assess the impact of tobacco control activities at the state level. Jemal
and colleagues correlated an index of state tobacco control activities
with lung cancer death rates in young adults (ages 30–​39  years) to
assess the early effects of state tobacco control efforts on risk (Jemal
et al., 2003). Lung cancer mortality rates in this age group and trends
in the rates over a 10-​year period were strongly and inversely corre-
lated with the index of state tobacco control activities.
Temporal Variation
The increase in lung cancer occurrence during the first half of the
twentieth century was captured largely by mortality statistics, since
very few population-​based cancer incidence registries were then in
existence. The temporal patterns are similar for incidence and mortal-
ity data however. Figure 28–​3 shows the trends in gender-​specific inci-
dence rates in selected high-​and middle-​income countries from 1954
to 2005, based on Cancer Incidence in Five Continents (Parkin et al.,
2014). We first discuss the trends in age-​standardized incidence rates
in these countries, and then illustrate how age-​specific rates and birth
cohort trends provide an earlier indication of changes in smoking-​
related lung cancer than age-​standardized rates.
Age-​Standardized Incidence Rates
Much of the long-​term increase in lung cancer occurrence among men
preceded the advent of population-​based cancer incidence registries.
An exception to this is the National Cancer Registry in Denmark,
which captures several decades of the protracted increase in lung can-
cer incidence in men as well as women (Figure 28–​3). In all of the
high-​income countries for which data are shown, the dominant feature
among men is the large decrease in the age-​standardized lung cancer
  521
Men Women

0 20 40 60 80 0 10 20 30 40

Figure 28–​2.  Map of age-​standardized lung cancer incidence rates (per 100,000) in men and women* by country of residence, 2012. *Note that scale differs for men and women.
Source: Ferlay et al. (2013).
52

522 PART IV:  Cancers by Tissue of Origin

(a) Males (b) Females
140 45

40
120
US Black
US Black
35

100
30

UK, Scotland

Rate per 100,000

Rate per 100,000

80
25

UK, Scotland
Italy
US White 20 US White
60

Denmark Australia 15
Australia
40
Italy
10

Denmark
20
5
India India

0 0
1954 1964 1974 1984 1994 2004 1955 1965 1975 1985 1995 2005
Year Year

Figure 28–​3.  Trends in lung cancer incidence in selected countries among males and females. Source: Ferlay et al. (2013).

incidence rate, beginning in the mid-​1980s. This contrasts with the
continuing increase in incidence among women in Italy, Denmark,
and Australia, and the absence of a major change in lung cancer inci-
dence in either sex in India. In the United Kingdom (Scotland) and
among US blacks, the incidence rates in women reached a plateau dur-
ing the 1990s. Only among whites in the United States did the age-​
standardized lung cancer incidence rate begin to decrease in women as
well as men during the time period shown.
Not shown in Figure 28–​3 are the decreasing trends in the age-​
standardized lung cancer incidence rates among men in many other
high-​and middle-​income countries, including Hungary, Slovakia, and
others in Eastern Europe (Ferlay J et al., 2013). It is not yet possible to
assess the long-​term impact of smoking on lung cancer among men in
China (Zhao et al., 2010) or Japan (Funatogawa et al., 2013). Access
to cigarettes in these countries was limited during and after World War
II, and widespread cigarette smoking began considerably later than in
the West. In general, middle-​and low-​income countries have limited
historical data on cigarette smoking, and even past trends in lung can-
cer are difficult to assess. The age-​standardized death rate from lung
cancer is reportedly increasing among men in Uganda, as represented
by the population-​based cancer registry (Ferlay et al., 2013).
Age-​Specific and Birth Cohort Trends
As noted, age-​specific rates and birth cohort trends are more sensi-
tive to changes in smoking behavior and lung cancer risk at younger
ages than are age-​standardized rates. Birth cohort patterns represent
the age-​specific incidence rates among people born in the same 5-​or
10-​year calendar period as they advance together through age and
calendar time. Birth cohort patterns are highly informative about the
evolution of tobacco smoking in the United States, as discussed in
Chapter 11. They reflect shared patterns of tobacco use that people in
the same birth cohort acquire as they pass through critical periods of
life. The birth cohort patterns of smoking are mirrored by similar pat-
terns in lung cancer risk, 20–​50 years later.
Figure 28–​4 shows birth cohort patterns in lung cancer mortality
rates by sex in the US general population from 1930 to 2009. In men,
the age-​specific death rates increase from the birth cohort 1870–​1874
to 1910–​1914, and then decrease in later birth cohorts. In women, the
age-​specific death rates continue to increase until at least the birth
cohort 1930–​1934. In both sexes, the slope of the initial increase in
lung cancer before age 40 years appears to flatten in birth cohorts after
1910–​1914 in men and after 1930–​1934 in women. This is consist-
ent with a reduction in smoking-​related lung cancer at younger ages,
following reductions in smoking initiation and, more recently, in
consumption.
Birth cohort patterns and age-​specific rates at younger ages are
informative in several ways. First, they show the same wave-​like
progression in lung cancer risk across successive birth cohorts of
men and women that characterizes the trends in smoking prevalence
(Holford et  al., 2014)  (Chapter  11). Second, they provide an earlier
indication of the changing impact of smoking than age-​standardized
 523

Lung Cancer 523

(a) Males (b) Females
600 600

500 500

400 400
Deaths per 100,000

Deaths per 100,000

300 300

200 200

100 100

1880
1870 1880
1870
40
00

20

30

50
90

10

60

60
50
40
19

19 0

30
20
19

19

19

19
18

19

19

0
1

189900

19
19

19
19

1 19

0 0
1930– 1940– 1950– 1960– 1970– 1980– 1990– 2000– 1930– 1940– 1950– 1960– 1970– 1980– 1990– 2000–
1934 1944 1954 1964 1974 1984 1994 2004 1934 1944 1954 1964 1974 1984 1994 2004

Calendar Period of Death Calendar Period of Death

Figure 28–​4.  Birth cohort patterns in lung cancer death rates by sex, United States, 1930–​2009. Source: National Center for Health Statistics (2013a).

rates or age-​specific rates at older ages. Third, they help to inform the 1983; Holford et al., 2014). These statistical models provide a some-
interpretation of trends in age-​standardized cancer rates in the general what more formal approach for partitioning age, cohort, and period
population. effects, based on a log-​linear model of temporal trends in cancer
Figure 28–​5 shows the age-​standardized lung cancer death rates for rates. The