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DOI 10.1007/s10549-015-3293-7
PRECLINICAL STUDY
Received: 28 January 2015 / Accepted: 31 January 2015 / Published online: 15 February 2015
Springer Science+Business Media New York 2015
Introduction
TNBC describes a subgroup of breast cancers that are
negative for the oestrogen, progesterone and HER2 receptors. They account for between 15 and 20 % of all
breast cancers diagnosed but are over-represented in young
women and in black women in the United States.
123
72
Australian
patients,
N = 439 (%)
57 15 years
59 10 years
Australian cohort
Age at diagnosis
B50 years
153 (34.9)
49 (14.6)
[50 years
286 (65.1)
286 (85.4)
80 (18.2)
11 (2.5)
2 (0.5)
43 (9.8)
Ovarian cancer
only
5 (1.1)
6 (1.3)
Other cancer
85 (19.4)
No recorded family
history of cancer
207 (47.2)
Family history of
cancer
Methods
Study cohort
409 (93.2)
Papillary
3 (0.7)
2 (0.6)
Medullary
10 (2.3)
42 (12.5)
Apocrine
4 (1.2)
Lobular (Invasive/
in situ/not
otherwise
specified)
9 (2)
14 (4.2)
Metaplastic
7 (2.1)
3 (0.9)
8 (1.8)
36 (10.7)
N = 219
Others
Unknown
Tumour grade
227 (67.8)
6 (1.4)
1 (0.5)
48 (10.9)
54 (24.6)
374 (85.2)
143 (65.3)
Not known
11 (2.5)
21 (9.6)
BRCA1 and BRCA2 are breast cancer susceptibility genes that are part of the DNA repair pathway. Pathogenic
mutations in both genes confer a high risk of breast cancer
[1], and together they account for approximately 5 % of all
breast cancer cases [2]. A large proportion of tumours in
women with a BRCA1 mutation exhibited a triple-negative
phenotype. Not all women with breast cancer qualify for
BRCA1 and BRCA2 testing. Testing is currently based on
123
the age of onset, the family history and in some cases (e.g.
Ashkenazi Jews) on the ethnic group. Currently, tumour
histology is not a clear criterion for the recommendation
for genetic testing, but some have suggested that all women
with triple-negative breast cancer be candidates for genetic
testing, regardless of age of onset or family history. With
the advent of next-generation DNA sequencing (NGS), it is
cost-effective to perform BRCA1 and BRCA2 testing to
women outside of a familial cancer setting. Several studies
have reported that up to 20 % of women with TNBC breast
cancer carry a BRCA mutation [312]. The aim of this
study was to define the prevalence of germline BRCA1 and
BRCA2 mutations in two independent populations of consecutively collected TNBC cases, in Poland and in Australia, unselected for family history and age of diagnosis.
Exon
BRCA1
p.Val233Asnfs*4
p.Leu502Alafs*2
p.Gln563*
p.Lys652Glufs*21
p.Lys654Serfs*47
c.213-11T[G
c.514delC
c.697_698del
c.1504_1508del
c.1687C[T
c.1952dup
c.1961del
int 5
11
p.Gln172Asnfs*62
Results in frameshift
p.Cys61Gly
c.181T[G
Intronic retention of 58 bp
p.Cys24Serfs*13
c.70_80del
c.135-2A[G
p.Glu23Valfs*17
c.68_69del
Nucleotide
change
int 3
Australian cohort
Gene
rs80357747
rs80357522
rs80357885
rs80356898
rs80357888
Y/class 5pathogenic
Y/class 5pathogenic
Y/class 5pathogenic
Y/class 5pathogenic
Y/class 5pathogenic
Y/class 5pathogenic
Y/class 5pathogenic
rs80358061
rs80357872
Y/class 5pathogenic
Y/UV
Y/class 5pathogenic
Y/class 5pathogenic
BIC
(Y/Nclass)
rs28897672
rs80358065
rs80359877
rs80357713
dbSNP
45
03-11-043
02-12-076
02-08-102
05-08-009
05-11-096
04-08-214
08-12-105
01-10-155
04-10-067
07-12-007
01-10-014
47
36
62
68
43
41
69
41
37
47
40
55
03-09-148
03-11-100
26
Age of
diagnosis
01-07-014
Patient
Mother, ovarian, 66
Sister, colorectal, 55
Sister, ovarian, 53
Father, pancreatic, 76
Mother, breast, 73
Mother, cervical, 38
Mother, breast, 38
Father, non-Hodgkins
lymphoma and colon, 75
Family history
(relationship, type of
cancer, age of diagnosis)
Table 2 Deleterious mutations detected in the Australian and Polish cohorts and any recorded family history of diseases associated with the mutation carriers
123
123
BRCA2
Gene
c.5266dup
c.5272A[T
20
p.Cys419Trpfs*11
p.Phe620Leufs*24
p.Thr630Asnfs*14
c.1257del
c.1860del
c.1889del
10
Classified as pathogenic
according to kConFab
c.631?2T[G
int 7
p.Leu105*
c.314T[G
p.Leu1764*
p.His1732Phefs*5
p.Thr1677Ilefs*2
c.5289del
p.Arg1758*
c.5194-12G[A
int 19
21
p.Gln1756Profs*74
c.5030_5033del
17
p.Trp1508*
p.Leu1404*
p.Ser1253Argfs*10
c.3756_3759del
c.4523G[A
p.Gln1200*
c.3598C[T
c.4210del
p.Ile946Tyrfs*6
c.2835dup
15
Nucleotide
change
13
Exon
Table 2 continued
rs80359315
rs80359272
rs81002899
rs80358561
rs80357906
rs80358079
rs80357862
rs80357765
rs80357868
rs62625307
rs80357519
dbSNP
Y/class 5pathogenic
Y/class 5pathogenic
Y/UV
Y/class 5pathogenic
Y/class 5pathogenic
Y/class 5pathogenic
Y/class 5pathogenic
Y/class 5pathogenic
Y/class 5pathogenic
Y/class 5pathogenic
BIC
(Y/Nclass)
05-10-073
03-07-065
01-08-025
01-06-021
48
56
84
34
89
46
05-09-110
55
36
47
45
55
45
04-11-051
01-11-082
03-09-059
04-10-126
01-08-061
02-08-30S
01-12-021
29
33
04-11-088
03-06-041
30
43
44
Age of
diagnosis
02-08-124
08-10-069
02-08-049
Patient
Mother, breast, 39
Mother, breast, 58
Mother, breast, 40
Mother, bladder, 74
Mother, breast, 60
Mother, breast, 47
Cousin, breast
Cousin, breast
Father, throat, 40 s
Family history
(relationship, type of
cancer, age of diagnosis)
74
Breast Cancer Res Treat (2015) 150:7180
Exon
11
16
BRCA1
p.Gln1273*
c.3817C[T
BRCA2
p.Gln1096*
c.3286C[T
c.4689C[A
c.2886dup
p.Tyr1563*
p.Ile963Tyrfs*19
p.Gln1396*
p.Gln1090*
c.3268C[T
c.4186C[T
p.Gly563*
c.1687C[T
13
p.Gly284*
c.80?2T[C
c.850C[T
i2
11
p.Thr2766Asnfs*11
Nucleotide change
c.8297del
18
p.Ile2315Lysfs*12
p.Val2228Glyfs*5
c.6944_6947del
13
c.6682dup
p.Asn1784Thrfs*7
c.5351del
p.Leu1908Argfs*2
p.Tyr1710*
c.5130_5133del
p.Ser1970*
p.Asp1469Lysfs*11
c.4405_4409del
c.5909C[A
p.Gln1452*
c.4354C[T
c.5722_5723del
p.Ala938Profs*21
c.2808_2811del
11
Nucleotide
change
Exon
BRCA1
BRCA1
Polish cohort
Gene
Gene
Table 2 continued
rs80357433
rs80357011
rs80357208
rs80357485
rs80357402
rs80356898
rs80358128
dbSNP
rs80359705
rs80359629
rs80359621
rs80358824
rs80359531
rs80359509
rs80359485
rs80359352
dbSNP
Y/class 5pathogenic
NUV
Y/class 5pathogenic
Y/class 5pathogenic
Y/class 5pathogenic
Y/class 5pathogenic
Y/class 5pathogenic
Y/class 5pathogenic
Y/class 5pathogenic
Y/class 5pathogenic
Y/class 5pathogenic
Y/class 5pathogenic
Y/class 5pathogenic
Y/class 5pathogenic
Y/class 5pathogenic
BIC
(Y/Nclass)
01-08-037
08-11-063
04-08-036
05-10-118
04-09-164
08-10-074
02-09-527
01-12-019
03-11-109
04-12-030
Patient
43
136,755
160,333#
220,693
161,467
36
41
54
53
62
55
349,099
192,682
33
59
342,887
40
Family history
of breast
and/or ovarian
cancer (Y/N)
Brother, melanoma, 35
Maternal grandmother,
melanoma, 90 s
Brother, skin, 40 s
Father, skin, 60 s
Father, prostate, 65
Daughter, thyroid, 54
Maternal grandmother,
gastrointestinal, unknown
Brother, prostate, 59
Father, bowel, 54
Mother, breast, 50 s
Family history
(relationship, type of
cancer, age of diagnosis)
Age of
diagnosis
285,146
228,532
146,990
Patient
44
44
39
63
57
83
60
78
58
59
Age of
diagnosis
123
123
c.9097dup
c.9253dup
24
p.Glu2089Aspfs*2
c.6267_6269delinsC
c.8946del
p.Tyr1894*
c.5682C[G
23
p.Ser1882*
c.5645C[A
22
p.Asn1784Lysfs*7
c.5352del
c.7558C[T
p.Asn1747*
c.5237dup
15
p.Lys1025Asn;Lys1026*
c.3075_3016delinsTT
11
p.Thr3085Asnfs*26
p.Thr3033Asnfs*11
p.Asp2983Ilefs*5
p.Arg2520*
p.Asn433Glnfs*18
p.Val220Ilefs*4
c.1296_1297del
p.Arg1835*
c.658_659del
c.5503C[T
24
p.Thr1677Ilefs*2
10
c.5278-2A[T
i20
Intronic retention of 65 bp
c.5030_5033del
17
p.Met1663Valfs*14
p.Glu1661*
c.4981G[T
c.4986?3G[C
Nucleotide change
i16
Exon
BRCA2
Gene
Table 2 continued
rs80359752
rs80359747
rs80358981
rs41293497
rs80358785
rs80359499
rs80358552
rs80359276
rs80359604
rs41293465
rs80357862
rs80358023
rs80357401
dbSNP
Y/class 5pathogenic
Y/class 5pathogenic
NUV
Y/class 5pathogenic
Y/class 5pathogenic
Y/class 5pathogenic
Y/class 5pathogenic
COSMICdistribution in
ovary and endometrium
N/UV
Y/class 5pathogenic
Y/class 5pathogenic
Y/class 5pathogenic
Y/class 5pathogenic
COSMICdistribution in
ovary and large intestine
Y/UV
NUV
Y/class 5pathogenic
Y/class 5pathogenic
33
41
73,032
353,587
53
174,157
192,325
285,224
266,895
99,173
151,271
45
68
73
62
52
58
50
195,860
68
349,466
346,635
63
273,641
49
52
171,190
87,035
58
71
77
58
66
38
54
135,383
119,568
334,861
173,119
156,407
166,662
94,836
62
53
101,115
136,084
Age of
diagnosis
Patient
Family history
of breast
and/or ovarian
cancer (Y/N)
76
Breast Cancer Res Treat (2015) 150:7180
77
35
30
25
20
15
10
5
0
25-34
35-44
45-54
55-64
65-74
75-84
85
Non-mutation carriers
30
25
20
15
10
5
0
25-34
35-44
45-54
55-64
65-74
75-84
85
Results
We identified 74 mutations in the 774 triple-negative breast
cancer patients (9.6 %). Mutations were present in 9.3 %
123
78
40.0
35.0
30.0
25.0
20.0
15.0
10.0
5.0
0.0
<40
40-60
>60
Table 3 Percentage of patients with BRCA1 or BRCA2 mutations compared to non-mutation carriers diagnosed with breast cancer
Age of diagnosis (years)
Non-mutation carriers
(%, n = 26)
(%, n = 15)
(%, n = 398)
\40
26.9
13.3
12.6
4060
57.7
60
43.7
C60
15.4
26.7
43.7
(%, n = 18)
(%, n = 15)
(%, n = 302)
\40
22.2
2.3
4060
61.1
60
54
C60
16.7
40
43.7
of the Australian patients and in 9.9 % of the Polish patients (see Table 2 for a complete list of deleterious mutations and Supplementary Table 1 for all other alterations
identified in BRCA1 and BRCA2). In Australia, 63 % of
the mutations were in BRCA1; in Poland 54.5 % of the
mutations were in BRCA1. The distribution of the age of
diagnoses is shown in Fig. 1.
In the Australian cohort, four of the 41 mutations are
novel and have not been reported in BIC, Leiden Open
(source) Variation Database (LOVD), Clinvar, or any
published literature. Of these, two are in BRCA1
(c.4523G[A, c.5272A[T) and two in BRCA2 (c.1860del,
c.4354C[T).
Among the 41 Australian patients with a mutation, 17
(41.5 %) had a family history of breast or ovarian cancer
(Table 2). In the Australian cohort, the mean age of disease
onset for BRCA1 mutation carriers is 46.0 years of age and
for BRCA2 mutation carriers is 57.6 years of age, and for
non-carriers, it was 57.8 years of age (p = 0.004).
A deleterious mutation was detected in 33 of 335 patients in Poland (9.9 %). Two mutations have not been
reported in BIC, Leiden Open (source) Variation Database
(LOVD) or Clinvar. These include one in BRCA1
(c.80?2T[C) and one in BRCA2 (c.2886dup).
123
Discussion
In both Poland and in Australia, approximately 10 % of the
patients with triple-negative phenotype harbour a germline
BRCA1 or BRCA2 mutation. Our study highlights the
importance of genetic testing for patients with TNBC regardless of age and in the absence of a family history. In
Poland, genetic testing for three founder mutations is already recommended for all breast cancer patients. We
recommend that in the absence of one of the founder mutations, Polish patients with triple-negative breast cancer be
considered for additional genetic testing, which should
include full sequencing of the coding regions of both genes.
79
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