Breast Cancer Res Treat DOI 10.1007/s10549-012-2159-5
EPIDEMIOLOGY
Characteristics and spectrum of BRCA1 and BRCA2 mutations in 3,922 Korean patients with breast and ovarian cancer Haeyoung Kim • Dae-Yeon Cho • Doo Ho Choi • Su-Youn Choi • Inkyung Shin Won Park • Seung Jae Huh • Sung-Hee Han • Min Hyuk Lee • Sei Hyun Ahn • Byung Ho Son • Sung-Won Kim • Korean Breast Cancer Study Group • Bruce G. Haffty
•
Received: 26 June 2012 / Accepted: 27 June 2012 Ó Springer Science+Business Media, LLC. 2012
Haeyoung Kim and Dae-Yeon Cho equally contributed to this research.
patients covered in ten previous reports. Overall, 420 (150 distinct) pathogenic mutations were identified, 211 (73 distinct) in BRCA1 and 209 (77 distinct) in BRCA2. The majority (134 of 150) of the distinct mutations resulted in premature termination codon of the BRCA1/2 translation. BRCA1 c.4186-1593_4676-1465del was the only large genomic rearrangements mutation. Out of 150 distinct BRCA1/2 mutations, 84 (56 %) mutations were considered specific to Korean BOC. Eighty-five BRCA1/2 mutations were detected in at least two unrelated patients. These recurrent mutations account for 84.5 % (355 of 420) of mutations detected in the Korean population. In the pooled mutational data of BRCA1/2 genes, this study discovered the prevalence of BRCA1/2 mutations in the Korean BOC patients is similar to those found in other ethnic groups. Large genomic rearrangements in BRCA1/2 genes were infrequently detected among the Korean patients with
H. Kim Department of Radiation Oncology, Hallym University Sacred Heart Hospital, Anyang, Korea
S. H. Ahn B. H. Son Department of Surgery, College of Medicine, University of Ulsan and Asan Medical Center, Seoul, Korea
D.-Y. Cho S.-Y. Choi I. Shin LabGenomics Clinical Research Institute, LabGenomics, Seongnam, Korea
S.-W. Kim Department of Surgery, Breast and Endocrine Service, Seoul National University, Seoul, Korea
D. H. Choi (&) W. Park S. J. Huh Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Seoul 135-710, Gangnam-gu, South Korea e-mail:
[email protected]
Korean Breast Cancer Study Group Korean Breast Cancer Society, Seoul, Korea
Abstract This investigation is aimed at evaluating the epidemiologic characteristics of BRCA1/2 germline mutations in Korean patients with breast and ovarian cancer (BOC). We analyzed the entire mutational data of BRCA1/2 genes in BOC patients who were tested in Korea since the first Korean report of BRCA1 mutation in 1995 with the exception of the data covered in the Korean Hereditary Breast Cancer (KOHBRA) study, the project launched in 2007 for establishing BRCA1/2 carrier cohorts in Korea. In total, BRCA1/2 gene mutations of 3,922 Korean BOC patients were evaluated, including the unpublished data of 2,139 breast cancer patients examined by four Korean institutions and the data of 1,783 BOC
S.-H. Han Department of Molecular Genetics, Seoul Medical Science Institute, Seoul Clinical Laboratories, Seoul, Korea
B. G. Haffty Department of Radiation Oncology, Robert Wood Johnson Medical School, Cancer Institute of New Jersey, New Brunswick, NJ, USA
M. H. Lee Department of Surgery, Soonchunhyang University, Seoul, Korea
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BOC. There were several BRCA1/2 mutation candidates for founder mutations. To further establish a Korean cohort for BRCA1/2 mutations, the nationwide KOHBRA study is in progress.
epidemiologic characteristics and to comprehend the mutational spectrum of BRCA 1/2 mutations in the Korean population.
Keywords BRCA1 BRCA2 Breast cancer Korean Epidemiology
Materials and methods Patients and criteria
Introduction Mutations of BRCA1 and BRCA2 (BRCA1/2) are the most important genetic alterations that cause susceptibility to breast and ovarian cancers (BOC). About 10–15 % of BOC are caused by inherited genetic mutations, and around 20 % of the hereditary BOC are associated with mutations in BRCA1/2 genes [1, 2]. Individuals carrying BRCA1 mutations have a 57–65 % probability of developing breast cancer, and a 39–40 % chance of developing ovarian cancer, while women having BRCA2 mutations present a 45–49 % risk of developing breast cancer, along with an 11–18 % risk of ovarian cancer over a lifetime [3, 4]. The prevalence of these mutations is found to be higher among women who have family history of BOC, a personal history of breast cancer at young age, or women diagnosed with triple-negative breast cancer (i.e., estrogen receptor, progesterone receptor, and HER2-negative) [2, 5–7]. Furthermore, the frequency and spectrum of these genetic mutations are diverse among ethnic groups and countries [8, 9]. Breast cancers of Korean patients characteristically develop at younger age when compared with counterparts from Western countries. The median age of Korean breast cancer patients is in the late 40s, which is more than 10 years younger than that of patients from North America or Europe. Furthermore, about half of the breast cancer patients are under 50 years of age in the Korean population [10]. There is a strong association between age-of-onset and genetic susceptibility for cancer development. Therefore, a significant proportion of Korean breast cancer cases are expected to have been caused by genetic mutations. Several studies have analyzed BRCA1/2 mutations in Korean patients with BOC; however, the prevalence and genetic characteristics of BRCA mutations in Korean patients are not well defined. To optimize patient counseling and to specify criteria for BRCA testing for Korean BOC patients, evaluation of epidemiologic characteristics of BRCA mutations in Korean population is warranted. To date, ten studies have evaluated the prevalence of BRCA 1/2 mutations among Korean BOC patients [11– 20]. In addition to these studies, four unpublished researches investigated mutations of BRCA genes in Korean BOC patients. Here, we reviewed the 14 reports to identify
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Four institutes from Korea have contributed to this study: LabGenomics Clinical Research Institute (LGI), Samsung Medical Center (SSM), Seoul Medical Science Institute (SMI), and Soonchunhyang University Hospital (SUH). Overall, the study subjects included 2,139 pathologically confirmed breast cancer patients, who were divided into two groups: Study of SMI comprised 471 patients with unselected breast cancer (UB); Other three studies were made up of 1,668 patients with breast cancer carrying at least one of the risk factors (familial, bilateral, early onset, male, and multiple organ cancer; HRB). All patients included were the index case of the family, and received genetic counseling and gave informed consent for genetic analysis to be performed. All patients were checked carefully and confirmed as not enrolling in any previous reports. BRCA1/2 mutation analysis Genomic DNA was extracted from the patient’s peripheral blood. The whole coding sequences and exon/intron boundaries of BRCA1/2 genes were amplified by PCR. The PCR fragments obtained were analyzed for sequence variants using a combination of different methods: Fully direct sequencing (DS) at SSM and SUH; fluorescenceconformation sensitive capillary (gel) electrophoresis (F-CSCE/CSGE) at LGI; denaturing high-performance liquid chromatography (DHPLC) at SMI. Overall, 1,174 patients were analyzed by F-CSCE/CSGE, 471 by DHPLC, and 494 by DS. Heteroduplex scanning (F-CSCE/CSGE and DHPLC) and direct sequencing were performed based on the institute’s own protocols, and described previously [13, 16, 17, 21]. Details for individual analysis will be provided on request. Mutation nomenclature All mutations are described according to HUGO-approved systematic nomenclature (Nomenclature for the description of sequence variations, Human Genome Variation Society. (http://www.hgvs.org/mutnomen/) [22]. HUGO-approved mutation nomenclature of BRCA1 (GenBank accession no. NP_009225.1) and BRCA2 (GenBank accession no. NP_000050.2) defines the A of the ATG translation
Detection methods: F-CSCE/CSGE fluorescence-conformation sensitive capillary (gel) electrophoresis, DS direct sequencing, DHPLC denaturing high-performance liquid chromatography b
Type of study: HRB breast cancer patients at high risk (with one or more risk factors for BRCA mutations, such as familial, bilateral, early onset, male, and multiorgan cancer), UB unselected breast cancer patients
a
DS 5 (12.2) 1 (2.4) 4 (9.8) HRB 41 Soonchunhyang University Hospital (SUH) D
Soonchunhyang University Hospital
DHPLC 14 (3.0) 7 (1.5) 7 (1.5) UB 471 Seoul Medical Science Institute (SMI) C
Ewha women’s hospital
DS 87 (19.2) 48 (10.6) 39 (8.6) HRB 453 Samsung Medical Center (SSM) B
Samsung Medical Center
158 (13.5) 81 (6.9) 77 (6.6) HRB 1,174 LabGenomics Clinical Research Institute (LGI) A
27 sites (Asan Medical Center et al.)
BRCA1 (%)
Inclusion criteriaa No. of patients Site Institution No.
Table 1 Unpublished studies of BRCA1 and BRCA2 mutations in Korean breast/ovarian cancer patients
Mutation analysis of BRCA1/2 genes was performed in 2,139 Korean breast cancer patients at four institutes. Study design and the prevalence of mutations detected are summarized in Table 1. Overall, 264 (116 distinct) pathogenic mutations were identified, 127 (53 distinct) in BRCA1 and 137 (63 distinct) in BRCA2. All the sequence variant is considered to be a pathogenic mutation if each is predicted to result in premature termination codons in all but the last exon of BRCA2 [23], or splice defect caused by any alteration of the two invariant bases immediately preceding or following exons. Relatively low BRCA1/2 mutation prevalence (3.0 %) was found in patients with unselected breast cancer (SMI). Among the breast cancer patients at high risk of carrying mutations (LGI, SSM, and SUH), prevalence of mutations were 12.2–19.2 %, or 4.7–6.4-fold higher than in patients with UB. Besides original data from this investigation, we collected and reviewed the previous studies on BRCA1/2 mutations in Korean BOC patients. Since the first report on BRCA1 mutation [11], to date, 11 studies have reported BRCA1/2 mutations in the Korean population, and estimated the prevalence of those genes. One report [24] overlapped with the other study of Han et al. [16], and is therefore not included in this comprehensive review. In Table 2, we summarized the study designs and mutation prevalence in ten previous studies of BRCA1/2 mutations in Korean population. Except for the first report that analyzed BRCA1 only, all other studies examined both BRCA1 and BRCA2 genes. Three studies included ovarian cancer patients. Mutation analysis in each study was performed using various detection techniques, including single-strand conformation polymorphism (SSCP), protein truncation test (PTT), fluorescence-conformation sensitive gel electrophoresis (F-CSGE), denaturing highperformance liquid chromatography (DHPLC), and direct sequencing (DS). Two studies examined large genomic rearrangements (LGR) of BRCA1/2 genes, using multiplex ligation-dependent probe amplification (MLPA). Depending on the detection methods and the inclusion criteria of patients, the prevalence of BRCA1/2 mutations in ten individual studies was so diverse ranging from 0 to 42.9 %.
Mutation cases (prevalence, %)
Results
BRCA2 (%)
Total (%)
Methodb
initiation codon as nucleotide ?1. Splicing-defect mutations in intronic region are described at the genomic DNA level using GenBank genomic reference sequence NC_000017.10 (BRCA1) and NC_000013.10 (BRCA2). The nomenclature for BIC (Breast cancer Information Core) traditional mutations is also used in tables, and based on U14680 (BRCA1) and U43746 (BRCA2), where A of the ATG translation initiation codon is at positions 120 and 229, respectively.
F-CSCE/CSGE
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Breast Cancer Res Treat Table 2 Studies of BRCA mutations among Korean breast/ovarian cancer patients No.
Reference
No. of patients
Type of patientsa
BRCA1 (%) 1
Oh et al. [11]
2
Kang et al. [12]
30 21
Methodc
Mutation cases (prevalence)
SB (12)
0 (0)
HRB (18)
1 (5.5)
FB,FO
5 (23.8)
BRCA2 (%) –
Total (%) 0 (0)
SSCP
1 (5.5) 4 (19)
9 (42.9) b
PTT, SSCP, DHPLC
3
Choi et al. [13]
60
EB
6 (10.0)
5 (8.3)
9 (15)
4
Seo et al. [14]
97
SB
2 (2.1)
1 (1)
3 (3.1)
F-CSGE
5
Kim et al. [15]
37
6 7
Han et al. [16] Ahn et al. [17]
793 354
8
Seong et al. [19]
206
9
Lim et al. [18]
10
Seong et al. [20]
63 122
SO SB HRB SB (50)
DS
1 (2.7)
0 (0)
1 (2.7)
DHPLC
8 (1.0) 24 (6.8)
10 (1.3) 16 (4.5)
18 (2.3) 40 (11.3)
DHPLC, F-CSGE
1 (0.5)
3 (1.5)
4 (1.9)
HRB (156)
14 (6.8)
21 (10.2)
35 (17.0)
FO (40)
11 (27.5)
2 (5)
13 (32.5)
SO (23)
2 (8.7)
0 (0)
2 (8.7)
HRB/BRCAN
1 (0.8)
0 (0)
1 (0.8)
MLPA, DS DS MLPA
a Type of patients: SB sporadic breast cancer patients; HRB breast cancer patients at high risk (with one or more risk factors for BRCA mutations, such as familial, bilateral, early onset, male, multi-organ cancer); DS direct-sequencing; FB familial breast cancer patients; FO familial ovarian cancer patients;EB early onset breast cancer patients; SO sporadic ovarian cancer patients; BRCAN BRCA mutation-negative patients b
Two patients had pathogenic mutations in both BRCA1 and BRCA2 (double heterozygosity)
c
Detection methods: SSCP single strand conformation polymorphism, PTT protein truncation test, DHPLC denaturing high performance liquid chromatography, DS direct sequencing, F-CSGE fluorescence-conformation sensitive gel electrophoresis, MLPA multiple ligation-dependent probe amplification
Combining the data from this original investigation of four institutes and ten previous reports, all the BRCA1/2 germline mutations detected in Korean BOC patients were summarized in Tables 3 (BRCA1) and 4 (BRCA2). Overall, 420 (150 distinct) pathogenic mutations were identified, 211 (73 distinct) in BRCA1 and 209 (77 distinct) in BRCA2. The majority (134 of 150) of the distinct mutations resulted in premature termination codon of the BRCA1/2 translation. This number included 18 nonsense and 46 frameshift mutations in BRCA1 gene (Table 3) and 17 nonsense and 53 frameshift mutations in BRCA2 gene (Table 4). Eight BRCA1 and seven BRCA2 splice-defect mutations were also identified. BRCA1 c.4186-1593_46761465del was the only LGR mutation. Twenty-two of 73 BRCA1 and 31 of 77 BRCA2 mutations have not been previously reported in database including BIC database or other publications, and therefore are considered novel. In addition, 20 BRCA1 and 11 BRCA2 mutations have been reported only in Korean populations (summarized in Tables 3 and 4). Thus, out of 150 distinct BRCA1/2 mutations, 84 (56 %) mutations were considered specific to the Korean population. Thirty-four BRCA1 and 31 BRCA2 mutations were found in only one patient. Conversely, 85 BRCA1/2 mutations were detected in at least two unrelated patients. These recurrent mutations account for 84.5 % (355 of 420) of mutations detected in Korean population.
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Discussion Our study presents the research to date on BRCA1/2 mutations in Korean BOC patients. In the 14 reports, mutational analyses of BRCA1/2 genes were performed for 3,922 patients with BOC in the Korean population. The prevalence of BRCA 1/2 mutations varied across the studies, owing to the different numbers of patients, variable inclusion criteria, and diverse methods for mutation ascertainment in the individual studies. The patients inclusion criteria of the Korean reports included BOC patients having two or more first- or second-degree relatives affected with BOC (familial BOC patients) [11, 12, 18], patients with breast cancers that developed before age of 35 or 40 years (early onset breast cancer patients) [13], breast cancer patients having high risk for hereditary BOC (high-risk BOC patients) [17, 19], or patients unselected for family history or age of disease onset (sporadic BOC patients) [14–16, 18, 19]. Ranges in the prevalence of BRCA1/2 mutations among sporadic and high-risk breast cancer patients in the Korean population were 1.9–3.0 and 11.3–42.9 % respectively. The mutation frequencies among the Korean breast cancer patients unselected for family history or age-of-onset were similar to those of other ethnic groups [25, 26]. Of the 14 studies, 2 specified the frequencies of mutations in familial
Breast Cancer Res Treat Table 3 BRCA1 germline mutations detected in Korean patients with breast/ovarian cancer Exon/Intron
Sequence varienta
BIC traditional nomenclature
Effect on amino acids
BIC entriesb
2
c.38_39delATinsGGG
157delATinsGGG
p.N13RfsX4
0
3
A/9
2
c.66insA
185insA
p.E23RfsX18
29
1
B
IVS5
c.212?1G[A
IVS5?1G[A
Splicing defect
6
1
9
IVS7
c.302-2A[C
IVS06-2A[C
Splicing defect
1
4
7
c.390C[A
509C[A
p.Y130X
1
12
IVS7
c.441?1G[A
IVS7?1G[A
Splicing defect
0
1
11 11
c.922_924delAGCinsT c.928C[T
1041_1043delAGC insT 1047C[T
p.S308X p.Q310X
0 0
13 4
11
c.1293_1295delACTinsGA
1412delACTinsGA
p.L432RfsX9
Novel
1
A
11
c.1480C[T
1599C[T
p.Q494X
5
1
B
11
c.1511dupG
1630dupG
p.K505X
2
5
A, B, C
11
c.1516_1520delAGGAG
1635_1639delAGGAG
p.R506TfsX8
0
1
3
11
c.1612C[T
1731C[T
p.Q538X
3
1
7
11
c.1716delA
1835delA
p.E572DfsX16
0
4
A/7, 8
11
c.1823delA
1942delA
p.K608RfsX4
0
1
7
11
c.1831delC
1950delC
p.L611X
0
3
A/8
11
c.1936delA
2055delA
p.S646AfsX5
Novel
2
B
11
c.1961delA
2080delA
p.K654SfsX47
31
2
C/7
11
c.1962insT
2081insT
p.Y655LfsX18
0
2
9
11
c.2048delA
2167delA
p.K683SfsX18
0
3
6, 7, 9
11
c.2296_2297delAG
2415_2416delAG
p.S766X
3
1
A
11 11
c.2235T[A c.2359delG
2473T[A 2478delG
p.L785X p.E787KfsX5
Novel 0
1 2
A A/6
11
c.2433delC
2552delC
p.K812RfsX3
11
5
B/6, 7, 9
11
c.2830delT
2949delT
p.C944VfsX56
Novel
1
C
11
c.2856_2857delTT
2975_2976delTT
p.F952LfsX18
Novel
2
A
11
c.2914G[T
3033G[T
p.G972X
0
1
7
11
c.2934delT
3053delT
p.R979VfsX21
3
1
A
11
c.3157delG
3276delG
p.E1053KfsX9
0
1
9
11
c.3183delA
3302delA
p.I1061MfsX12
Novel
1
C
11
c.3228_3229delAG
3347_3348delAG
p.G1077AfsX8
24
1
8
11
c.3296delC
3415delC
p.P1099LfsX10
2
5
A/7, 8, 9
11
c.3329delA
3448delA
p.K1110SfsX7
Novel
1
A
11
c.3340G[T
3459G[T
p.E1114X
1
3
2
11
c.3436_3439delTGTT
3555_3558delTGTT
p.C1146LfsX8
Novel
1
A
11
c.3442delG
3561delG
p.E1148RfsX7
2
2
A
11
c.3472G[T
3591G[T
p.E1158X
Novel
1
A
11 11
c.3540_3541delCG c.3593T[A
3659delCG 3712T[A
p.V1181PfsX6 p.L1198X
Novel 0
1 1
A 7 A
Affected patients (n)
Studyc/referenced
A, B A, B, D/8 7 A, B/3, 4, 7, 9 A/6, 8
11
c.3607C[T
3726C[T
p.R1203X
28
2
11
c.3627dupA
3746dupA
p.E1210RfsX9
6
26
11
c.3756_3759delGTCT
3875_3878delGTCT
p.S1253RfsX10
121
2
A/3
11
c.3782T[G
3901T[G
p.K1261X
0
2
A/8
11
c.3813dupT
3932dupT
p.N1272X
Novel
3
A, B
11
c.3814insT
3933insT
p.N1272IfsX14
Novel
1
C
11
c.3895C[T
4014C[T
p.Q1299X
1
3
2
11
c.3982dupT
4101dupT
p.S1328FfsX2
Novel
1
A
A, B, C/5, 6, 7, 8, 9
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Breast Cancer Res Treat Table 3 continued Exon/Intron
Sequence varienta
BIC traditional nomenclature
Effect on amino acids
BIC entriesb
Affected patients (n)
Studyc/referenced
11
c.3991C[T
4110C[T
p.Q1331X
Novel
1
A
11
c.4041_4042delAG
4160_4161delAG
p.G1348NfsX7
0
3
2
11
c.4065_4069delTCAA
4184_4187delTCAA
p.N1355KfsX10
132
4
A/6, 7
11
c.4092_4093delCT
4211_4212delCT
p.L1365RfsX2
Novel
1
A
IVS12
c.4185?1G[T
IVS12?1G[T
Splicing defect
1
1
D
13
c.4327C[T
4446C[T
p.R1443X
126
1
A
13
c.4335_4338dupAGAA
4454dupAGAA
p.Q1447RfsX16
Novel
2
A
16
c.4981G[T
5100G[T
p.E1661X
1
4
A, C/3, 7
IVS16 17
c.4986?1G[T c.5074?1G[T
IVS16?1G[T IVS17?1G[T
Splicing defect Splicing defect
Novel 3
1 1
A 3
17
c.5030_5033delCTAA
5149_5152delCTAA
p.T1677IfsX2
17
3
A, B
18
c.5080G[T
5199G[T
p.E1694X
12
5
A/8
18
c.5102_5103delTG
5221_5222delTG
p.L1701QfsX14
3
2
2
IVS18
c.5152?1G[C
IVS18?1G[C
Splicing defect
2
4
A, B/8
21
c.5323_5324delAT
5442_5443delAT
p.M1775AfsX54
Novel
1
A
IVS22
c.5333-2A[T
IVS21-2A[T
Splicing defect
Novel
2
B
23
c.5444G[A
5563G[A
p.W1815X
4
2
2
23
c.5445G[A
5564G[A
p.W1815X
0
10
24
c.5470_5477del8
5589_5596del8
p.I1824DfsX3
2
3
24
c.5496_5506del11insA
5615_5616del11 bp insA
p.V1833SfsX7
2
15
24
c.5483delG
5602delG
p.C1828LfsX6
Novel
1
A
24
c.5497_5506del10
5616_5625del10
p.V1833SfsX7
0
1
6
24
c.5532_5533insG
5651insG
p.Y1845VfsX35
Novel
2
A
24 24
c.5548delC c.5553dupC
5667delC 5672dupC
p.L1850WfsX5 p.T1852HfsX28
Novel 0
1 1
A 7
13–15
c.4186-1593_4676-1465del
IVS12-1593del11467
p.Gln1376ArgfsX42
0
2
A/10
A, B/1, 4 3, 7 A, B, D/7, 8
Novel mutations are in italics face a
According to HUGO-approved systematic nomenclature
b
BIC entries: 0, Korean specific
c
Study: A Labgenomics Clinical Research Institute, B Samsung Medical Center, C Seoul Medical Science Institute, D Soonchunhyang University Hospital
d
References: 1 Oh et al. [11], 2 Kang et al. [12], 3 Choi et al. [13], 4 Seo et al. [14], 5 Kim et al. [15], 6 Han et al. [16], 7 Ahn et al. [17], 8 Seong et al. [19], 9 Lim et al. [18], 10 Seong et al. [20], 11 Kim et al. [24]
breast cancers (FB) as 19.4–30.0 % [17, 19]. The likelihoods of mutations in FB among Koreans were comparable to those of other Asian, Asian-American, or AfricanAmerican patients, while they were lower than those of Ashkenazi-Jews, or Caucasian from North America (Table 5) [27–34]. Different definitions of FB and inconsistent methods for genotyping across the studies could have influenced the results. However, by comparing a study by Seong et al. [19] of Korea and the study by Nanda et al. [27] of the United States, we ascertained a lower prevalence of mutations in FB among Koreans than that in Ashkenazi-Jews or other whites. The two studies used similar criteria for patient’s selection and similar methods for mutation detection. A lower penetrance of BRCA1/2
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genes in Korean women than that in Ashkenazi-Jews or whites is thought to attribute to the lower frequencies of BRCA mutations in the Korean FB patients. Meanwhile, four reports have evaluated the proportion of early onset breast cancer patients who have BRCA1/2 mutations. Definition of early onset breast cancer was diverse among the studies, such as 35 [17, 19] or 40 years [13, 35] of age. The prevalence of BRCA1/2 mutations in early onset breast cancer patients in Korea ranged between 10.4 and 21.4 %. Unfortunately, BRCA1/2 mutations cannot fully explain the demographic characteristic of Korean breast cancers that develop at young age. Other genetic or environmental factors may be related to this distinctive feature of breast cancer in Korean women.
Breast Cancer Res Treat Table 4 BRCA2 germline mutations detected in Korean patients with breast/ovarian cancer Exon/Intron
Sequence varienta
BIC traditional nomenclature
Effect on amino acids
BIC entriesb
Affected patients (number)
Studyc/referenced
IVS2
c.67?2T[C
IVS2?2T[C
Splicing defect
2
1
A
3
c.97G[T
325G[T
p.E33X
0
6
A, B/8
3 3
c.196C[T c.276dupA
424C[T 504dupA
p.Q66X p.S93IfsX8
Novel 1
3 2
B A
4
c.370delA
598delA
p.M124WfsX12
Novel
1
B
5
c.475G[A
703G[A
p.F143GfsX26
2
1
A
IVS6
c.516?1G[A
IVS6?1G[A
Splicing defect
Novel
1
A
IVS07
c.632-1G[T
IVS07-1G[T
Splicing defect
0
1
8
8
c.658_659delGT
886_887delGT
p.V220IfsX4
37
4
A/8
9
c.700delT
928delT
p.S234PfsX7
3
1
8
10
c.880G[T
1108G[T
p.E294X
Novel
1
A
10
c.994delA
1222delA
p.I332FfsX17
3
2
A
10
c.1176_1180delCTGTG
1404_1408delCTGTG
p.C393MfsX26
Novel
1
A
10
c.1310_1313delAAGA
1538_1541delAAGA
p.K437IfsX22
10
4
A, B/6 A, B, C, D/2, 6, 7
10
c.1399A[T
1627A[T
p.K467X
2
16
10
c.1514delT
1742 delT
p.I505NfsX4
Novel
2
B
10
c.1547delT
1775delT
p.F516SfsX9
1
1
3
10 11
c.1796delCTTAT c.2259delT
2024_2028delCTTAT 2487delT
p.S599X p.S754QfsX18
12 0
1 3
C A/4, 6
11
c.2798_2799delCA
3026_3027delCA
p.T933RfsX2
1
3
A/3
11
c.2808_2811delACAA
3036_3039delACAA
p.A938PfsX21
105
1
A
11
c.2912T[G
3140T[G
p.L971X
Novel
2
A
11
c.3018delA
3246delA
p.G1007VfsX36
Novel
2
B
11
c.3096_3110del15insT
3324del15insT
p.K1032NfsX5
Novel
1
A
11
c.3195_3198delTAAT
3423_3426delTAAT
p.N1066LfsX10
2
1
6
11
c.3352_3356delTTAGA
3580delTTAGA
p.L1118RfsX7
Novel
1
A
11
c.3599delGT
3827_3828delGT
p.C1200X
6
2
B/9
11
c.3744_3747delTGAG
3972_3975delTGAG
p.S1248RfsX10
8
15
A, B, C/2, 6, 7, 8
11
c.4478_4481delAAAG
4706_4709delAAAG
p.E1493VfsX10
33
1
A
11
c.4593delA
4821delA
p.V1532LfsX11
Novel
1
A
11
c.4766delC
4994delC
p.P1589QfsX28
0
3
B/7
11
c.4829_4830delTG
5057_5058delTG
p.V1610GfsX4
4
2
A/7
11
c.4894_4895delAG
5122_5123delAG
p.S1632YfsX6
0
1
8
11 11
c.5116_5119delAATA c.5207_5208delAA
5344_5347delAATA 5435_5436delAA
p.N1706LfsX5 p.Q1736RfsX6
Novel Novel
2 1
B A
11
c.5250delC
5478delC
p.Y1751TfsX26
Novel
1
A
11
c.5351delA
5579delA
p.N1784TfsX7
5
1
A
11
c.5471delA
5699delA
p.N1824MfsX16
Novel
1
B
11
c.5576_5579delTTAA
5804_5807delTTAA
p.I1859KfsX3
29
14
A, B, C/8
11
c.5592_5593delCA
5820_5821delCA
p.F1866YfsX6
Novel
1
A
11
c.5645C[A
5873C[A
p.S1882X
26
1
A A/8
11
c.5656C[T
5884C[T
p.Q1886X
2
3
11
c.5722_5723delCT
5950_5951delCT
p.L1908RfsX2
42
1
A
11
c.6082G[T
6310G[T
p.E2028X
Novel
2
A
11
c.5946_5949delTGGA
6174_6177delTGGA
p.S1982RfsX21
1
1
3
11
c.6239T[G
6467T[G
p.L2080X
1
1
3
11
c.6353_6366del14
6581_6594del14
p.V2118GfsX6
0
1
8
123
Breast Cancer Res Treat Table 4 continued Exon/Intron
Sequence varienta
11
c.6437_6440delATCA
6665_6668delATCA
p.N2146TfsX21
0
1
8
11
c.6553delG
6781delG
p.A2185LfsX6
1
3
A, B
11
c.6600delTT
6828_6829delTT
p.S2201X
2
1
C
11 11
c.6688delA c.6724_6725delGA
6916delA 6952_6953delGA
p.I2230LfsX11 p.D2242FfsX2
Novel 0
1 5
A A, B/8
BIC traditional nomenclature
Effect on amino acids
BIC entriesb
Affected patients (number)
Studyc/referenced
13
c.6952C[T
7180C[T
p.R2318X
5
4
B
14
c.7258G[T
7486G[T
p.E2420X
Novel
2
B
14
c.7375A[T
7603A[T
p.K2459X
Novel
1
A A, B, C/2, 3, 6, 7, 8, 9
15
c.7480C[T
7708C[T
p.R2494X
10
41
15
c.7538delC
7766delC
p.A2513EfsX11
Novel
1
B
15
c.7543insA
7771insA
p.T2515NfsX24
2
1
B
18
c.8002_8008dupAGAAGAT
8230_8236dupAGAAGAT
p.Ser2670X
Novel
1
B
18
c.8299_8300insAC
8527insAC
p.P2767HfsX11
Novel
1
A
18
c.8314G[T
8542G[T
p.E2772X
0
1
8
IVS20
c.8488-1G[A
IVS19-1G[A
Splicing defect
Novel
1
A
20
c.8537_8538delAG
8765_8766delAG
p.E2846GfsX22
75
1
8
IVS21
c.8633-2A[T
IVS20-2A[T
Splicing defect
Novel
2
B
21
c.8717_8718delAA
8945_8946delAA
p.E2906GfsX12
0
2
2
22
c.8827_8828insG
9055insG
p.Q2943RfsX7
Novel
1
A
22 22
c.8915delT c.8951C[G
9143delT 9179C[G
p.L2972CfsX4 p.S2984X
Novel 1
1 1
B 7
23
c.8991T[G
9219T[G
p.Y2997X
0
1
7
23
c.9076C[T
9304C[T
p.Q3026X
3
2
A
23
c.9117G[A
9345G[A
Splicing defect
14
4
A, B/8
23
c.9097dupA
9325dupA
p.T3033NfsX11
Novel
2
A
24
c.9253dupA
9481dupA
p.T3085NfsX26
19
4
A/7, 8
24
c.9253delA
9481delA
p.T3085QfsX19
Novel
1
C
25
c.9275_9276delAT
9503delAT
p.Y3092FfsX18
Novel
1
A
25
c.9431delC
9659delC
p.S3144LfsX19
Novel
1
A
25
c.9435_9436delGT
9663_9664delGT
p.S3147CfsX2
27
1
A
Novel mutations are in italics face a
According to HUGO-approved systematic nomenclature
b
BIC entries: 0, Korean specific
c
Study: A Labgenomics Clinical Research Institute, B Samsung Medical Center, C Seoul Medical Science Institute, D Soonchunhyang University Hospital
d
References: 1 Oh et al. [11], 2 Kang et al. [12], 3 Choi et al. [13], 4 Seo et al. [14], 5 Kim et al. [15], 6 Han et al. [16], 7 Ahn et al. [17], 8 Seong et al. [19], 9 Lim et al. [18], 10 Seong et al. [20], 11 Kim et al. [24]
Nonetheless, based on the fact that [10 % of young Korean breast cancer patients carried BRCA1/2 mutations, genetic testing for those patients could be proposed even if they have no family history. In considering that a large percentage of Korean breast cancers develop at young age, mutation screening can be helpful for guiding treatment or preventive strategies in the management of breast cancers in the Korean populations [36–39]. Based on the research by Haffty et al. [35] that compared the mutation
123
frequencies in early onset breast cancer patients among three different races, the mutation prevalence of Korean patients is thought to be identical to those of Caucasians or African-Americans. The frequencies of BRCA1/2 mutations in the two groups were in the range between 13.6 and 16.9 % [35]. Unlike the abovementioned studies, others reported lower likelihoods of BRCA1/2 mutations in the young breast cancers patients of various ethnic groups at 4.9–9.3 % (Table 5). Because the techniques of mutation
Breast Cancer Res Treat Table 5 Frequencies of BRCA1 and BRCA2 mutations among familial or early onset breast cancers according to race and ethnicity Population
No. of patients
Prevalence BRCA1 (%)
BRCA2 (%)
Total (%)
Methods
References
Nanda et al. [27]
Familial breast cancer USA Whites
78
30.8
15.4
46.2
DS
Ashkenazi Jews
29
41.4
27.6
69.0
DS
African-Americans Hispanic Americans Asian-Americans
46
16.3
11.6
27.9
DS
110
22.7
8.2
30.9
DS
Weitzel et al. [28].
95
16.8
7.4
24.2
DS
Vogel et al. [51]
200
11.5
13.0
24.5
DS
Kurian et al. [29] Li et al. [31]
Asia Chinese
241
7.1
5.8
12.9
SSCP, DHPLC
Japanese
113
13.3
18.6
31.9
SSCP
Ikeda et al. [33]
Pakistani
176
13.1
3.9
17.0
PTT, SSCP, DHPLC
Rashid et al. [34]
Korean
144 90
10.4 11.1
9.0 18.9
19.4 30.0
F-CSGE DS, MLPA
Ahn et al. [17] Seong et al. [19]
617
2.6
2.3
4.9
SSCP
Peto et al. [52].
91
25.3
7.7
33.0
Founder mutation
Robson et al. [6]
Early onset breast cancer Whites, UK Ashkenazi Jews, USA Whites, USA
203
5.9
3.4
9.3
SSCP
Malone et al. [53]
166
12.7
4.2
16.9
DS
Haffty et al. [35]
African-American
66
4.5
9.1
13.6
DS
Haffty et al. [35]
Germany
91
3.3
2.2
5.5
PTT, SSCP
Hamann et al. [54]
Swedish
234
6.8
2.1
8.9
PTT, SSCP, DHPLC
Loman et al. [55]
Asia Filipino
161
1.9
4.3
6.2
PTT, DGGE
De Leon Matsuda et al. [56]
Iranian
83
3.6
2.4
6.0
PTT, SSCP
Yassaee et al. [57].
Korean
60
10.0
8.3
18.3
DS
Choi et al. [13]
183
7.1
3.3
10.4
F-CSGE
Ahn et al. [17]
65
10.7
10.7
21.4
DS, MLPA
Seong et al. [19]
101
7.9
5.9
13.8
DS
Haffty et al. [35]
DS direct sequencing, SSCP single strand conformation polymorphism, PTT protein truncation test, DHPLC denaturing high performance liquid chromatography, F-CSGE fluorescence-conformation sensitive gel electrophoresis, MLPA multiple ligation-dependent probe amplification, DGGE denaturing gradient gel electrophoresis
detection used in these studies were less sensitive than complete sequencing [40], accurate comparison of the frequencies of mutations in Korean young breast cancer patients to those of other races except Caucasians or African-Americans could not be made. From the 14 Korean studies, 150 different BRCA1/2 mutations have been identified in 420 Korean BOC patients. Seventy-three types of BRCA1 mutations were found in 211 patients, and 77 distinct BRCA2 mutations were detected in 209 patients. Of these mutations, 84 mutations were not found in other ethnic groups, suggesting their Korean-specific origin. Notably, the mutation c.7480C[T (7708C[T) in BRCA2 gene was identified as Korean founder mutation through haplotype analysis by Seong et al. [19]. In accordance with the aforementioned
report, the c.7480C[T was the most frequently detected mutation in the pooled data of the current review, constituting 19.6 % (41 of 209) of BRCA2 mutations. In addition, the mutation 3746dupA accounted for 12.3 % (26 of 211) of BRCA1 mutations, suggesting that this genetic alteration also have potential to be a founder mutation of Korean breast cancer patients. However, further haplotype analyses are warrant to ascertain founder effects of the mutation c.3627dupA (3746dupA). Unlike Ashkenazi-Jews [41] or Icelanders [42], highly recurrent founder mutations were not detected in the Korean population. Nonetheless, 26 mutations comprising 24 in BRCA1 and 17 in BRCA2 were repeatedly found more than three times. These recurrent mutations accounted for 69.7 % (147 of 211) of BRCA1 mutations and 64.6 % (135 of 209) of BRCA2
123
Breast Cancer Res Treat
mutations, respectively. Based on this result, these 41 recurrent mutations might be applicable for pre-screening tests of BRCA1/2 mutations in Korean BOC patients in considering the cost-effectiveness of screening for mutations. One of the distinctive characteristics in genetic epidemiology of Korean breast cancer is the low prevalence of large genomic rearrangement (LGR) of BRCA1/2 genes [19, 20]. In the reports by Seong et al. [19], LGRs in BRCA1/2 genes were tested using multiplex ligation-dependent probe amplification (MLPA) in 206 high-risk or sporadic breast cancer patients [19], and in 122 high-risk breast cancer patients without BRCA1/2 mutations [20]. LGR in BRCA1/ 2 genes was not observed in the former report, and it was detected in one patient from the latter study, presenting 0.8 % of prevalence of these genetic alterations. In the pooled data of this investigation, BRCA1 c.41861593_4676-1465del was the only LGR found in Korean patients, and it was detected among two unrelated patients (Table 3, one in unpublished data of LabGenomics). Accordingly, LGR accounted 0.5 % (2 of 384) of all disease-causing BRCA1/2 mutations among Korean breast cancer patients. Because only small proportions of patients in the Korean studies had tests for LGR in BRCA1/2 genes, there is a possibility that the prevalence of this genetic alteration was underestimated. Nevertheless, LGRs have been observed infrequently in commercial testing populations even since screening for LGRs began as standard tests in genotyping for BRCA1/2 mutations among high-risk breast cancer patients. The prevalence of LGRs in high-risk breast cancer patients who tested negative for BRCA1/2 mutations among other ethnic groups is as such: 0 % in Ashkenazi-Jews [43, 44], 0.9 % in Malaysian [45], 1.8 % in Italian [46], 2.3 % in Danish [47], 2.7 % in Czech [48], and 8.0–12.0 % in non-Ashkenazi Jewish from United States [44, 49]. LGRs constituted 6.5–19.0 % of all pathogenic BRCA1/2 mutations in other populations [44–48]. The frequency of LGR in BRCA mutations-negative breast cancer among Korean women is thought to be lower than that of other ethnic groups. Furthermore, the proportion of LGR of BRCA1/2 mutations is considered rather insignificant in Korean patients in comparison to those in other populations. Therefore, contributions of BRCA1/2 genomic rearrangements to Korean breast cancer are thought to be minor. However, further research is necessary to ascertain the effect of BRCA genomic rearrangements on the development of breast cancer among the Korean population. Additionally, subtypes of patients who have a higher probability of harboring BRCA1/2 genomic rearrangements should be defined in the future research. Research on BRCA1/2 mutations in the Korean population has been performed by diverse institutions with different patient selection criteria heretofore. Accordingly,
123
mutation frequencies are inconsistent among the studies, resulting in difficulty in genetic counseling for Korean BOC patients. To provide accurate data on genetic mutations in BRCA1/2 for high-risk Korean women, a large cohort study has been called for. Recently, the Korean Breast Cancer Study Group (KBCSG) has initiated the Korean Hereditary Breast Cancer (KOHBRA) study on BRCA1/2 mutations in high-risk breast cancer patients [50]. Through this investigation, exact prevalence of BRCA1/2 mutations and natural history of BRCA1/2 carriers in the high-risk Korean patients are expected to be accomplished. Besides the KOHBRA study, this investigation provides pooled mutational data on BRCA1/2 genes in the Korean population.
Conclusions The prevalence of BRCA1/2 mutations in Korean patients with sporadic or early onset breast cancer was comparable with those of other ethnic groups. For Korean familial breast cancer patients, the likelihood of BRCA1/2 mutations was lower than Ashkenazi-Jews or non-Ashkenazi Jewish whites, whereas it was similar to that of other Asian, Asian-American, or African-American patients. The mutation c.7480C[T in BRCA2 gene is proven to be founder mutation, and the c.3627dupA in BRCA1 gene is a candidate for a founder mutation in the Korean population. In total, there were 26 BRCA1/2 mutations repeatedly detected more than three times, and these mutations amounted to more than half of the BRCA mutations of Korean patients. Of note, genomic rearrangements in BRCA1/2 genes were infrequently found among Koreans. To establish a prospective Korean cohort for BRCA1/2 mutations, a large population-based study is warranted. Acknowledgments This study was supported by a grant from the National R&D Program for Cancer Control funded by the Ministry for Health, Welfare and Family Affairs (#1020350), and a grant from the Industrial Strategic Technology Development Program funded by the Ministry of Knowledge Economy (#10038662), Republic of Korea. Conflict of interest of interest.
The authors declare that they have no conflict
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