Identification and evaluation of 55 genetic variations in the BRCA1 and the BRCA2 genes of patients from 50 Japanese breast cancer families

Kawahara, Manabu; Sakayori, Masato; Shiraishi, Kazuko; Nomizu, Tadashi; Takeda, Motohiro; Abe, Rikiya; Ohuchi, Noriaki; Takenoshita, Seiichi; Ishioka, Chikashi

doi:10.1007/s10038-004-0160-5

Cited by 15 publications

(15 citation statements)

References 17 publications

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“…(9)(10)(11) As for genetic variants of uncertain significance, two mutational types (G2044V [c.6131G > T] and V2109I [c.6325G > A]) were reported in Japanese, and G2044V was found in at least one of 28 Japanese healthy volunteers. (12) M524I (c.1572G > C), K610Q (c.1828 A > C), I770V (c.2308 A > G), and S2616F (c.7847C > T) were previously unreported mutational types.…”

Section: Discussionmentioning

confidence: 98%

“…(7)(8)(9)(10)(11)(12) The methods of genetic analysis employed in these studies varied, such as polymerase chain reaction (PCR)/ single strand conformational polymorphisms (SSCP), protein truncation test, and PCR/direct sequencing, but they were performed as preliminary in-house tests in the research setting. In the US, commercial BRCA1/2 gene testing was initiated by Myriad Genetic Laboratories in 1996.…”

Section: -664) (Cancer Sci 2008; 99: 1967-1976)mentioning

confidence: 99%

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Cross‐sectional analysis of germline BRCA1 and BRCA2 mutations in Japanese patients suspected to have hereditary breast/ovarian cancer

Sugano

Nakamura

Ando³

et al. 2008

Cancer Science

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The prevalence of BRCA1/2 germline mutations in Japanese patients suspected to have hereditary breast/ovarian cancer was examined by a multi-institutional study, aiming at the clinical application of total sequencing analysis and validation of assay sensitivity in Japanese people using a cross-sectional approach based on genetic factors estimated from personal and family histories. One hundred and thirty-five subjects were referred to the genetic counseling clinics and enrolled in the study. Full sequencing analysis of the BRCA1/2 gene showed 28 types of deleterious mutations in 36 subjects (26.7%), including 13 types of BRCA1 mutations in 17 subjects (12.6%) and 15 types of BRCA2 mutations in 19 subjects (14.1%). Subjects were classified into five groups and 22 subgroups according to their personal and family history of breast and/or ovarian cancer, and the prevalence of deleterious mutations was compared with previously reported data in non-Ashkenazi individuals. Statistical analysis using the Mantel-Haenszel test for groups I through IV revealed that the prevalence of Japanese subjects was significantly higher than that of non-Ashkenazi individuals (P = 0.005, odds ratio 1.87, 95% confidence interval 1.22-2.88). Family history of the probands suffering from breast cancer indicated risk factors for the presence of deleterious mutations of BRCA1/2 as follows: (1) I n Japan, breast cancer is the most frequent malignancy in women and estimates of new cases and deaths in 2002 were 32 245 and 9178, respectively.(1) The standardized incidence ratio of breast cancer in Japan was approximately one-third that of the US (32.7 vs 101.7 per 100 000 women).(1) The incidence of breast cancer in Japanese women shows a steady increase; however, it is still much lower than in Western countries. In breast cancer, family history is the strongest risk factor for cancer predisposition. Epidemiological studies showed that 12% of women with breast cancer have one affected family member and 1% have two or more affected relatives.(2) Women with one, two, and three or more first-degree affected relatives have an increased breast cancer risk when compared with women who do not have an affected relative (risk ratios 1.8, 2.9, and 3.9, respectively).(2) Recent advances in molecular genetics elucidated BRCA1 and BRCA2 (BRCA1/2) as two major susceptibility genes for breast cancer predisposition.(3,4) Gene testing of BRCA1/2 is available as a routine clinical test for diagnosing hereditary breast/ovarian cancer (HBOC) in the US and other Western countries, (5,6) while only a few reports have been published concerning the prevalence of BRCA1/2 mutations among Japanese people. (7)(8)(9)(10)(11)(12) The methods of genetic analysis employed in these studies varied, such as polymerase chain reaction (PCR)/ single strand conformational polymorphisms (SSCP), protein truncation test, and PCR/direct sequencing, but they were performed as preliminary in-house tests in the research setting. In the US, commercial BRCA1/2 gene testing was initiated by M...

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Section: Discussionmentioning

confidence: 98%

Section: -664) (Cancer Sci 2008; 99: 1967-1976)mentioning

confidence: 99%

Cross‐sectional analysis of germline BRCA1 and BRCA2 mutations in Japanese patients suspected to have hereditary breast/ovarian cancer

Sugano

Nakamura

Ando³

et al. 2008

Cancer Science

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“…Of these, 14 are deleterious, 18 are unidentified, and 12 are not clinically important. Eight variants have not previously been reported in the BIC database, although one, BRCA2 IVS4 + 67A [ G, has been published in a Japanese HBOC study [10]. Of the remaining variants, Q284X is a nonsense mutation, P58A, P62L and M1083L are point mutations, while IVS17 + 23A [ G, IVS7-27C [ G and IVS16-43del5 are intronic.…”

Section: Resultsmentioning

confidence: 97%

Results of a population-based screening for hereditary breast cancer in a region of North-Central Italy: contribution of BRCA1/2 germ-line mutations

Seymour

Casadei

Zampiga

et al. 2007

Breast Cancer Res Treat

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BRCA1/2 mutation status is of paramount importance to identify families at risk of Hereditary Breast and Ovarian Cancer (HBOC). Most HBOC and BRCA1/2 mutation studies have focused on highly selected sub-populations, and few data are available for large population cohorts. For this reason, as part of a regional cancer prevention strategy in North-Central Italy, we set up a population-based screening programme to identify all resident HBOC families, and to determine their BRCA1/2 mutation status. To date, 44 different BRCA1/2 variants have been identified in 55 HBOC families. Of the seven newly reported mutations, only BRCA1 Q284X is clearly deleterious. The analysis of clinical disease characteristics in relation to age of disease onset and family history showed a difference between BRCA1/2 wild type and mutation carrier families. Interestingly, BRCA1/2 mutations were significantly more common in women who developed breast cancer

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“…Although the function of BRCA2 is not hensive framework in an effort to belier distinguish between fully defined at the biochemical level, there is strong support for a disease predisposing and neutral UCVs. This combined role in DNA damage repair and in maintenance of genomic integrity approach represents a useful means of addressing the (12). Specifically, BRCA2 binds to the Rad5l DNA recombination functional siguificance and cancer relevance of UCVs in enzyme and regulates formation of the rad5l nucleoprotein filament fuctional (Ca nificances 205 65(2) r re1e othat is required for homologous recombination repair of DNA damage (13,14).…”

Section: Introductionmentioning

confidence: 99%

“…The pathogenicity of only a small number of these variants has been inferred genetically [12][13][14][15][16] or tested functionally [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35]. Underscoring the interest in and need for accurate classification of sequence variants in BRCA1 are recent descriptions of novel approaches to predict the pathogenicity of non-synonymous amino acid substitutions.…”

Section: Introductionmentioning

confidence: 99%

Characterization of BRCA2 Mutation in a Series of Functional Assays

Couch¹

2005

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Public reporting burden for this collection of information is estimated to average I hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE (DD-MM-YYYY)2. REPORT TYPE 3. DATES COVERED (From -To) 5f. WORK UNIT NUMBER PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBERMayo Clinic Rochester Rochester, MN 55905 SPONSORING I MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S)U BodyAim #1: To assess the role of BRCA2 in cell growth.We proposed to establish Capan-1 BRCA2 mutant cells that stably express wildtype BRCA2. However, using multiple different transfection techniques we were unable to achieve greater than 0.01% transfection efficiency, which is insufficient for the outlined experiments. To overcome this problem we proposed to overexpress BRCA2 in MCF7 breast cancer cells because the cells were readily transfected and because overexpression of mutant forms could competitively inhibit wildtype BRCA2 function. We focused our efforts on the use of MCF7 cells stably expressing wtBRCA2, vector alone, and 6174deIT-BRCA2. Expression was confirmed by western blot (Task 1). We also tried to generate MCF7 Tet-On and MCF7 Tet-Off inducible BRCA2 cell lines to no avail (Task 2 and 6). The stably expressing MCF7 cells were subsequently assessed for alterations in growth rate (MTT assays), anchorage independence (soft agar assays), colony formation, and cell cycle (FACS) (Task 3). In MTT assays two independent wtBRCA2 expressing cell lines grew significantly slower than vector transfected cells, while cells expressing mutant BRCA2 grew the most rapidly. In soft agar and colony formation assays more colonies formed from mutant or vector expressing cells. Cell cycle analysis revealed no change in the cell cycle over time. Overall, the data suggested that BRCA2 regulates cell growth and transformation in a cell cycle independent manner.A total of 8 BRCA2 mutant constructs containing 7 missense mutations and 1 truncating mutation (K3326X) in different domains of BRCA2 were generated. The Y42C mutation is located in a putative transactivation domain, while E462G, P655R, 4812C>T, and K1690N are all located in the BRC repeat region that has been associated with DNA repair activity, and the D2723...

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Identification and evaluation of 55 genetic variations in the BRCA1 and the BRCA2 genes of patients from 50 Japanese breast cancer families

Cited by 15 publications

References 17 publications

Cross‐sectional analysis of germline BRCA1 and BRCA2 mutations in Japanese patients suspected to have hereditary breast/ovarian cancer

Cross‐sectional analysis of germline BRCA1 and BRCA2 mutations in Japanese patients suspected to have hereditary breast/ovarian cancer

Results of a population-based screening for hereditary breast cancer in a region of North-Central Italy: contribution of BRCA1/2 germ-line mutations

Characterization of BRCA2 Mutation in a Series of Functional Assays

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