Breast and ovarian cancer risk and risk reduction in Jewish BRCA1/2 mutation carriers.

PURPOSE Mutations in BRCA1/2 dramatically increase the risk of both breast and ovarian cancers. Three mutations in these genes (185delAG, 5382insC, and 6174delT) occur at high frequency in Ashkenazi Jews. We evaluated how these common Jewish mutations (CJMs) affect cancer risks and risk reduction. METHODS Our cohort comprised 4,649 women with disease-associated BRCA1/2 mutations from 22 centers in the Prevention and Observation of Surgical End Points Consortium. Of these women, 969 were self-identified Jewish women. Cox proportional hazards models were used to estimate breast and ovarian cancer risks, as well as risk reduction from risk-reducing salpingo-oophorectomy (RRSO), by CJM and self-identified Jewish status. RESULTS Ninety-one percent of Jewish BRCA1/2-positive women carried a CJM. Jewish women were significantly more likely to undergo RRSO than non-Jewish women (54% v 41%, respectively; odds ratio, 1.87; 95% CI, 1.44 to 2.42). Relative risks of cancer varied by CJM, with the relative risk of breast cancer being significantly lower in 6174delT mutation carriers than in non-CJM BRCA2 carriers (hazard ratio, 0.35; 95% CI, 0.18 to 0.69). No significant difference was seen in cancer risk reduction after RRSO among subgroups. CONCLUSION Consistent with previous results, risks for breast and ovarian cancer varied by CJM in BRCA1/2 carriers. In particular, 6174delT carriers had a lower risk of breast cancer. This finding requires additional confirmation in larger prospective and population-based cohort studies before being integrated into clinical care.

[1]  R. Portenoy,et al.  Medical oncologists' attitudes and practice in cancer pain management: a national survey. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  T. Golub,et al.  mRNA expression signature of Gleason grade predicts lethal prostate cancer. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  W. Willett,et al.  Late age at first full term birth is strongly associated with lobular breast cancer , 2011, Cancer.

[4]  C. Greenwood,et al.  On the origin and diffusion of BRCA1 c.5266dupC (5382insC) in European populations , 2011, European Journal of Human Genetics.

[5]  D. Bercovich,et al.  Two BRCA1/2 founder mutations in Jews of Sephardic origin , 2011, Familial Cancer.

[6]  M. Daly,et al.  Correction: Common Genetic Variants and Modification of Penetrance of BRCA2-Associated Breast Cancer , 2010, PLoS Genetics.

[7]  M. Daly,et al.  Common Genetic Variants and Modification of Penetrance of BRCA2-Associated Breast Cancer , 2010, PLoS genetics.

[8]  B. Bonanni,et al.  Oral contraceptive use and breast or ovarian cancer risk in BRCA1/2 carriers: a meta-analysis. , 2010, European journal of cancer.

[9]  A. Rademaker,et al.  Cost-effectiveness of population-based BRCA1/2 testing and ovarian cancer prevention for Ashkenazi Jews: A call for dialogue , 2009, Genetics in Medicine.

[10]  Susan M. Domchek,et al.  Meta-analysis of Risk Reduction Estimates Associated With Risk-Reducing Salpingo-oophorectomy in BRCA1 or BRCA2 Mutation Carriers , 2009, Journal of the National Cancer Institute.

[11]  K. Oberle,et al.  Ethical Issues Related To BRCA Gene Testing in Orthodox Jewish Women , 2008, Nursing ethics.

[12]  J. Chang-Claude,et al.  Oral contraceptives and breast cancer risk in the international BRCA1/2 carrier cohort study: a report from EMBRACE, GENEPSO, GEO-HEBON, and the IBCCS Collaborating Group. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  Julie O. Culver,et al.  Limited family structure and BRCA gene mutation status in single cases of breast cancer. , 2007, JAMA.

[14]  J. Berliner,et al.  Risk Assessment and Genetic Counseling for Hereditary Breast and Ovarian Cancer: Recommendations of the National Society of Genetic Counselors , 2007, Journal of Genetic Counseling.

[15]  Giovanni Parmigiani,et al.  Meta-analysis of BRCA1 and BRCA2 penetrance. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[16]  Douglas F. Easton,et al.  Age at Menarche and Menopause and Breast Cancer Risk in the International BRCA1/2 Carrier Cohort Study , 2007, Cancer Epidemiology Biomarkers & Prevention.

[17]  D. Easton,et al.  Parity and breast cancer risk among BRCA1 and BRCA2 mutation carriers , 2006, Breast Cancer Research.

[18]  O. Olopade,et al.  Mortality after bilateral salpingo-oophorectomy in BRCA1 and BRCA2 mutation carriers: a prospective cohort study. , 2006, The Lancet. Oncology.

[19]  M. Weinstein,et al.  Medicare and cost-effectiveness analysis. , 2005, The New England journal of medicine.

[20]  D. Easton,et al.  Breast and ovarian cancer risks to carriers of the BRCA1 5382insC and 185delAG and BRCA2 6174delT mutations: a combined analysis of 22 population based studies , 2005, Journal of Medical Genetics.

[21]  J. Hopper,et al.  Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. , 2003, American journal of human genetics.

[22]  K. Weaver.  Oral contraceptives and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. Narod SA, Dube MP, Klijn J, et al. J Natl Cancer Inst 2002; 94(23): 1773-1779. , 2003, Journal of Family Planning and Reproductive Health Care.

[23]  F. Couch,et al.  Oral contraceptives and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. , 2002, Journal of the National Cancer Institute.

[24]  J. Satagopan,et al.  Ovarian cancer risk in Ashkenazi Jewish carriers of BRCA1 and BRCA2 mutations. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[25]  C. Begg.  On the use of familial aggregation in population-based case probands for calculating penetrance. , 2002, Journal of the National Cancer Institute.

[26]  Susan L Neuhausen,et al.  Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. , 2002, The New England journal of medicine.

[27]  J. Klijn,et al.  Breast cancer after prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation. , 2001, The New England journal of medicine.

[28]  B. Modan,et al.  The Tyr978X BRCA1 Mutation in Non-Ashkenazi Jews: Occurrence in High-Risk Families, General Population and Unselected Ovarian Cancer Patients , 2001, Public Health Genomics.

[29]  B. Rosen,et al.  Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. , 2001, American journal of human genetics.

[30]  D. Easton,et al.  Variation in cancer risks, by mutation position, in BRCA2 mutation carriers. , 2001, American journal of human genetics.

[31]  D. Easton,et al.  Risk models for familial ovarian and breast cancer , 2000, Genetic epidemiology.

[32]  G. Giles,et al.  Population-based estimate of the average age-specific cumulative risk of breast cancer for a defined set of protein-truncating mutations in BRCA1 and BRCA2. Australian Breast Cancer Family Study. , 1999, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[33]  S Wacholder,et al.  The prevalence of common BRCA1 and BRCA2 mutations among Ashkenazi Jews. , 1999, American journal of human genetics.

[34]  J. Struewing,et al.  Population-based study of risk of breast cancer in carriers of BRCA2 mutation , 1998, The Lancet.

[35]  F. Rosner.  Judaism, genetic screening and genetic therapy. , 1998, The Mount Sinai journal of medicine, New York.

[36]  K. Offit,et al.  A family with three germline mutations in BRCAl and BRCA2 , 1998, Clinical genetics.

[37]  H. Gutman,et al.  The 8765delAG mutation in BRCA2 is common among Jews of Yemenite extraction. , 1998, American journal of human genetics.

[38]  M. King,et al.  Haplotype and phenotype analysis of nine recurrent BRCA2 mutations in 111 families: results of an international study. , 1998, American journal of human genetics.

[39]  J Chang-Claude,et al.  Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. , 1998, American journal of human genetics.

[40]  P. Hartge,et al.  The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. , 1997, The New England journal of medicine.

[41]  B. Weber,et al.  Founder BRCA1 and BRCA2 mutations in Ashkenazi Jews in Israel: frequency and differential penetrance in ovarian cancer and in breast-ovarian cancer families. , 1997, American journal of human genetics.

[42]  Alfred A. Boyd,et al.  Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2 , 1996, Nature Genetics.

[43]  Kenneth Offit,et al.  The carrier frequency of the BRCA2 6174delT mutation among Ashkenazi Jewish individuals is approximately 1% , 1996, Nature Genetics.

[44]  Kenneth Offit,et al.  Recurrent BRCA2 6174delT mutations in Ashkenazi Jewish women affected by breast cancer , 1996, Nature Genetics.

[45]  D. Clayton,et al.  Germline mutations of the BRCA1 gene in breast and ovarian cancer families provide evidence for a genotype–phenotype correlation , 1995, Nature Genetics.

[46]  M. Seller,et al.  Unusual case of Smith-Lemli-Opitz syndrome "type II". , 1995, American journal of medical genetics.

[47]  D. Easton,et al.  Risks of cancer in BRCA1-mutation carriers , 1994, The Lancet.

[48]  E. B. Wilson.  Probable Inference, the Law of Succession, and Statistical Inference , 1927 .

[49]  S. Miller,et al.  Association of Risk-Reducing Surgery in BRCA1 or BRCA2 Mutation Carriers With Cancer Risk and Mortality , 2012 .

[50]  A. Antoniou,et al.  Genetic modifiers of cancer risk for BRCA1 and BRCA2 mutation carriers. , 2011, Annals of oncology : official journal of the European Society for Medical Oncology.

[51]  M. Urioste,et al.  Parity and the risk of breast and ovarian cancer in BRCA1 and BRCA2 mutation carriers , 2009, Breast Cancer Research and Treatment.

[52]  W. Rubinstein.  Roles and responsibilities of a medical geneticist , 2007, Familial Cancer.

[53]  W. Rubinstein.  Hereditary breast cancer in Jews , 2004, Familial Cancer.

[54]  D. Horsman,et al.  Cancer variation associated with the position of the mutation in the BRCA2 gene , 2004, Familial Cancer.

[55]  Holly Neibergs,et al.  Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2 , 2004 .

[56]  S. Seal,et al.  Variation of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene , 1997, Nature Genetics.

[57]  M. King,et al.  Haplotype and phenotype analysis of six recurrent BRCA1 mutations in 61 families: results of an international study. , 1996, American journal of human genetics.

[58]  D. Easton,et al.  Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. , 1995, American journal of human genetics.

[59]  L. J. Wei,et al.  The Robust Inference for the Cox Proportional Hazards Model , 1989 .