BRCA1 and BRCA2 pathways and the risk of cancers other than breast or ovarian.

OBJECTIVE Germline mutations in the tumor suppressor genes BRCA1 and BRCA2 predispose women to breast and ovarian cancer. Female carriers of BRCA1 or BRCA2 gene mutations have very high lifetime risks for breast and ovarian cancers. Genetic abnormalities occur in all cancers, so BRCA-related pathways are critical because they serve to safeguard genetic content. Although protecting genetic information is a general function, BRCA-related pathways seem largely specific to preventing breast and ovarian cancer. The objective of this study was to resolve this difference between the theoretical functions of BRCA genes and their specific clinical effects. DATA SOURCES, DATA EXTRACTION, DATA SYNTHESIS The author collected data published in > 30 epidemiologic studies on the incidence of cancers other than breast or ovarian in mutation carriers and in large populations eligible for mutation testing. Data were extracted and used directly as published whenever possible with a minimum of statistical manipulation. CONCLUSIONS Although mutations target breast and ovary, a broader spectrum of cancers also occur with statistically significant elevated frequencies. Risks for "all cancers except breast or ovary" are elevated, with some population subgroups differing with regard to how frequently elevated risks were found at individual sites. Additional sites at risk included stomach, pancreas, prostate, and colon. The increased risk ranged from about 20% to 60%, with the greatest increases in risk in stomach and pancreas. The collected data show BRCA-pathway functions are probably required at multiple sites, not just in breast or ovary. Known interactions and relationships among BRCA-related pathways strongly support the idea that their inactivation provides growth or survival advantages for a variety of cancers. The data suggest applying an increased level of clinical alertness to those with defects in BRCA-related pathways. Identifying molecules that confer growth or survival advantages to BRCA-related cancers may provide broadly useful targets for chemotherapy or chemoprevention.

[1]  Lesley McGuffog,et al.  Cancer risks and mortality in heterozygous ATM mutation carriers. , 2005, Journal of the National Cancer Institute.

[2]  A. Schatzkin,et al.  Colonoscopic screening of average-risk women for colorectal neoplasia. , 2005, The New England journal of medicine.

[3]  M. Yaffe.  Faculty Opinions recommendation of ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex. , 2005 .

[4]  K. Hemminki,et al.  Risk of cancer at sites other than the breast in Swedish families eligible for BRCA1 or BRCA2 mutation testing. , 2004, Annals of oncology : official journal of the European Society for Medical Oncology.

[5]  K. Offit,et al.  BRCA Mutations and Risk of Prostate Cancer in Ashkenazi Jews , 2004, Clinical Cancer Research.

[6]  W. Foulkes,et al.  Germline truncating mutations in both MSH2 and BRCA2 in a single kindred , 2004, British Journal of Cancer.

[7]  Ronit Almog,et al.  BRCA1 and BRCA2 founder mutations and the risk of colorectal cancer. , 2004, Journal of the National Cancer Institute.

[8]  J. Satagopan,et al.  Frequency of BRCA1 and BRCA2 mutations in unselected Ashkenazi Jewish patients with colorectal cancer. , 2004, Journal of the National Cancer Institute.

[9]  M. Federico,et al.  Different Expressivity of BRCA1 and BRCA2: Analysis of 179 Italian Pedigrees with Identified Mutation , 2003, Breast Cancer Research and Treatment.

[10]  Luke Hughes-Davies,et al.  EMSY Links the BRCA2 Pathway to Sporadic Breast and Ovarian Cancer , 2003, Cell.

[11]  D. Haber.  The BRCA2-EMSY Connection Implications for Breast and Ovarian Tumorigenesis , 2003, Cell.

[12]  A. Ziegler,et al.  BRCA2 germline mutations in familial pancreatic carcinoma. , 2003, Journal of the National Cancer Institute.

[13]  B. Ponder,et al.  Two percent of men with early-onset prostate cancer harbor germline mutations in the BRCA2 gene. , 2003, American journal of human genetics.

[14]  R. DePinho,et al.  Pancreatic cancer biology and genetics , 2002, Nature Reviews Cancer.

[15]  J. Aitken,et al.  BRCA2 mutations in a population‐based series of patients with ocular melanoma , 2002, International journal of cancer.

[16]  Douglas F Easton,et al.  Cancer Incidence in BRCA1 mutation carriers. , 2002, Journal of the National Cancer Institute.

[17]  T. Rebbeck,et al.  Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program. , 2002, Journal of the National Cancer Institute.

[18]  Kathleen M Murphy,et al.  Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: deleterious BRCA2 mutations in 17%. , 2002, Cancer research.

[19]  Hans Joenje,et al.  Biallelic Inactivation of BRCA2 in Fanconi Anemia , 2002, Science.

[20]  D. Goldgar,et al.  Prevalence of the BRCA2 6174 del T mutation in Israeli uveal melanoma patients , 2002, International journal of cancer.

[21]  C. Lewis,et al.  Incidence of multiple primary cancers in a cohort of women diagnosed with breast cancer in southeast England , 2001, British Journal of Cancer.

[22]  E. Friedman,et al.  The frequency of the predominant Jewish mutations in BRCA1 and BRCA2 in unselected Ashkenazi colorectal cancer patients , 2001, British Journal of Cancer.

[23]  S. Seal,et al.  BRCA1 and BRCA2 mutations in breast cancer families with multiple primary cancers. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[24]  E. Friedman,et al.  The rate of the founder Jewish mutations in BRCA1 and BRCA2 in prostate cancer patients in Israel , 2000, British Journal of Cancer.

[25]  D. Fishman,et al.  BRCA1 and BRCA2 mutation analysis of 208 Ashkenazi Jewish women with ovarian cancer. , 2000, American journal of human genetics.

[26]  S. Gallinger,et al.  Inherited predisposition to pancreatic adenocarcinoma: role of family history and germ-line p16, BRCA1, and BRCA2 mutations. , 2000, Cancer research.

[27]  L. Drucker,et al.  Incidence of BRCA1 and BRCA2 mutations in Ashkenazi colorectal cancer patients: preliminary study. , 2000, Anticancer research.

[28]  O. Manor,et al.  The Jewish Ashkenazi founder mutations in the BRCA1/BRCA2 genes are not found at an increased frequency in Ashkenazi patients with prostate cancer. , 1999, American journal of human genetics.

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

[30]  S. Semba,et al.  Frequent microsatellite instability and loss of heterozygosity in the region including BRCA1 (17q21) in young patients with gastric cancer. , 1998, International journal of oncology.

[31]  J. Eyfjörd,et al.  BRCA2 mutation in Icelandic prostate cancer patients , 1997, Journal of Molecular Medicine.

[32]  D E Goldgar,et al.  Cancer risks in two large breast cancer families linked to BRCA2 on chromosome 13q12-13. , 1997, American journal of human genetics.

[33]  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.

[34]  M H Skolnick,et al.  Systematic population-based assessment of cancer risk in first-degree relatives of cancer probands. , 1994, Journal of the National Cancer Institute.

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

[36]  L. Brinton,et al.  Second cancer following cancer of the breast in Connecticut, 1935-82. , 1985, National Cancer Institute monograph.