BRCA 1 and 2--A Genetic Link to Familial Breast and Ovarian Cancer

Female carriers of germline BRCA1 mutations have a lifetime risk of breast cancer exceeding 80% and of ovarian cancer approaching 60%. The cumulative lifetime risk of developing either breast or ovarian cancer, therefore, approaches 100%. Carriers of BRCA2 mutants have a similar risk of breast cancer and a more moderately increased risk of ovarian cancer. BRCA1 and BRCA2, located on the long arms of chromosomes 17 and 13, respectively, are thought to be tumor suppressor genes, inhibiting tumor development when functioning normally. Both are large genes, distributed over approximately 100,000 base pairs of genomic DNA, encoding large negatively charged proteins. Inactivating mutations identified to date are distributed throughout both genes, with an increased frequency of two distinct BRCA1 mutations and one BRCA2 mutation in individuals of Ashkenazi Jewish descent. Given the high lifetime penetrance of germline BRCA1 and BRCA2 mutations and the early age of onset in many carriers, it may seem prudent to carry out regular mammography on carriers from a young age. The benefits or risks of such screening, however, have yet to be demonstrated. Preventative measures, including prophylactic mastectomy, oophorectomy, and chemoprevention, still require assessment within research protocols.