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

, , , Duke University Medical Center

In This Article

Abstract and Introduction


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.


The impact of breast and ovarian cancer on Western society is enormous. Breast cancer affects approximately 180,000 women annually in the United States, resulting in 46,000 deaths.[1] Ovarian cancer kills more women than any other gynecologic malignancy, with 23,000 cases diagnosed annually. Many factors, including age and reproductive history, influence a woman's risk of developing breast or ovarian cancer; however, family history is the most significant risk factor for both types of malignancy. It is suggestive in 5% to 10% of cases of the inheritance of a dominant susceptibility gene. Familial breast cancer syndromes include site-specific breast cancer syndrome, breast/ovarian cancer syndrome, and Li-Fraumeni syndrome.[2,3] Familial ovarian cancer syndromes include site-specific ovarian cancer syndrome, breast/ovarian cancer syndrome, and hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch II syndrome.[4,5] In addition, nonepithelial ovarian tumors have been associated with basal cell nevus and Peutz-Jeghers syndromes.[6,7] Recently, 2 of the genes responsible for familial breast and ovarian cancers, BRCA1 and BRCA2, have been identified.[8,9]


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