Breast cancer susceptibility genes. BRCA1 and BRCA2.

Mutations in the BRCA1 and BRCA2 genes lead to an increased susceptibility to breast, ovarian, and other cancers. It is estimated that 3%-8% of all women with breast cancer will be found to carry a mutation in 1 of these genes. Families with multiple affected first-degree relatives and patients with early-onset disease have been found to harbor mutations at a higher frequency. The BRCA1 and BRCA2 genes code for large proteins that bear no resemblance to other known genes. In the cell, they appear to act as tumor suppressor genes and play a role in the maintenance of genome integrity, although the precise function of these genes has yet to be discovered. A large number of distinct mutations have been found in cancer families around the world. The majority of the defined pathologic mutations result in premature truncation of the protein (frameshift and nonsense mutations). These mutations may substantially increase the risk for breast and ovarian cancer, but a precise risk estimate for each different mutation cannot be determined. Depending on the familial context, the risk of breast cancer associated with carrying a mutation has been estimated to range from 50% to 85%. The role of these genes in sporadic cancer remains unknown. Patients and physicians considering BRCA1 and BRCA2 genetic testing are faced with a difficult decision. The diversity of mutations and lack of general population data prevent accurate risk prediction. This is further complicated by the paucity of data on effective prevention strategies for those identified at higher risk. Thus, the nature of clinical testing for BRCA1 and BRCA2 continues to present challenges that reinforce the necessity of personal choice within the context of thorough genetic counseling.