Update on breast cancer susceptibility genes.

BRCA1 and BRCA2 have now been isolated and a large number of families characterized for the presence of mutations in these breast cancer susceptibility genes. Data from these studies are beginning to provide us with answers to many important questions. It is clear that estimates of attributable risk and penetrance are dependent on the population being studied. For example, studies of large, extensively affected families suggest that 45% of inherited breast cancer is due to BRCA1 mutations, while similar studies in individuals ascertained from breast cancer risk evaluation clinics suggest that the attributable risk is only 15%-20%. Similarly the large families yield penetrance estimates of 87% by age 85, while a more population-based study suggests somewhat lower rates--60% by age 70. In addition, studies of BRCA1-related tumors suggest that there may be some important molecular differences as compared to sporadic tumors, with a predominance of high grade lesions that are ER negative and an increased rate of p53 mutations. Controversy remains about the potential for genotype/phenotype correlation, and previous anecdotal reports of improved survival in families with familial breast cancer have yet to be fully evaluated. Finally, clinical recommendations are being formulated, with current recommendations centered on screening for breast cancer risk and prophylactic oophorectomy for presumed reduction of ovarian cancer risk.