BRCA mutation frequency and penetrance: new data, old debate.

EDITORIALS 1675 More than a decade after the discovery of the BRCA1 and BRCA2 genes, a consensus has yet to emerge regarding the frequency and precise magnitude and spectrum of cancer risks for individuals carrying mutations of these genes. Although these questions constitute a topic of heated debate among cancer epidemiologists ( 1 – 9 ) , they are also of clinical concern to women and men considering BRCA testing and the various options, including preventive surgeries, if such testing produces a positive fi nding ( 10 , 11 ) . The study by Risch et al. ( 12 ) not only helps to settle some of these issues but also adds interesting new data to an already extensive literature. Expanding their previous analysis (13) of 649 case patients to 1171 case patients with epithelial ovarian cancer and 8680 fi rstdegree relatives ascertained in Ontario for a 5-year period, Risch et al. analyzed DNA samples for BRCA mutations and documented self-reported family history information. When a subset of 977 case patients with invasive ovarian cancer was analyzed, BRCA mutations were found in 129 (13.2%). Among BRCA1 and BRCA2 mutation carriers, corresponding risks for breast cancer to age 80 years were 90% and 41% and corresponding risks for ovarian cancer 24% and 8.4%. For BRCA1 mutation carriers, increased risks were noted for gastric, hepatobiliary, renal, and testis cancers, as well as leukemia. For BRCA2 mutation carriers, increased risks of prostate and pancreas cancers were described. The estimated carrier frequency for combined BRCA1 and BRCA2 mutations was estimated as 1 in 100 in the Ontario population. For the most part, the fi ndings of this study that were derived from direct measurement confi rm previous studies, whereas other estimates derived from indirect measurements vary somewhat from the literature. For example, the estimate of the proportion of ovarian cancers attributable to BRCA mutations is fully consistent with previous estimates of approximately 10% (in contrast to the Ashkenazi subset of case patients with BRCA-linked ovarian cancer, in which BRCA Mutation Frequency and Penetrance: New Data, Old Debate