ONLINE MUTATION REPORT Prevalence of BRCA2 mutations in a hospital based series of unselected breast cancer cases

E pidemiological data suggest that 7% of breast cancer cases and 10% of ovarian cancer cases in the general population are attributable to one or more autosomal dominant susceptibility alleles. The breast and ovarian cancer susceptibility genes BRCA1 and BRCA2 were isolated in 1994 and 1995, 4 respectively, and since then, a large volume of literature attests to the involvement of these genes in the great majority of ovarian cancers associated with dominant genetic predisposition, and a substantial, yet still poorly defined, proportion of such breast cancers. With respect to breast cancer, estimates of BRCA attributable risk are based largely on analyses of populations with founder mutations and those affected by early onset breast cancer, and to a lesser extent, on analyses of unselected population or hospital based series of breast cancer cases. The BRCA genes are very large and subject to a broad spectrum of mutations. 8 Thus, population based estimates of the role of BRCA genes in breast cancer are more readily accomplished through the study of populations affected by a limited number of founder mutations. For example, the BRCA1 185delAG and 5382insC mutations and the BRCA2 6174delT mutation are present in 2.5% of Ashkenazi Jews, and account for approximately 30% of the early onset breast cancers and 12% of all breast cancers in this population. In Iceland, the founder mutation BRCA2 999del5 is present in 0.5% of the population, and accounts for 24% of early onset breast cancers and 8% of all breast cancers. 14 The contribution of BRCA mutations to breast cancer in outbred populations is difficult to extrapolate from these types of estimates, however. Towards that end, other studies have examined populations of women selected only for early onset breast cancer, with or without a family history. Representative data from this literature indicate that breast cancers in women aged ,45 years are attributable to BRCA1 in 6–13% of cases and to BRCA2 in 4–5% of cases, suggesting that only 10–18% of early onset breast cancers are attributable to a BRCA mutation. The largest population based study of BRCA mutation in breast cancer contained 1435 cases diagnosed before the age of 55 years in the UK, and found BRCA mutations associated with 2% of cases; 0.7% with BRCA1 and 1.3% with BRCA2. In the only population based study of unselected breast cancer cases, BRCA1 mutations were found in 3/211 American patients (1.4%), and the BRCA2 mutation was not studied. Several hospital based series of unselected breast cancers implicate BRCA1 and BRCA2 in 2–5% and 0–2% of all cases, respectively, but these studies are limited by small sample sizes. Together, these data are consistent with the conclusion that 1–3% of all breast cancers in outbred populations are attributable to BRCA1. While it may be inferred from the population based studies of young women that the fraction of all breast cancers attributable to BRCA2 is smaller than for BRCA1, there are insufficient data to support this conclusion directly. The purpose of this study was to determine the prevalence of germline BRCA2 mutations in a relatively large, hospital based series of unselected breast cancer cases to estimate the fraction of all breast cancers attributable to BRCA2. We report here that this frequency appears to be ,0.5%.