Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer

A population-based series of 649 unselected incident cases of ovarian cance r diagnosed in Ontario, Canada, during 1995-96 was screened for germline mu tations in BRCA1 and BRCA2. We specifically tested for 11 of the most commo nly reported mutations in the two genes. Then, cases were assessed with the protein-truncation test (PTT) for exon 11 of BRCA1, with denaturing gradie nt gel electrophoresis for the remainder of BRCA1, and with PTT for exons 1 0 and 11 of BRCA2. No mutations were found in all 134 women with tumors of borderline histology. Among the 515 women with invasive cancers, we identif ied 60 mutations, 39 in BRCA1 and 21 in BRCA2. The total mutation frequency among women with invasive cancers, 11.7% (95% confidence interval [95% CI] 9.2%-14.8%), is higher than previous estimates. Hereditary ovarian cancers diagnosed at age <50 years were mostly (83%) due to BRCA1, whereas the maj ority (60%) of those diagnosed at age >60 years were due to BRCA2. Mutation s were found in 19% of women reporting first-degree relatives with breast o r ovarian cancer and in 6.5% of women with no affected first-degree relativ es. Risks of ovarian, breast, and stomach cancers and leukemias/ lymphomas were increased nine-, five-, six- and threefold, respectively, among first- degree relatives of cases carrying BRCA1 mutations, compared with relatives of noncarriers, and risk of colorectal cancer was increased threefold for relatives of cases carrying BRCA2 mutations. For carriers of BRCA1 mutation s, the estimated penetrance by age 80 years was 36% for ovarian cancer and 68% for breast cancer. In breast-cancer risk for first-degree relatives, th ere was a strong trend according to mutation location along the coding sequ ence of BRCA1, with little evidence of increased risk for mutations in the 5' fifth, but 8.8-fold increased risk for mutations in the 3' fifth (95% CI 3.6-22.0), corresponding to a carrier penetrance of essentially 100%. Ovar ian, colorectal, stomach, pancreatic, and prostate cancer occurred among fi rst-degree relatives of carriers of BRCA2 mutations only when mutations wer e in the ovarian cancer-cluster region (OCCR) of exon 11, whereas an excess of breast cancer was seen when mutations were outside the OCCR. For cancer s of all sites combined, the estimated penetrance of BRCA2 mutations was gr eater for males than for females, 53% versus 38%. Past studies may have und erestimated the contribution of BRCA2 to ovarian cancer, because mutations in this gene cause predominantly late-onset cancer, and previous work has f ocused more on early-onset disease. If confirmed in future studies, the tre nd in breast-cancer penetrance, according to mutation location along the BR CA1 coding sequence, may have significant impact on treatment decisions for carriers of BRCA1-mutations. As well, BRCA2 mutations may prove to be a gr eater cause of cancer in male carriers than previously has been thought.