A population-based series of 649 unselected incident cases of ovarian cancer diagnosed in Ontario, Canada, during 1995-96 was screened for germline mutations in BRCA1 and BRCA2. We specifically tested for 11 of the most commonly reported mutations in the two genes. Then, cases were assessed with the protein-truncation test (PTT) for exon 11 of BRCA1, with denaturing gradient gel electrophoresis for the remainder of BRCA1, and with PTT for exons 10 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 identified 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 majority (60%) of those diagnosed at age >60 years were due to BRCA2. Mutations were found in 19% of women reporting first-degree relatives with breast or ovarian cancer and in 6.5% of women with no affected first-degree relatives. 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 mutations, 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, there was a strong trend according to mutation location along the coding sequence 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%. Ovarian, colorectal, stomach, pancreatic, and prostate cancer occurred among first-degree relatives of carriers of BRCA2 mutations only when mutations were 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 cancers of all sites combined, the estimated penetrance of BRCA2 mutations was greater for males than for females, 53% versus 38%. Past studies may have underestimated the contribution of BRCA2 to ovarian cancer, because mutations in this gene cause predominantly late-onset cancer, and previous work has focused more on early-onset disease. If confirmed in future studies, the trend in breast-cancer penetrance, according to mutation location along the BRCA1 coding sequence, may have significant impact on treatment decisions for carriers of BRCA1-mutations. As well, BRCA2 mutations may prove to be a greater cause of cancer in male carriers than previously has been thought.

BRCA1 and BRCA2 mutations may be more frequent in general populations than previously thought and may be associated with various types of cancers.

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Background Approximately 13% of ovarian cancers in Canada are attributable to a mutation in BRCA1 or BRCA2. In 2001, genetic testing for BRCA1 and BRCA2 became freely available to all women in Ontario with a diagnosis of invasive ovarian cancer. It is unknown what proportion of women with ovarian cancer receive genetic testing as a result of this recommendation. Methods Patients in Ontario who had been diagnosed with epithelial ovarian cancer from 2002 to 2004 were identified using the Ontario Cancer Registry. Information was collected on demographic and risk factors, including information on previous testing for BRCA1 and BRCA2. Women were asked to provide a blood sample for genetic testing or to provide a genetic test result if clinical testing had been done. Genetic testing for BRCA1 and BRCA2 mutations was conducted on all blood samples. Results Of the 416 women, 80 women (19%) had undergone previous clinical genetic testing for BRCA1 and BRCA2. Of these 80 women, 30% had a positive genetic test result, compared to 5% of 336 women who had not had clinical genetic testing (p <0.0001). Sixty percent of all mutations were identified within this group of 80 women. Conclusions Genetic testing is available in Ontario to all women with invasive ovarian cancer. However, only a small proportion of women are being referred for testing. This study suggests that increased public awareness directed at physicians and at women with cancer may expand the use of genetic testing.

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