Prevalence and penetrance of BRCA1 and BRCA2 gene mutations in unselected Ashkenazi Jewish women with breast cancer

Background: Approximately 2.0%-2.5% of Ashkenazi Jewish women carry one of three founding mutations in the BRCA1 and BRCA2 genes, and each mutation is associated with a high lifetime risk of invasive breast cancer. We investi gated the extent to which these three mutations contribute to breast cancer incidence in the Ashkenazi Jewish population. Methods: We ascertained 457 Jewish women with prevalent cases of breast cancer who were unselected for age or family history of the disease; 412 of these women were tested for th e three founder mutations (case patients). Control subjects consisted of 36 0 non-Jewish women with breast cancer (control patients) and 380 healthy Je wish women with no history of cancer (control subjects). Results: Mutations were found in 48 (11.7%) of 412 Jewish case patients. Forty-six of 48 muta tions occurred in women with early-onset breast cancer (<50 years) or a his tory of ovarian or early-onset breast cancer in a first-, second-, or third -degree relative. The estimated penetrance to age 70 years for breast cance r was 59.9% for the BRCA1 gene mutations and 28.3% for the BRCA2 gene mutat ion. Compared with Jewish control subjects, the relative risk (RR) of breas t cancer for first-degree relatives of mutation carriers was 5.16 (95% conf idence interval [CI] = 3.14-8.48), but risk was also increased for relative s of noncarriers (RR = 1.66; 95% CI = 1.18-2.33). The RR of prostate cancer for first-degree relatives of Jewish case patients was 3.36 (95% CI = 1.49 -7.56). Conclusions: Approximately 12% of breast cancers in the Ashkenazi J ewish population are attributable to mutations in the BRCA1 or BRCA2 gene. Genetic testing may be useful when Jewish women with breast cancer are diag nosed before age 50 years or have a close relative with ovarian or early-on set breast cancer. An association between breast and prostate cancers was o bserved in our study population.