Familial clustering of site-specific cancer risks associated with BRCA1 and BRCA2 mutations in the Ashkenazi Jewish population

Abstract

Inherited mutations in BRCA1 and BRCA2 lead to significantly increased risks of breast and ovarian cancer. We used epidemiologic methods to evaluate the relative risks of breast cancer vs. ovarian cancer among women of Ashkenazi Jewish ancestry with inherited mutations in BRCA1 or BRCA2. The cancer of a family's index case (i.e., breast cancer vs. ovarian cancer) was significantly associated with site-specific risks of cancer in relatives known to carry mutations in BRCA1 or BRCA2. Specifically, breast cancer risks were higher among relatives of breast cancer index cases compared with relatives of ovarian cancer index cases [hazard ratio (HR) = 3.0, P < 0.001 for BRCA1 carriers and HR = 4.8, P = 0.017 for BRCA2 carriers], and ovarian cancer risks were higher among relatives of ovarian cancer index cases compared with relatives of breast cancer index cases (HR = 7.2, P = 0.001 for BRCA1 carriers and HR = 15.8, P = 0.018 for BRCA2 carriers). Breast and ovarian cancer risks also increased with more recent year of birth. For each later decade of birth, risk increased 1.2-fold (P = 0.03). Effects of cancer site of the index case and of birth cohort were independent. These results suggest that both genetic and nongenetic factors modify cancer risks among BRCA1 and BRCA2 mutation carriers, and that genetic modifiers and other familial factors may influence risk specifically for either breast or ovarian cancer.

Fig. 1.

Cumulative risks of breast cancer, ovarian cancer, and cancer of either site for relatives with BRCA1 or BRCA2 mutations, based on cancer site in the index case. (A) Women with BRCA1 mutations, ascertained through index cases with breast cancer. (B) Women with BRCA1 mutations, ascertained through index cases with ovarian cancer. (C) Women with BRCA2 mutations, ascertained through index cases with breast cancer. (D) Women with BRCA2 mutations, ascertained through index cases with ovarian cancer. SEs are shown for risk estimates at each age. For women with mutations in either BRCA1 or BRCA2, risks of breast cancer are higher for relatives of index cases with breast cancer, whereas risks of ovarian cancer are higher for relatives of index cases with ovarian cancer. Ascertainment of families is from consecutive series of cases in Israel and the U.S (4) and from genetics clinics in Israel, so absolute risks may not represent those for families with the same mutations in the general population.