Mutational analyses of BRCA1 and BRCA2 with Ashkenazi and non-Ashkenazi Jewish women with familial breast and ovarian cancer

In Ashkenazi (East European) Jews, three predominant mutations in BRCA1 (18 5delAG and 5382insC) and BRCA2 (6174-delT) account for the majority of germ line mutations in high risk breast and/or ovarian cancer families. Among no n-Ashkenazi Jews, the 185delAG, Tyr978Ter, and a handful of "private" mutat ions have been reported anecdotally within both genes. In this study we att empted to determine the spectrum of BRCA1 and BRCA2 mutations in high-risk Jewish individuals, non-carriers of any of the predominant Jewish mutations . We employed multiplex PCR and denaturing gradient gel electrophoresis (DG GE) analysis for BRCA2, and combined denaturing high performance liquid chr omatography (DHPLC) and protein truncation rest (PTT) for BRCA1, complement ed by DNA sequencing. We screened 47 high-risk Jewish individuals, 26 Ashke nazis, and 21 non-Ashkenazis. Overall, 13 sequence alterations in BRCA1 and eight in BRCA2 were detected: nine neutral polymorphisms and 12 missense m utations, including five novel ones. The novel missense mutations did not c o-segregate with disease in BRCA1 and were detected at rates of 6.25% to 52 .5% in the general population for BRCA2, Our findings suggest that except f or the predominant mutations in BRCA1 and BRCA2 in Jewish individuals, ther e are only a handful of pathogenic mutations within these genes. It may imp ly novel genes may underlie inherited susceptibility to breast/ovarian canc er in Jewish individuals. Hum Mutat 16:491-501, 2000. (C) 2000 Wiley-Liss, Inc.