Mutational analyses of BRCA1 and BRCA2 in Ashkenazi and non-Ashkenazi Jewish women with familial breast and ovarian cancer. R. Shiri-Sverdlov¹, P. Oefner³, R. Gershoni-Baruch², L. Green¹, RMW. Hofstra⁵, T. Wagner⁴, E. Friedman¹. 1) Oncogenetics Unit, Sheba Medical Center, Tel-Hashomer, Israel; 2) The Genetics Institute, Rambam Medical Center, Haifa; 3) The Department of Genetics, Stanford DNA sequencing and technology Center, Palo Alto CA; 4) Department of Obstetrics and Gynecology, Division of Senology, University of Vienna, Vienna, Austria; 5) The Department of Medical Genetics, Groningen, Netherlands.
   ABSTRACT In Ashkenazi (East European) Jews, three predominant mutations in BRCA1 (185delAG and 5382insC) and BRCA2 (6174delT) account for the majority of germline mutations in high risk breast and/or ovarian cancer families. Among non-Ashkenazi Jews, the 185delAG, Tyr978X, and a handful of "private" mutations have anecdotally been reported within both genes. In this study we attempted 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 analysis for BRCA2, and combined denaturing high pressure liquid chromatography and protein truncation test (PTT) for BRCA1, complemented by DNA sequencing. We screened 47 high risk Jewish individuals, 26 Ashkenazis and 21 non-Ashkenazis. Overall, 13 sequence alterations in BRCA1 and 8 in BRCA2 were detected: 9 neutral polymorphisms and 12 missense mutations, including 5 novel ones. The novel missense mutations did not cosegraegate 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 for the predominant mutations in BRCA1 and BRCA2 in Jewish individuals, there are only a handful of pathogenic mutations within these genes. It may imply novel genes may underlie inherited susceptibility to breast/ovarian cancer in Jewish individuals.