A COMMON MUTATION IN BRCA2 THAT PREDISPOSES TO A VARIETY OF CANCERS IS FOUND IN BOTH JEWISH ASHKENAZI AND NON-JEWISH INDIVIDUALS

Recent studies have identified mutations in the breast and ovarian can cer susceptibility gene 2 (BRCA2), one which has been found in the ger mline of several males and one female affected with breast cancer. To establish the carrier frequency of this mutation in a large population of individuals affected with cancer, we evaluated constitutional DNA isolated from 83 individuals diagnosed with breast cancer and 93 diagn osed with ovarian cancer at any age, 42 of whom reported a family hist ory of cancer. Using a simple allele-specific PCR-based nonradioactive method, we detected a total of eight individuals (4.5%) carrying a 1- bp deletion at nucleotide 6174 of the BRCA2 gene (6174delT). The age o f disease onset in the mutant allele carriers was highly variable and typically late onset (41-72 years for breast cancer and 48-73 years fo r ovarian cancer). Evaluation of family histories for the eight mutant allele carriers revealed that several individuals had significant can cer histories that included, in addition to breast and/or ovarian canc er, an increased incidence of colon, esophageal, pancreatic, stomach, and hematopoietic cancers. Interestingly, seven of the eight individua ls were of Ashkenazi Jewish descent. Haplotype data for the mutant all ele carriers using markers spanning the region of the BRCA2 gene on ch romosome 13q12-q13 suggest that only two of the confirmed Jewish Ashke nazi individuals share a single common ancestry, indicating several in dependent origins for this mutation. These data provide evidence for t he presence of a specific BRCA2 mutation which has its origins in both Jewish Ashkenazi and non-Jewish populations. The observed overreprese ntation of specific mutations within a subgroup of the general populat ion may eventually help contribute to the development of inexpensive a nd routine tests such as the one described in our study.