MUTATION ANALYSIS OF THE BRCA1 GENE IN OVARIAN CANCERS

Germline mutations of the BRCA1 tumor suppressor gene on chromosome 17 q are involved in a significant fraction of hereditary breast and ovar ian cancers. Allelic deletions that include the BRCA1 locus are common in breast and ovarian cancers, implying that somatic mutations of thi s gene may play an important role in the more common sporadic forms of these tumors as well. The recent cloning of BRCA1 allows direct testi ng of this hypothesis. A combination of single strand conformation and sequencing analyses was used to examine the 22 coding exons and intro nic splice donor and acceptor regions of BRCA1 for mutations in 115 un selected Eases of epithelial ovarian carcinoma. Seven mutations were i dentified, all of which were present in the germlines of patients with remarkable family or medical histories of breast and/or ovarian cance r, Eighty-nine of these tumors were examined for loss of heterozygosit y in the BRCA1 region of chromosome 17q, and 67% of the tumors studied exhibited allelic deletions that included this region. These data are consistent with the hypothesis that BRCA1 mutations are involved in t he etiology of hereditary ovarian carcinomas but occur rarely in spora dic tumors, and that the frequent allelic loss on chromosome 17q in th is cancer type reflects the involvement of an additional tumor suppres sor gene(s).