Molecular Genetic Characterization of BRCA1- and 5/?CA2-Linked Hereditary Ovarian Cancers1

Hereditary ovarian cancers associated with germline mutations in ei ther BRCAl or BRCA2 were studied to determine whether somatic mu tation of the /'.I.I gene is required for BRCA-linked ovarian tumorigenesis and further, whether the spectrum of additional somatic molecular genetic alterations present in these tumors differs from that known to exist in sporadic ovarian cancers. Forty tumors, 29 linked to BRCAl and 11 linked to BRCA2, were examined for mutational alterations in P53, K-RAS, ERBB-2, C-MYC, and AKT2. The presence of a P53 mutation in 80% of these cancers indicates that P53 mutation is common but not required for BRCA -linked ovarian tumorigenesis; notably, a significantly higher pro portion of the P53 mutations in BRCA2-\inked cancers were deletions or insertions compared with the more typical spectrum of missense muta tions seen in BRCAl -linked cancers. Additionally, BRCA -linked ovarian carcinomas seem to develop through a unique pathway of tumorigenesis that does not involve mutation of K-RAS or amplification of ERBB-2, C-MYC, or AKT2.