title: Mutation analysis of BRCA1, TP53, and KRAS2 in ovarian and related pelvic tumors.
abstract: Cancer may be viewed as a genetic disease resulting from critical mutations that disrupt normal cell growth. To characterize the involvement of the BRCA1 and TP53 tumor suppressor genes and of the KRAS2 protooncogene in gynecologic cancer, mutation analysis of these genes was conducted in pelvic tumors of 85 patients that included 49 epithelial ovarian carcinoma cases. The 85 pelvic tumors contained 5 tumors with BRCA1 mutations, 33 with TP53 mutations, and 1 with a KRAS2 mutation. Each of the BRCA1 and KRAS2 mutations, and 25 of the TP53 mutations, were in ovarian carcinomas. Four of the BRCA1 mutations were germline and 1 was somatic. The 4 patients with germline BRCA1 mutations had an early age of disease onset (33-48 years) relative to the mean age of onset (58 years) of all 49 ovarian carcinoma patients, and 3 of these 4 patients had a family history of ovarian or breast cancer. None of the 4 tumors with germline BRCA1 mutations had a KRAS2 mutation or a TP53 mutation, despite a 51% frequency of TP53 mutations in the 49 ovarian carcinomas. Three of the 4 tumors with germline BRCA1 mutations retained a wild-type BRCA1 allele. The tumor with the somatic BRCA1 mutation contained a TP53 mutation and had no evidence for wild-type BRCA1 and TP53 alleles. These data suggest that both BRCA1 and TP53 were inactivated in 1 of 49 ovarian carcinomas. Moreover, mutational inactivation of both BRCA1 and TP53 did not occur in 4 tumors with a germline BRCA1 mutation. It has been proposed that tumorigenesis in cells with a heterozygous BRCA1 mutation requires inactivation of the wild-type BRCA1 and TP53 alleles, which results in genomic instability and acquisition of mutations in protooncogenes. Clearly, mutational inactivation of TP53 and the wild-type BRCA1 allele in ovarian tumors with a heterozygous, germline BRCA1 mutation is not an absolute requirement for tumor formation. It is possible that these alleles may be inactivated by nonmutational mechanisms or that other tumor formation pathways exist.
authors.affiliation: Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: H
authors.initials: H
authors.lastname: Tworek
authors.forename: R
authors.initials: R
authors.lastname: Peng
authors.forename: S
authors.initials: S
authors.lastname: Fetzer
authors.forename: B A
authors.initials: BA
authors.lastname: Werness
authors.forename: M S
authors.initials: MS
authors.lastname: Piver
authors.forename: H J
authors.initials: HJ
authors.lastname: Allen
authors.forename: R A
authors.initials: RA
authors.lastname: DiCioccio
mesh_terms: D000328:Adult; D001483:Base Sequence; D017931:DNA Primers; D005260:Female; D019398:Genes, BRCA1; D016158:Genes, p53; D011905:Genes, ras; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D010386:Pelvic Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D017931:DNA Primers