MOLECULAR EVIDENCE FOR MULTIFOCAL PAPILLARY SEROUS CARCINOMA OF THE PERITONEUM IN PATIENTS WITH GERMLINE BRCA1 MUTATIONS

Background: Papillary serous carcinoma of the peritoneum (PSCP) diffus ely involves peritoneal surfaces, while it spares or only superficiall y involves the ovaries. PSCP is histologically indistinguishable from serous epithelial ovarian carcinoma, and it may develop years after oo phorectomy, The molecular pathogenesis of PSCP remains unresolved, alt hough preliminary data suggest a multifocal origin in some cases. Pati ents with germline BRCA1 mutations may develop PSCP in addition to bre ast and ovarian carcinomas. The purpose of this study was to utilize t he androgen receptor (AR) gene locus to test the hypothesis that some cases of PSCP have a multifocal origin and to determine if patients wi th germline BRCA1 mutations develop multifocal PSCP. Methods: Specimen s of normal and tumor tissues from 22 women with PSCP were obtained, a nd DNA was extracted. The AR gene locus was evaluated for patterns of loss of heterozygosity (LOH) and X-chromosome inactivation. The methyl ation-sensitive Hpa II restriction enzyme was used to differentiate th e active and inactive X chromosomes. Germline BRCA1 mutation status of the patients was determined previously, Results: Genetic analysis of tumor specimens indicated that five (23%) of 22 case subjects had patt erns of selective LOH at the AR locus, consistent with multifocal, pol yclonal disease origin. Two patients with selective LOH also had alter nating X-chromosome inactivation patterns. Patients with germline BRCA 1 mutations were more likely to have evidence of multifocal disease (t wo-sided Fisher's exact test, P = .01), Conclusions: Our results show that PSCP has a multifocal origin in at least some cases. Furthermore, patients with germline BRCA1 mutations are more likely to develop mul tifocal PSCP than are patients without BRCA1 mutations.