Genetic versus epigenetic BRCA1 silencing pathways: clinical effects in primary ovarian cancer patients. A study of the tumor bank ovarian cancer consortium

Objectives: The aim of the present study was to assess in a large cohort of primary epithelial ovarian cancer patients the incidence and the clinical effect of BRCA1 genetic and epigenetic silencing mechanisms. Methods: Atotal of 188 primary epithelial ovarian cancer patients, treated between 2000 and 2011 at the Charité UniversityHospital of Berlin,were included. The patients' tumor and blood sampleswere obtained fromthe Tumor Bank Ovarian Cancer Network (www.toc-network.de). Direct sequencing of BRCA1 exon 11 was performed to detect germline mutations, whereas tumor samples were assessed for BRCA1 promoter hypermethylation by bisulphite-converted methylation-specific polymerase chain reaction. Basing on their BRCA1 status, patients were compared regarding clinicopathological variables and survival. Results: Twenty-one patients (11.2%) showed hypermethylation in BRCA1 promoter (HMB), and 18 patients (9.6%) presented germline mutations in BRCA1 exon 11 (GMB). Patients with HMBshowed a significantly younger age at diagnosis comparedwith BRCA1 wild type (BWT) patients (54 vs 61 years, P = 0.045), and bothGMB andHMB patientsweremore likely to have high-grade serous ovarian cancer (76.2% and 77.8% vs 52.7%, P = 0.043 and P = 0.043). Positive family history of breast or ovarian cancer (OC) was more frequently reported among GMB patients with respect to BWT patients (44.4% vs 13.5%, P = 0.003); GMB, HMB, and BWT patients did not show significant differences in terms of tumor dissemination pattern, surgical outcomes, platinum response or survival; neither mutational nor hypermethylation BRCA1 status was found to be an independent prognostic factor for OC patients. Conclusions: Hypermethylation in BRCA1 is associated with earlier occurrence of OC. In addition, the coexistence of bothGBMandHMBis an infrequent event, occurring in 0.5%ofOC cases. Silencing of BRCA1 through mutation and hypermethylation confers to distinct clinical characteristics of OC patients but similar clinical outcome with respect to BWT patients.