Abstract 290: Constitutional BRCA1 methylation is a major predisposition factor for high-grade serous ovarian cancer

Abstract

Abstract This study aimed to determine whether constitutional methylation of the BRCA1 promoter region was a predisposition factor for ovarian cancer. We had previously shown that in a case control study of early-onset breast cancer patients, the presence of constitutional BRCA1 methylation in the blood was associated with tumors that phenocopied pathogenic germline BRCA1 mutations, indicating that BRCA1 methylation predisposed to and drove the development of these tumors. Germline BRCA1 mutations also predispose to ovarian cancer, in particular, high-grade serous ovarian cancer. In collaboration with the Australian Ovarian Cancer Study, we determined the presence of detectable BRCA1 methylation in 154 high-grade serous cancers. Twenty patients showed detectable levels of BRCA1 methylation in DNA extracted from their peripheral blood. Remarkably, when the corresponding tumor samples were assessed for methylation, 14 of the 20 that showed any methylation corresponded to a highly methylated tumour. When tumors occurring before the age of 55 were considered, 9 of the 10 bloods with detectable mutation corresponded to a strongly methylated tumour. This study also determined the frequency of BRCA1 and BRCA2 mutations. Fifteen women had germline BRCA1 mutations and 11 had germline BRCA2 mutations. The germline BRCA1 mutation carriers were predominantly younger at diagnosis and 11 pathogenic BRCA1 mutations were seen in the under 55 group. BRCA1 methylation was mutually exclusive with BRCA1 mutation. This data strongly suggests that constitutional BRCA1 methylation can drive ovarian cancer, in particular early onset ovarian cancer, and moreover is as important a predisposition factor as BRCA1 mutation. Citation Format: Alexander Dobrovic, Thomas Mikeska, Kathryn Alsop, Ida Candiloro, Joshy George, Gillian Mitchell, David Bowtell. Constitutional BRCA1 methylation is a major predisposition factor for high-grade serous ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 290. doi:10.1158/1538-7445.AM2014-290