Constitutional BRCA1Italic Text methylation is a major predisposition factor for high-grade serous ovarian cancer. A. Dobrovic1.2,3, T. Mikeska2,3, K. Alsop2, G. V. Zapparoli1, I. L. Candiloro2.3, J. George2, G. Mitchell2, D. Bowtell2,3, Australian Ovarian Cancer Study 1) Translational Genomics & Epigenomics Lab, Ludwig Institute for Cancer Research, Olivia Newton-John Cancer and Wellness Centre, Heidelberg (Melbourne), Victoria, Australia; 2) Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; 3) Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.

   Constitutional methylation refers to specific promoter methylation present in the normal tissues of some individuals. This study aimed to determine whether constitutional methylation of the BRCA1 promoter region was a predisposition factor for high-grade serous ovarian cancer. We had previously shown in a case-control study of early-onset breast cancer patients that the presence of BRCA1 methylation in the blood was associated with tumors that phenocopied pathogenic germline BRCA1 mutations. This indicated 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 mutations and detectable BRCA1 methylation in 154 high-grade serous cancers. Fifteen women had germline BRCA1 mutations and 11 had germline BRCA2 mutations. The germline BRCA1 mutation carriers were predominantly younger at diagnosis and 11/15 pathogenic BRCA1 mutations were seen in patients under 55 at diagnosis. Similarly, patients with BRCA1 methylated tumors were predominantly (15/25) under 55 at diagnosis. BRCA1 methylation was mutually exclusive with BRCA1 and BRCA2 mutation. Nineteen patients showed detectable levels of BRCA1 methylation in DNA extracted from their peripheral blood. Remarkably, when the corresponding tumor samples were assessed for methylation, 13 of these 19 patients had high level BRCA1 methylation in their tumor (p<.0001 for the association of blood and tumour methylation). When the 50 tumors occurring before the age of 55 were considered, 9 of the 10 patients with detectable peripheral blood mutation had a corresponding BRCA1 methylated tumor (p<.0001). This data indicates that constitutional BRCA1 methylation can drive high-grade serous ovarian cancer, in particular early onset cancer, and moreover is as important a predisposition factor as BRCA1 mutation.

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