Epigenetic Loss of Brca1 is Common in Highgrade Serous Ovarian Carcinomas, But Not in Other Histopathologic Subtypes of Ovarian Carcinoma

To characterize loss of BRCA1 at DNA, RNA and protein level from unselected, consecutive series of non- mucinous epithelial ovarian carcinoma. Germline and tumor DNA from 49 consecutive women consenting to participate was assessed by denaturing high performance liquid chromatography for BRCA1/BRCA2 mutations, and abnormal peaks were sequenced. Assessment of BRCA1 loss included loss of heterozygosity (LOH), promoter hypermethylation (PHM), reduced RNA expression (RRE), and negative immunohistochemistry (B1-IHC). BRCA1 loss was defined as loss of expression (RRE and/or B1-IHC) and either LOH or PHM. Tumors showing only LOH or no BRCA1 abnormalities were not considered to have BRCA1 loss. Mutation analysis revealed 7/49 (14%) germline BRCA1 mutations, 2/49 (4%) germline BRCA2 mutations, 1/49 (2%) somatic BRCA1 mutations, and 1/49 (2%) somatic BRCA2 mutation (tumors were high-grade papillary serous (HGPS)). Eleven tumors (22%) of non-HGPS histopathology (5 endometrioid, 4 clear cell, and 2 low-grade PS) did not show BRCA1 loss. The remaining tumors were all HGPS, and of these 14 tumors (29%) showed BRCA1 loss without evidence of BRCA1 mutation, 12 (24%) tumors did not show BRCA1 1oss, and 1 (2%) tumor was indeterminate for BRCA1 loss. BRCA1 loss was only seen in HGPS carcinomas, and was not seen in low-grade PS, endometrioid, and clear cell carcinomas. BRCA1 loss is common in HGPS carcinomas even in the absence of BRCA1 mutations. Therapies targeting DNA double-strand break repair, as a result of BRCA1 loss of function (eg, PARP inhibitors), may be efficacious in this group of tumors.