BRCA Methylation Testing Identifies a Subset of Ovarian Carcinomas without Germline Variants That Can Benefit from PARP Inhibitor.

Homologous Recombination Deficiency (HRD) is a frequent feature of high-grade epithelial ovarian carcinoma (EOC), associated with sensitivity to PARP-inhibitors (PARPi). The best characterized causes of HRD in EOCs are germline or somatic mutations in and genes. Although promoter methylation is a well-known mechanism of gene transcriptional repression, few data have been published about gene methylation in EOCs. In this retrospective study, we quantitatively analyzed by pyrosequencing a selected series of 90 formalin-fixed (FFPE) primary EOCs without germline mutations. We identified 20/88 (22.7%) EOCs showing promoter methylation, including 17/88 (19.3%) in and 4/86 (4.6%) in promoters, one of which showing concomitant methylation. Mean methylation levels were 49.6% and 45.8% for and respectively, with methylation levels ≥50% in 10/20 methylated EOCs. Constitutive methylation was excluded by testing blood-derived DNA. In conclusion, pyrosequencing methylation analysis of genes is a robust, quantitative and sensitive assay applicable to FFPE samples. Remarkably, a considerable subset of germline -negative EOCs showed somatic methylation and, likely, HRD. A subpopulation of women with methylation, even without mutations, could potentially benefit from PARP-inhibitors; further clinical studies are needed to clarify the predictive role of somatic methylation of PARP-therapy response.