The Effects of BRCA1 and BRCA2 Promoter Methylation on Clinicopathological Characteristics and Clinical Outcomes in HGSOC

Ovarian cancer is a highly lethal disease. Tumors with a deficiency in the homologous recombination repair pathway (HRD) resulting from mutations in <i>BRCA1</i>/<i>2</i> genes have a favorable response to platinum-based chemotherapy and targeted therapy with PARP inhibitors (PARPi) mediated by synthetic lethality. Promoter methylation of <i>BRCA1/2</i> genes was previously associated with HRD, but little is known about whether it translates to clinical benefit. Here, we evaluated the prevalence of <i>BRCA1/2</i> promoter methylation in HGSOC patients from Serbia and examined their clinicopathological characteristics and the effect on progression-free and overall survival. Using methylation-specific PCR, we screened for hypermethylation in the promoter region of <i>BRCA1/2</i> genes in a cohort of 244 patients. We found fully methylated <i>BRCA1</i> and <i>BRCA2</i> promoter in 4.1% and 0.45% of patients, and 23.36% and 11.21% intermediately methylated cases, respectively. Full <i>BRCA1/2</i> promoter methylation was significantly associated with younger age of onset (55 and 58 years, respectively) compared to <i>BRCA1/2</i>-mutated cases, suggestive of BRCAness phenotype. However, in the exploratory analysis of 68 patients with clinical follow-up, we did not find a strong survival advantage for <i>BRCA1/2</i> methylated over <i>BRCA1/2</i>-intact cases, yet more moderate effects cannot be ruled out due to the cohort size.