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

## TL;DR

This study examines how BRCA1 and BRCA2 gene methylation affects ovarian cancer patients' clinicopathological features and survival outcomes.

## Contribution

The study reports the prevalence of BRCA1/2 promoter methylation in a Serbian HGSOC cohort and its association with clinicopathological features.

## Key findings

- Full BRCA1/2 promoter methylation was found in 4.1% and 0.45% of patients, respectively.
- Methylation was associated with younger age of onset compared to BRCA1/2-mutated cases.
- No strong survival advantage was observed for methylated cases in the follow-up analysis.

## Abstract

Ovarian cancer is a highly lethal disease. Tumors with a deficiency in the homologous recombination repair pathway (HRD) resulting from mutations in BRCA1/2 genes have a favorable response to platinum-based chemotherapy and targeted therapy with PARP inhibitors (PARPi) mediated by synthetic lethality. Promoter methylation of BRCA1/2 genes was previously associated with HRD, but little is known about whether it translates to clinical benefit. Here, we evaluated the prevalence of BRCA1/2 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 BRCA1/2 genes in a cohort of 244 patients. We found fully methylated BRCA1 and BRCA2 promoter in 4.1% and 0.45% of patients, and 23.36% and 11.21% intermediately methylated cases, respectively. Full BRCA1/2 promoter methylation was significantly associated with younger age of onset (55 and 58 years, respectively) compared to BRCA1/2-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 BRCA1/2 methylated over BRCA1/2-intact cases, yet more moderate effects cannot be ruled out due to the cohort size.