Constitutional BRCA1 Promoter Methylation in Patients with Ovarian Cancer: Results of the Observational AGO-TR1 Study

PURPOSE Constitutional epimutations arise early in development and are present across normal tissues, including peripheral blood. Constitutional BRCA1 promoter methylation has emerged as a risk factor for BRCA1 -associated cancers, such as ovarian cancer (OC), and may serve as a biomarker for OC risk. This study retrospectively evaluated the clinical relevance of constitutional BRCA1 promoter methylation in 473 patients with OC enrolled in the observational AGO-TR1 study (ClinicalTrials.gov identifier: NCT02222883 ). MATERIALS AND METHODS BRCA1 promoter methylation was quantified by the methylation-specific real-time polymerase chain reaction using whole blood-derived DNA from 476 female controls and 473 patients with OC along with 473 corresponding tumor-derived DNA samples. Methylation levels ≥1.0% were considered methylation-positive. RESULTS BRCA1 promoter methylation in blood-derived DNA was detected in 42 of 473 patients with OC and in 26 of 476 controls (8.9% v 5.5%; odds ratio [OR], 1.69 [95% CI, 1.02 to 2.80], P = .0432), with the strongest association observed with methylation levels ≥10% (OR, 6.17 [95% CI, 1.37 to 27.72], P = .018). Patients with BRCA1 promoter methylation in blood-derived DNA were diagnosed at a younger median age than those without (54.0 v 60.0 years, P = .018). Constitutional BRCA1 promoter methylation was less frequent in patients carrying pathogenic germline variants in OC predisposition genes than in noncarriers (4.1% v 10.5%; OR, 0.37 [95% CI, 0.14 to 0.96], P = .04) and showed no association with a family history of cancer or platinum-based chemotherapy before blood draw. BRCA1 promoter methylation in blood-derived DNA was correlated with tumor BRCA1 promoter methylation ( P < .001). Tumor BRCA1 promoter methylation was observed in 64 of 473 samples (13.5%), half (32 of 64) of which were attributable to constitutional BRCA1 promoter methylation also detectable in the blood. CONCLUSION Constitutional BRCA1 promoter methylation accounts for a substantial proportion of OCs and represents a robust biomarker for individual OC risk.