Constitutional <i>BRCA1</i> Promoter Methylation in Patients With Ovarian Cancer: Results of the Observational AGO-TR1 Study.

Abstract

Constitutional epimutations arise early in development and are present across normal tissues, including peripheral blood. Constitutional <i>BRCA1</i> promoter methylation has emerged as a risk factor for <i>BRCA1</i>-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 <i>BRCA1</i> promoter methylation in 473 patients with OC enrolled in the observational AGO-TR1 study (ClinicalTrials.gov identifier: NCT02222883). <i>BRCA1</i> 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. <i>BRCA1</i> promoter methylation in blood-derived DNA was detected in 42 of 473 patients with OC and in 26 of 476 controls (8.9% <i>v</i> 5.5%; odds ratio [OR], 1.69 [95% CI, 1.02 to 2.80], <i>P</i> = .0432), with the strongest association observed with methylation levels ≥10% (OR, 6.17 [95% CI, 1.37 to 27.72], <i>P</i> = .018). Patients with <i>BRCA1</i> promoter methylation in blood-derived DNA were diagnosed at a younger median age than those without (54.0 <i>v</i> 60.0 years, <i>P</i> = .018). Constitutional <i>BRCA1</i> promoter methylation was less frequent in patients carrying pathogenic germline variants in OC predisposition genes than in noncarriers (4.1% <i>v</i> 10.5%; OR, 0.37 [95% CI, 0.14 to 0.96], <i>P</i> = .04) and showed no association with a family history of cancer or platinum-based chemotherapy before blood draw. <i>BRCA1</i> promoter methylation in blood-derived DNA was correlated with tumor <i>BRCA1</i> promoter methylation (<i>P</i> < .001). Tumor <i>BRCA1</i> promoter methylation was observed in 64 of 473 samples (13.5%), half (32 of 64) of which were attributable to constitutional <i>BRCA1</i> promoter methylation also detectable in the blood. Constitutional <i>BRCA1</i> promoter methylation accounts for a substantial proportion of OCs and represents a robust biomarker for individual OC risk.