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Published on: October 14, 2015
Constitutional BRCA1 Promoter Methylation in Patients With Ovarian Cancer: Results of the Observational AGO-TR1 Study
Mohamad Kayali1, Eric Hahnen1, Alexander Burges2
1Center for Familial Breast and Ovarian Cancer, Institute for Hereditary Cancers, Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
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.
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