{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T20:55:46Z","timestamp":1781297746876,"version":"3.54.1"},"reference-count":27,"publisher":"American Society of Clinical Oncology (ASCO)","issue":"6","content-domain":{"domain":["ascopubs.org"],"crossmark-restriction":true},"short-container-title":["JCO Precis Oncol"],"published-print":{"date-parts":[[2026,6]]},"abstract":"\n PURPOSE<\/jats:title>\n \n Constitutional epimutations arise early in development and are present across normal tissues, including peripheral blood. Constitutional\n BRCA1<\/jats:italic>\n promoter methylation has emerged as a risk factor for\n BRCA1<\/jats:italic>\n -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\n BRCA1<\/jats:italic>\n promoter methylation in 473 patients with OC enrolled in the observational AGO-TR1 study (ClinicalTrials.gov identifier:\n NCT02222883<\/jats:ext-link>\n ).\n <\/jats:p>\n <\/jats:sec>\n \n MATERIALS AND METHODS<\/jats:title>\n \n BRCA1<\/jats:italic>\n 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 \u22651.0% were considered methylation-positive.\n <\/jats:p>\n <\/jats:sec>\n \n RESULTS<\/jats:title>\n \n BRCA1<\/jats:italic>\n promoter methylation in blood-derived DNA was detected in 42 of 473 patients with OC and in 26 of 476 controls (8.9%\n v<\/jats:italic>\n 5.5%; odds ratio [OR], 1.69 [95% CI, 1.02 to 2.80],\n P<\/jats:italic>\n = .0432), with the strongest association observed with methylation levels \u226510% (OR, 6.17 [95% CI, 1.37 to 27.72],\n P<\/jats:italic>\n = .018). Patients with\n BRCA1<\/jats:italic>\n promoter methylation in blood-derived DNA were diagnosed at a younger median age than those without (54.0\n v<\/jats:italic>\n 60.0 years,\n P<\/jats:italic>\n = .018). Constitutional\n BRCA1<\/jats:italic>\n promoter methylation was less frequent in patients carrying pathogenic germline variants in OC predisposition genes than in noncarriers (4.1%\n v<\/jats:italic>\n 10.5%; OR, 0.37 [95% CI, 0.14 to 0.96],\n P<\/jats:italic>\n = .04) and showed no association with a family history of cancer or platinum-based chemotherapy before blood draw.\n BRCA1<\/jats:italic>\n promoter methylation in blood-derived DNA was correlated with tumor\n BRCA1<\/jats:italic>\n promoter methylation (\n P<\/jats:italic>\n < .001). Tumor\n BRCA1<\/jats:italic>\n promoter methylation was observed in 64 of 473 samples (13.5%), half (32 of 64) of which were attributable to constitutional\n BRCA1<\/jats:italic>\n promoter methylation also detectable in the blood.\n <\/jats:p>\n <\/jats:sec>\n \n CONCLUSION<\/jats:title>\n \n Constitutional\n BRCA1<\/jats:italic>\n promoter methylation accounts for a substantial proportion of OCs and represents a robust biomarker for individual OC risk.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1200\/po-25-01230","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T19:59:19Z","timestamp":1781294359000},"update-policy":"https:\/\/doi.org\/10.1200\/crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Constitutional\n BRCA1<\/i>\n Promoter Methylation in Patients With Ovarian Cancer: Results of the Observational AGO-TR1 Study"],"prefix":"10.1200","volume":"10","author":[{"given":"Mohamad","family":"Kayali","sequence":"first","affiliation":[{"name":"Center 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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1152-8367","authenticated-orcid":true,"given":"Eric","family":"Hahnen","sequence":"additional","affiliation":[{"name":"Center 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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9693-366X","authenticated-orcid":true,"given":"Alexander","family":"Burges","sequence":"additional","affiliation":[{"name":"Department of Gynecology, University Hospital Munich-Gro\u00dfhadern, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8804-4122","authenticated-orcid":true,"given":"Alexander","family":"Reuss","sequence":"additional","affiliation":[{"name":"Coordinating Center for Clinical Trials, Philipps-University of Marburg, Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1751-1638","authenticated-orcid":true,"given":"Julia","family":"Caro-Valenzuela","sequence":"additional","affiliation":[{"name":"Center 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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolaus","family":"de Gregorio","sequence":"additional","affiliation":[{"name":"Department of Gynecology, Klinikum am Gesundbrunnen, SLK-Kliniken Heilbronn GmbH, Heilbronn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2412-0352","authenticated-orcid":true,"given":"Florian","family":"Heitz","sequence":"additional","affiliation":[{"name":"Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte, Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Center 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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6591-3367","authenticated-orcid":true,"given":"Frederik","family":"Marm\u00e9","sequence":"additional","affiliation":[{"name":"Department of Gynecology, University Mannheim, Medical Faculty Mannheim of the University of Heidelberg, Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3492-9577","authenticated-orcid":true,"given":"Felix","family":"Hilpert","sequence":"additional","affiliation":[{"name":"Department of Gynecology, University of Kiel, Kiel, Germany"},{"name":"Onkologisches Therapiezentrum, Krankenhaus Jerusalem, Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7380-577X","authenticated-orcid":true,"given":"Pauline","family":"Wimberger","sequence":"additional","affiliation":[{"name":"Department of Carl-Gustav-Carus University, Technische Universit\u00e4t Dresden and National Cancer Center (NCT Dresden), Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Kommoss","sequence":"additional","affiliation":[{"name":"Department of Women's Health, University Hospital T\u00fcbingen, T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Prieske","sequence":"additional","affiliation":[{"name":"Onkologisches Therapiezentrum, Krankenhaus Jerusalem, Hamburg, Germany"},{"name":"Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7247-282X","authenticated-orcid":true,"given":"Christoph","family":"Engel","sequence":"additional","affiliation":[{"name":"Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany"},{"name":"LIFE - Leipzig Research Centre for Civilization Diseases, University of Leipzig, Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Buderath","sequence":"additional","affiliation":[{"name":"Department of Gynecology, University of Essen, Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9794-7927","authenticated-orcid":true,"given":"Dimo","family":"Dietrich","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Bonn, Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Schmutzler","sequence":"additional","affiliation":[{"name":"Center 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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5963-6623","authenticated-orcid":true,"given":"Jalid","family":"Sehouli","sequence":"additional","affiliation":[{"name":"Department of Gynecology and Gynecological Oncology, Charit\u00e9, Campus Virchow, Berlin, 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