biostudies-literatureNesic KVictorian Cancer AgencyU.S. Army Medical Research and Materiel CommandNHMRCNCI NIH HHSNational Health and Medical Research CouncilNIHNIGMS NIH HHS4709-4722https://www.ebi.ac.uk/biostudies/studies/S-EPMC12593227biostudies-literatureUnknown81(18)In high-grade serous ovarian carcinoma (HGSC), deleterious mutations in DNA repair gene <i>RAD51C</i> are established drivers of defective homologous recombination and are emerging biomarkers of PARP inhibitor (PARPi) sensitivity. <i>RAD51C</i> promoter methylation (me<i>RAD51C</i>) is detected at similar frequencies to mutations, yet its effects on PARPi responses remain unresolved.In this study, three HGSC patient-derived xenograft (PDX) models with methylation at most or all examined CpG sites in the <i>RAD51C</i> promoter show responses to PARPi. Both complete and heterogeneous methylation patterns were associated with <i>RAD51C</i> gene silencing and homologous recombination deficiency (HRD). PDX models lost me<i>RAD51C</i> following treatment with PARPi rucaparib or niraparib, where Cancer researchAcquired <i>RAD51C</i> Promoter Methylation Loss Causes PARP Inhibitor Resistance in High-Grade Serous Ovarian Carcinoma.PMC12593227T32 GM072474ID400281P50 CA0836362P50CA083636ID400413F30 CA2137371062702P50 CA136393ID199600ECRF19003CRF10–20DAMD17-01-1-0729CRF16014APP1139071Waddell NTraficante NNesic KRadke MMcNally OOlesen IChai ZQNones KHarrell MIBowtell DDLAustralian Ovarian Cancer StudyLieschke EDall GShield-Artin KKaufmann SHDobrovic AVandenberg CJKee DWakefield MJMusafer AHurley RMMcGehee CDHo GYDeFazio ASwisher EMBound NScott CLKondrashova OGhamsari MREWeroha SJfalseAcquired <i>RAD51C</i> Promoter Methylation Loss Causes PARP Inhibitor Resistance in High-Grade Serous Ovarian Carcinoma.In high-grade serous ovarian carcinoma (HGSC), deleterious mutations in DNA repair gene <i>RAD51C</i> are established drivers of defective homologous recombination and are emerging biomarkers of PARP inhibitor (PARPi) sensitivity. <i>RAD51C</i> promoter methylation (me<i>RAD51C</i>) is detected at similar frequencies to mutations, yet its effects on PARPi responses remain unresolved.In this study, three HGSC patient-derived xenograft (PDX) models with methylation at most or all examined CpG sites in the <i>RAD51C</i> promoter show responses to PARPi. Both complete and heterogeneous methylation patterns were associated with <i>RAD51C</i> gene silencing and homologous recombination deficiency (HRD). PDX models lost me<i>RAD51C</i> following treatment with PARPi rucaparib or niraparib, where 2021-01-01T00:00:00Z2021 Sep2026-06-05T13:46:56.276Z2026-06-05T03:07:03.133ZS-EPMC125932273432123910.1158/0008-5472.CAN-21-077410.1158/0008-5472.can-21-0774