{"doi":"10.1101/2020.12.10.419176","title":"Acquired <i>RAD51C</i> promoter methylation loss causes PARP inhibitor resistance in high grade serous ovarian carcinoma","abstract":"ABSTRACT While loss of BRCA1 promoter methylation has been shown to cause PARP inhibitor (PARPi) resistance in high-grade serous ovarian carcinoma (HGSC), the impacts of RAD51C methylation (me RAD51C ) remain unresolved. In this study, three PARPi-responsive HGSC patient-derived xenografts (PDX) with RAD51C gene silencing and homologous recombination deficiency were found to have either homogeneous or heterogeneous patterns of me RAD51C . PDX could lose me RAD51C following PARPi treatment (rucaparib/niraparib), where a single unmethylated RAD51C copy was sufficient to drive PARPi-resistance. Genomic profiling revealed this resistance was acquired independently in two distinct PDX lineages. Furthermore, we describe a patient sample where 1/3 RAD51C gene copies lost methylation following neoadjuvant chemotherapy. We show me RAD51C is a positive predictive biomarker for PARPi response and should be screened for routinely in patients. However, methylation loss in a single gene copy is sufficient to cause PARPi resistance and should be carefully assessed in previously treated patients considering PARPi therapy.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":125677,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9572,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":572412,"name":"Olga Kondrashova","orcid":"0000-0003-0022-5149","position":1,"is_corresponding":false},{"id":573109,"name":"Rachel M. Hurley","orcid":null,"position":2,"is_corresponding":false},{"id":573110,"name":"Cordelia D. McGehee","orcid":null,"position":3,"is_corresponding":false},{"id":461705,"name":"Cassandra J. Vandenberg","orcid":"0000-0002-8891-8873","position":4,"is_corresponding":false},{"id":572413,"name":"Gwo‐Yaw Ho","orcid":"0000-0003-1195-2296","position":5,"is_corresponding":false},{"id":572414,"name":"Elizabeth Lieschke","orcid":"0000-0003-3320-1565","position":6,"is_corresponding":false},{"id":572415,"name":"Genevieve Dall","orcid":"0000-0001-6205-7342","position":7,"is_corresponding":false},{"id":572416,"name":"Nirashaa Bound","orcid":"0009-0006-5847-0277","position":8,"is_corresponding":false},{"id":572417,"name":"Kristy Shield‐Artin","orcid":"0000-0002-3969-9846","position":9,"is_corresponding":false},{"id":242500,"name":"Marc R. Radke","orcid":"0000-0003-0983-7838","position":10,"is_corresponding":false},{"id":573111,"name":"Ashan Musafer","orcid":null,"position":11,"is_corresponding":false},{"id":573112,"name":"Zi Qing Chai","orcid":null,"position":12,"is_corresponding":false},{"id":572418,"name":"Mohammad Reza Eftekhariyan Ghamsari","orcid":"0000-0003-3531-3042","position":13,"is_corresponding":false},{"id":573113,"name":"Maria I. Harrell","orcid":null,"position":14,"is_corresponding":false},{"id":572419,"name":"Damien Kee","orcid":"0000-0002-4685-1666","position":15,"is_corresponding":false},{"id":573114,"name":"Inger Olesen","orcid":null,"position":16,"is_corresponding":false},{"id":285103,"name":"Orla McNally","orcid":"0000-0001-7340-9489","position":17,"is_corresponding":false},{"id":14148,"name":"Nadia Traficante","orcid":"0000-0001-7459-8576","position":18,"is_corresponding":false},{"id":573115,"name":"Australian Ovarian Cancer Study","orcid":null,"position":19,"is_corresponding":false},{"id":14293,"name":"Anna deFazio","orcid":"0000-0003-0057-4744","position":20,"is_corresponding":false},{"id":1733,"name":"David D.L. Bowtell","orcid":"0000-0001-9089-7525","position":21,"is_corresponding":false},{"id":70261,"name":"Elizabeth M. Swisher","orcid":"0000-0003-2331-0434","position":22,"is_corresponding":false},{"id":30189,"name":"S. John Weroha","orcid":"0000-0002-7130-7259","position":23,"is_corresponding":false},{"id":14417,"name":"Kátia Nones","orcid":"0000-0003-1925-5196","position":24,"is_corresponding":false},{"id":108512,"name":"Nicola Waddell","orcid":"0000-0002-3950-2476","position":25,"is_corresponding":false},{"id":33561,"name":"Scott H. Kaufmann","orcid":"0000-0002-4900-7145","position":26,"is_corresponding":false},{"id":572420,"name":"Alexander Dobrovic","orcid":"0000-0003-3414-112X","position":27,"is_corresponding":false},{"id":94865,"name":"Matthew J. Wakefield","orcid":"0000-0001-6624-4698","position":28,"is_corresponding":false},{"id":285112,"name":"Clare L. 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