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Title: Acquired RAD51C Promoter Methylation Loss Causes PARP Inhibitor Resistance in High-Grade Serous Ovarian Carcinoma.
Austin Authors: Nesic, Ksenija;Kondrashova, Olga;Hurley, Rachel M;McGehee, Cordelia D;Vandenberg, Cassandra J;Ho, Gwo-Yaw;Lieschke, Elizabeth;Dall, Genevieve;Bound, Nirashaa;Shield-Artin, Kristy;Radke, Marc;Musafer, Ashan;Chai, Zi Qing;Ghamsari, Mohammad Reza Eftekhariyan;Harrell, Maria I;Kee, Damien ;Olesen, Inger;McNally, Orla;Traficante, Nadia;Australian Ovarian Cancer Study, null;DeFazio, Anna;Bowtell, David D L;Swisher, Elizabeth M;Weroha, S John;Nones, Katia;Waddell, Nicola;Kaufmann, Scott H;Dobrovic, Alexander ;Wakefield, Matthew J;Scott, Clare L
Affiliation: The University of Sydney, Sydney, NSW, Australia..
Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, NSW, Australia..
QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia..
Department of Gynaecological Oncology, Westmead Hospital, Sydney, NSW, Australia..
Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia..
Royal Women's Hospital, Parkville, Victoria, Australia..
The Andrew Love Cancer Centre, Barwon Health, Geelong, Victoria, Australia..
Sir Peter MacCallum Cancer Centre Department of Oncology, University of Melbourne, Parkville, Victoria, Australia..
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia..
Medical Oncology
School of Clinical Sciences, Monash University, Clayton, Victoria, Australia..
Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Victoria, Australia..
Surgery (University of Melbourne)
Olivia Newton-John Cancer Research Institute
Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia..
Departments of Oncology and Molecular Pharmacology, Mayo Clinic, Rochester, Minnesota..
University of Washington, Seattle, Washington..
Departments of Oncology and Molecular Pharmacology, Mayo Clinic, Rochester, Minnesota..
Issue Date: 15-Sep-2021
Date: 2021
Publication information: Cancer Research 2021; 81(18): 4709-4722
Abstract: In high-grade serous ovarian carcinoma (HGSC), deleterious mutations in DNA repair gene RAD51C are established drivers of defective homologous recombination and are emerging biomarkers of PARP inhibitor (PARPi) sensitivity. RAD51C promoter methylation (meRAD51C) 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 RAD51C promoter show responses to PARPi. Both complete and heterogeneous methylation patterns were associated with RAD51C gene silencing and homologous recombination deficiency (HRD). PDX models lost meRAD51C following treatment with PARPi rucaparib or niraparib, where a single unmethylated copy of RAD51C was sufficient to drive PARPi resistance. Genomic copy number profiling of one of the PDX models using SNP arrays revealed that this resistance was acquired independently in two genetically distinct lineages.In a cohort of 12 patients with RAD51C-methylated HGSC, various patterns of meRAD51C were associated with genomic "scarring," indicative of HRD history, but exhibited no clear correlations with clinical outcome. Differences in methylation stability under treatment pressure were also observed between patients, where one HGSC was found to maintain meRAD51C after six lines of therapy (four platinum-based), whereas another HGSC sample was found to have heterozygous meRAD51C and elevated RAD51C gene expression (relative to homozygous meRAD51C controls) after only neoadjuvant chemotherapy.As meRAD51C loss in a single gene copy was sufficient to cause PARPi resistance in PDX, methylation zygosity should be carefully assessed in previously treated patients when considering PARPi therapy. SIGNIFICANCE: Homozygous RAD51C methylation is a positive predictive biomarker for sensitivity to PARP inhibitors, whereas a single unmethylated gene copy is sufficient to confer resistance.
DOI: 10.1158/0008-5472.CAN-21-0774
ORCID: 0000-0003-0022-5149
Journal: Cancer Research
PubMed URL: 34321239
PubMed URL:
Type: Journal Article
Appears in Collections:Journal articles

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