Journal article

Acquired RAD51C Promoter Methylation Loss Causes PARP Inhibitor Resistance in High-Grade Serous Ovarian Carcinoma

Ksenija Nesic, Olga Kondrashova, Rachel M Hurley, Cordelia D McGehee, Cassandra J Vandenberg, Gwo-Yaw Ho, Elizabeth Lieschke, Genevieve Dall, Nirashaa Bound, Kristy Shield-Artin, Marc Radke, Ashan Musafer, Zi Qing Chai, Mohammad Reza Eftekhariyan Ghamsari, Maria Harrell, Damien Kee, Inger Olesen, Orla McNally, Nadia Traficante, Anna DeFazio Show all

CANCER RESEARCH | AMER ASSOC CANCER RESEARCH | Published : 2021

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 fol..

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Grants

Awarded by National Health and Medical Research Council (NHMRC Australia)


Awarded by Victorian Cancer Agency (Clinical Fellowships)


Awarded by NIH


Awarded by U.S. Army Medical Research and Materiel Command


Awarded by Cancer Foundation of Western Australia


Awarded by National Health and Medical Research Council of Australia (NHMRC)


Funding Acknowledgements

The authors thank Dr. Paul Haluska and Mariam AlHilli (Mayo Clinic) for the cryopreserved PDX material used to re-establish PDX PH039 within our laboratory and for original PH039 characterization. The authors also thank Silvia Stoev, Rachel Hancock, Kathy Barber, Scott Wood, Lambros T. Koufariotis, and Conrad Leonard for technical assistance. They thank Clovis Oncology for providing rucaparib for in vivo experiments. This work was supported by fellowships and grants from the National Health and Medical Research Council (NHMRC Australia; project grant 1062702 for C.L. Scott, M.J. Wakefield, A. De Fazio, D.D.L. Bowtell, and Senior Research Fellowship APP1139071 for N. Waddell); the Stafford Fox Medical Research Foundation (to C.L. Scott); Cancer Council Victoria (Sir Edward Dunlop Fellowship in Cancer Research to C.L. Scott); the Victorian Cancer Agency (Clinical Fellowships to C.L. Scott CRF10-20, CRF16014; and G. Dall ECRF19003); the Herman Trust, University of Melbourne (Fellowship to C.L. Scott); NIH (2P50CA083636 to E.M. Swisher) and the Wendy Feuer Ovarian Cancer Research Fund (to E.M. Swisher); the Bev Gray Ovarian Cancer Scholarship (PhD Top-Up Scholarship) and Research Training Program Scholarship (PhD Scholarship) to K. Nesic. The Olivia NewtonJohn Cancer Research Institute acknowledges the support of the Victorian Government Operational and Infrastructure Support Program. This work was also supported in part by grants from the NIH (P50 CA136393 to S.H. Kaufmann and S.J. Weroha; F30 CA213737 to C.D. McGehee; T32 GM072474 to R.M. Hurley), fellowship support from the Mayo Foundation for Education and Research (to R.M. Hurley, C.D. McGehee) and Stand Up To Cancer-Ovarian Cancer Research Fund AllianceNational Ovarian Cancer Coalition Dream Team Translational Cancer Research Grant (to E.M. Swisher, S.J. Weroha, and S. H. Kaufmann). Stand Up To Cancer is a division of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. This work was made possible through the Australian Cancer Research Foundation, the Victorian State Government Operational Infrastructure Support, and Australian Government NHMRC IRIISS. All authors, the WEHI Stafford Fox Rare Cancer Program, and the AOCS would like to thank all of the women who participated in these research programs. The AOCS would also like to acknowledge the contribution of the study nurses, research assistants, and all clinical and scientific collaborators to the study. The complete AOCS Study Group can be found at www.aocstudy.org.The Australian Ovarian Cancer Study gratefully acknowledges additional support from Ovarian Cancer Australia and the Peter MacCallum Foundation. The Australian Ovarian Cancer Study Group was supported by the U.S. Army Medical Research and Materiel Command under DAMD17-01-1-0729, The Cancer Council Victoria, Queensland Cancer Fund, The Cancer Council New South Wales, The Cancer Council South Australia, The Cancer Council Tasmania and The Cancer Foundation of Western Australia (Multi-State Applications 191, 211, and 182), and the National Health and Medical Research Council of Australia (NHMRC; ID199600, ID400413, and ID400281).