Methylation of all BRCA1 copies predicts response to the PARP inhibitor rucaparib in ovarian carcinoma
Year: 2018
Type: article
Abstract: Accurately identifying patients with high-grade serous ovarian carcinoma (HGSOC) who respond to poly(ADP-ribose) polymerase inhibitor (PARPi) therapy is of great clinical importance. Here we show that quantitative BRCA1 methylation analysis provides new insight into PARPi response in preclinical models and ovarian cancer patients. The response of 12 HGSOC patient-derived xenografts (PDX) to the PARPi rucaparib was assessed, with variable dose-dependent responses observed in chemo-naive BRCA1/2-mutated PDX, and no responses in PDX lacking DNA repair pathway defects. Among BRCA1-methylated PDX, silencing of all BRCA1 copies predicts rucaparib response, whilst heterozygous methylation is associated with resistance. Analysis of 21 BRCA1-methylated platinum-sensitive recurrent HGSOC (ARIEL2 Part 1 trial) confirmed that homozygous or hemizygous BRCA1 methylation predicts rucaparib clinical response, and that methylation loss can occur after exposure to chemotherapy. Accordingly, quantitative BRCA1 methylation analysis in a pre-treatment biopsy could allow identification of patients most likely to benefit, and facilitate tailoring of PARPi therapy.
Source: Nature Communications
Authors: Olga Kondrashova, Monique Topp, Ksenija Nesic, Elizabeth Lieschke, Gwo-Yaw Ho, Maria I. Harrell, Giada V. Zapparoli, Alison Hadley, Robert Holian, Emma Boehm, Valerie Heong, Elaine Sanij, Richard B. Pearson, John J. Krais, Neil Johnson, Orla McNally, Sumitra Ananda, Kathryn Alsop, Karla J. Hutt, Scott H. Kaufmann, Kevin K. Lin, Thomas C. Harding, Nadia Traficante, Australian Ovarian Cancer Study (AOCS), G. Chenevix-Trench, A. Green, P. Webb, D. Gertig, S. Fereday, S. Moore, J. Hung, K. Harrap, T. Sadkowsky, N. Pandeya, M. Malt, A. Mellon, R. Robertson, T. Vanden Bergh, M. Jones, P. Mackenzie, J. Maidens, K. Nattress, Y. E. Chiew, A. Stenlake, H. Sullivan, B. Alexander, P. Ashover, S. Brown, T. Corrish, L. Green, L. Jackman, K. Ferguson, K. Martin, A. Martyn, B. Ranieri, J. White, V. Jayde, P. Mamers, L. Bowes, L. Galletta, D. Giles, J. Hendley, T. Schmidt, H. Shirley, C. Ball, C. Young, S. Viduka, H. Tran, S. Bilic, L. Glavinas, J. Brooks, R. Stuart-Harris, F. Kirsten, J. Rutovitz, P. Clingan, A. Glasgow, A. Proietto, S. Braye, G. Otton, J. Shannon, T. Bonaventura, J. Stewart, S. Begbie, M. Friedlander, D. Bell, S. Baron-Hay, A. Ferrier, G. Gard, D. Nevell, N. Pavlakis, S. Valmadre, B. Young, C. Camaris, R. Crouch, L. Edwards, N. Hacker, D. Marsden, G. Robertson, P. Beale, J. Beith, J. Carter, C. Dalrymple, R. Houghton, P. Russell, M. Links, J. Grygiel, J. Hill, A. Brand, K. Byth, R. Jaworski, P. Harnett, R. Sharma, G. Wain, B. Ward, D. Papadimos, A. Crandon, M. Cummings, K. Horwood, A. Obermair, L. Perrin, D. Wyld, J. Nicklin, M. Davy, M. K. Oehler, C. Hall, T. Dodd, T. Healy, K. Pittman, D. Henderson, J. Miller, J. Pierdes, P. Blomfield, D. Challis, R. McIntosh, A. Parker, B. Brown, R. Rome, D. Allen, P. Grant, S. Hyde, R. Laurie, M. Robbie, D. Healy, T. Jobling, T. Manolitsas, J. McNealage, P. Rogers, B. Susil, E. Sumithran, I. Simpson, K. Phillips, D. Rischin, S. Fox, D. Johnson, S. Lade, M. Loughrey, N. O’Callaghan, W. Murray, P. Waring, V. Billson, J. Pyman, D. Neesham, M. Quinn, C. Underhill, R. Bell, L. F. Ng, R. Blum, V. Ganju, I. Hammond, Y. Leung, A. McCartney, M. Buck, I. Haviv, D. Purdie, D. Whiteman, N. Zeps, Anna deFazio, Iain A. McNeish, David D. Bowtell, Elizabeth M. Swisher, Alexander Dobrovic, Matthew J. Wakefield, Clare L. Scott
Institutions: The University of Melbourne, Walter and Eliza Hall Institute of Medical Research, Monash University, Royal Women's Hospital, Peter MacCallum Cancer Centre, University of Washington, La Trobe University, Olivia Newton-John Cancer Research Institute, Fox Chase Cancer Center, Mayo Clinic, Clovis Oncology (United States), QIMR Berghofer Medical Research Institute, The University of Sydney, Westmead Hospital, Westmead Institute for Medical Research, John Hunter Hospital, Royal Hospital for Women, Royal North Shore Hospital, Royal Prince Alfred Hospital, Royal Adelaide Hospital, Royal Hobart Hospital, Monash Medical Centre, St John of God Health Care, King Edward Memorial Hospital, Women and Infants Research Foundation, St John of God Subiaco Hospital, Canberra Hospital, Wollongong Hospital, Illawarra Shoalhaven Local Health District, Nepean Hospital, Port Macquarie Base Hospital, St George Hospital, St Vincent's Hospital Sydney, Wagga Wagga Base Hospital, Mater Misericordiae Hospital, Royal Brisbane and Women's Hospital, Wesley Hospital, Flinders Medical Centre, Queen Elizabeth Hospital, Mercy Hospital for Women, Ballarat Health Services, Bendigo Health, Peninsula Health, Bar-Ilan University, Imperial College London, Melbourne Bioinformatics
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: American Association for Cancer Research, Cancer Research Institute, Ovarian Cancer Research Fund, AstraZeneca, Entertainment Industry Foundation, Victorian Cancer Agency, National Ovarian Cancer Coalition, Ovarian Cancer Australia, Ovarian Cancer Research Fund Alliance, Clovis Oncology, Australian Government, Cancer Research UK, Ovarian Cancer Action, Australian Cancer Research Foundation, National Breast Cancer Foundation, Cancer Australia, Monash University, State Government of Victoria, Peter MacCallum Foundation, Stand Up To Cancer, Foundation Medicine, Medical Research Council, National Health and Medical Research Council, Cancer Council South Australia, Cancer Council Victoria, Cancer Council NSW, Cancer Council Tasmania, National Cancer Institute, Medical Research and Materiel Command
Awards: G1278869635, G1860401738, G2354119982, Mechanisms of resistance to novel therapies in DNA repair defective high-grade serous ovarian cancer, G3007270195, G339478068, G3800818364, Tailoring targeted therapy to DNA repair-defective High-Grade Serous Ovarian Cancer, AOCS Clinical Follow-Up Core, G4386224543, G531440438, G6192157051, G6433449787, G6567635072, G6941481897, G827758369, G8280589461, Compensatory Mechanisms that Promote Homologous Recombination in BRCA1 Mutant Cancers
OpenAlex ID: W2892812402