Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/19698
Title: Methylation of all BRCA1 copies predicts response to the PARP inhibitor rucaparib in ovarian carcinoma.
Authors: Kondrashova, Olga;Topp, Monique;Nesic, Ksenija;Lieschke, Elizabeth;Ho, Gwo-Yaw;Harrell, Maria I;Zapparoli, Giada V;Hadley, Alison;Holian, Robert;Boehm, Emma;Heong, Valerie;Sanij, Elaine;Pearson, Richard B;Krais, John J;Johnson, Neil;McNally, Orla;Ananda, Sumitra;Alsop, Kathryn;Hutt, Karla J;Kaufmann, Scott H;Lin, Kevin K;Harding, Thomas C;Traficante, Nadia;deFazio, Anna;McNeish, Iain A;Bowtell, David D;Swisher, Elizabeth M;Dobrovic, Alexander;Wakefield, Matthew J;Scott, Clare L
Affiliation: Departments of Oncology and Molecular Pharmacology, Mayo Clinic, Rochester, MN, 55905, USA
Clovis Oncology, Boulder, CO, 80301, USA
Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney Medical School, The University of Sydney and Department of Gynaecological Oncology, Westmead Hospital, Sydney, NSW, 2145, Australia
Division of Cancer, Department of Surgery and Cancer, Imperial College London, Kensington, London, SW7 2AZ, United Kingdom
Department of Obstetrics and Gynecology, University of Washington, Seattle, WA, 98195, USA
Melbourne Bioinformatics, University of Melbourne, Melbourne, VIC, 3010, Australia
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia
Department of Medicine and Health Sciences, Monash University, Clayton, VIC, 3168, Australia
Fox Chase Cancer Centre, Philadelphia, PA, 19111, USA
Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia
Royal Women's Hospital, Parkville, VIC, 3052, Australia
Research Division, Peter MacCallum Cancer Centre, Grattan Street, Parkville, VIC, 3010, Australia
Parent-Infant Research Institute, Austin Health, Heidelberg, Victoria, Australia
School of Cancer Medicine, La Trobe University, Bundoora, VIC, 3086, Australia
School of Medicine, University of Melbourne, Parkville, VIC, 3052, Australia
Department of Clinical Pathology, University of Melbourne, Melbourne, VIC, 3010, Australia
Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, 3010, Australia
Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, VIC, 3010, Australia
Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, 3168, Australia
Issue Date: 28-Sep-2018
EDate: 2018-09-28
Citation: Nature communications 2018; 9(1): 3970
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.
URI: http://ahro.austin.org.au/austinjspui/handle/1/19698
DOI: 10.1038/s41467-018-05564-z
ORCID: 0000-0003-3414-112X
0000-0003-0022-5149
0000-0001-5919-5090
0000-0002-4900-7145
0000-0002-9387-7586
0000-0001-6624-4698
0000-0002-3689-5956
PubMed URL: 30266954
Type: Journal Article
Appears in Collections:Journal articles

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