Journal
NATURE COMMUNICATIONS
Volume 9, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-05564-z
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Funding
- National Health and Medical Research Council (NHMRC Australia) [494836, 1062702]
- Stafford Fox Medical Research Foundation
- Cancer Council Victoria (Sir Edward Dunlop Fellowship in Cancer Research)
- Victorian Cancer Agency [CRF10-20, CRF16014]
- Monash University
- CRC for Cancer Therapeutics
- Bev Gray Ovarian Cancer Scholarship
- NHMRC [1076048]
- National Breast Cancer Foundation [PS-15-048]
- National Institute of Health [2P50CA083636]
- Wendy Feuer Ovarian Cancer Research Fund
- Victorian Government Operational and Infrastructure Support Program
- Clovis Oncology
- Stand Up To Cancer-Ovarian Cancer Research Fund Alliance-National Ovarian Cancer Coalition Dream Team Translational Research Grant [SU2C-AACR-DT16-15]
- U.S. Army Medical Research and Materiel Command [DAMD17-01-1-0729]
- Cancer Council Victoria
- Queensland Cancer Fund
- Cancer Council New South Wales
- Cancer Council South Australia
- Cancer Council Tasmania
- The Cancer Foundation of Western Australia [191, 211, 182]
- National Health and Medical Research Council of Australia (NHMRC) [ID400413, ID400281]
- Agar family
- Ovarian Cancer Action (UK)
- Ovarian Cancer Australia
- Peter MacCallum Foundation
- NATIONAL CANCER INSTITUTE [P50CA083636] Funding Source: NIH RePORTER
- MRC [G0501974, G0601891] Funding Source: UKRI
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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.
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