Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/117693
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Type: Journal article
Title: Methylation of all BRCA1 copies predicts response to the PARP inhibitor rucaparib in ovarian carcinoma
Author: Kondrashova, O.
Topp, M.
Nesic, K.
Lieschke, E.
Ho, G.
Harrell, M.
Zapparoli, G.
Hadley, A.
Holian, R.
Boehm, E.
Heong, V.
Sanij, E.
Pearson, R.
Krais, J.
Johnson, N.
McNally, O.
Ananda, S.
Alsop, K.
Hutt, K.
Kaufmann, S.
et al.
Citation: Nature Communications, 2018; 9(1):3970-1-3970-16
Publisher: Springer Nature
Issue Date: 2018
ISSN: 2041-1723
2041-1723
Statement of
Responsibility: 
Olga Kondrashova … M.K. Oehler … [et al.] (Australian Ovarian Cancer Study (AOCS))
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.
Keywords: Australian Ovarian Cancer Study (AOCS)
Rights: © The Author(s) 2018. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
RMID: 0030099910
DOI: 10.1038/s41467-018-05564-z
Grant ID: http://purl.org/au-research/grants/nhmrc/494836
http://purl.org/au-research/grants/nhmrc/1062702
http://purl.org/au-research/grants/nhmrc/1076048
http://purl.org/au-research/grants/nhmrc/400413
http://purl.org/au-research/grants/nhmrc/400281
Appears in Collections:Medicine publications

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