Whole-genome characterization of chemoresistant ovarian cancer

Ann-Marie Patch, Elizabeth Christie, Dariush Etemadmoghadam, Dale W. Garsed, Joshy George, Sian Fereday, Katia Nones, Prue Cowin, Kathryn Alsop, Peter J. Bailey, Karin S Kassahn, Felicity Newell, Michael C.J. Quinn, Stephen Kazakoff, Kelly Quek, Charlotte Wilhelm-Benartzi, Ed Curry, Huei San Leong, Anne Hamilton, Linda MileshkinGeorge H. Au-Yeung, Catherine Kennedy, Jillian Hung, Yoke Eng Chiew, Paul Harnett, Michael Friedlander, Michael Quinn, Jan M Pyman, Stephen Cordner, Patricia O'Brien, Jodie Leditschke, Greg Young, Kate Strachan, Paul Waring, Walid J Azar, Chris Mitchell, Nadia Traficante, Joy Hendley, Heather J Thorne, Mark Shackleton, David K Miller, Gisela Mir Arnau, Richard W. Tothill, Timothy P Holloway, Timothy Semple, Ivon Harliwong, Craig Nourse, Ehsan Nourbakhsh, Suzanne Manning, Senel Idrisoglu, Timothy J.C. Bruxner, Angelika N. Christ, Barsha Poudel, Oliver Holmes, Matthew Anderson, Conrad Leonard, Andrew Lonie, Nathan Hall, Scott Wood, Darrin F. Taylor, Qinying Xu, J. Lynn Fink, Nick Waddell, Ronny Drapkin, Euan Stronach, Hani Gabra, Robert Brown, Andrea Jewell, Shivashankar H Nagaraj, Emma Markham, Peter J. Wilson, Jason Ellul, Orla M McNally, Maria A Doyle, Ravikiran Vedururu, Collin Stewart, Ernst Lengyel, John V Pearson, Nicola Waddell, Anna DeFazio, Sean M. Grimmond, David D L Bowtell

Research output: Contribution to journalArticleResearchpeer-review

616 Citations (Scopus)

Abstract

Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in overall survival, and standard treatment has not advanced beyond platinum-based combination chemotherapy, during the past 30 years. To understand the drivers of clinical phenotypes better, here we use whole-genome sequencing of tumour and germline DNA samples from 92 patients with primary refractory, resistant, sensitive and matched acquired resistant disease. We show that gene breakage commonly inactivates the tumour suppressors RB1, NF1, RAD51B and PTEN in HGSC, and contributes to acquired chemotherapy resistance. CCNE1 amplification was common in primary resistant and refractory disease. We observed several molecular events associated with acquired resistance, including multiple independent reversions of germline BRCA1 or BRCA2 mutations in individual patients, loss of BRCA1 promoter methylation, an alteration in molecular subtype, and recurrent promoter fusion associated with overexpression of the drug efflux pump MDR1.

Original languageEnglish
Pages (from-to)489-494
Number of pages6
JournalNature
Volume521
Issue number7553
DOIs
Publication statusPublished - 28 May 2015
Externally publishedYes

Keywords

  • cancer genomics
  • ovarian cancer

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