Whole-genome characterization of chemoresistant ovarian cancer

Patch, Ann-Marie and Christie, Elizabeth L. and Etemadmoghadam, Dariush and Garsed, Dale W. and George, Joshy and Fereday, Sian and Nones, Katia and Cowin, Prue and Alsop, Kathryn and Bailey, Peter J. and Kassahn, Karin S. and Newell, Felicity and Quinn, Michael C. J. and Kazakoff, Stephen and Quek, Kelly and Wilhelm-Benartzi, Charlotte and Curry, Ed and Leong, Huei San and The Australian Ovarian Cancer Study Group, and Hamilton, Anne and Mileshkin, Linda and Au-Yeung, George and Kennedy, Catherine and Hung, Jillian and Chiew, Yoke-Eng and Harnett, Paul and Friedlander, Michael and Quinn, Michael and Pyman, Jan and Cordner, Stephen and O'Brien, Patricia and Leditschke, Jodie and Young, Greg and Strachan, Kate and Waring, Paul and Azar, Walid and Mitchell, Chris and Traficante, Nadia and Hendley, Joy and Thorne, Heather and Shackleton, Mark and Miller, David K. and Arnau, Gisela Mir and Tothill, Richard W. and Holloway, Timothy P. and Semple, Timothy and Harliwong, Ivon and Nourse, Craig and Nourbakhsh, Ehsan and Manning, Suzanne and Idrisoglu, Senel and Bruxner, Timothy J. C. and Christ, Angelika N. and Poudel, Barsha and Holmes, Oliver and Anderson, Matthew and Leonard, Conrad and Lonie, Andrew and Hall, Nathan and Wood, Scott and Taylor, Darrin F. and Xu, Qinying and Fink, J. Lynn and Waddell, Nick and Drapkin, Ronny and Stronach, Euan and Gabra, Hani and Brown, Robert and Jewell, Andrea and Nagaraj, Shivashankar H. and Markham, Emma and Wilson, Peter J. and Ellul, Jason and McNally, Orla and Doyle, Maria A. and Vedururu, Ravikiran and Stewart, Collin and Lengyel, Ernst and Pearson, John V. and Waddell, Nicola and deFazio, Anna and Grimmond, Sean M. and Bowtell, David D. L. (2015) Whole-genome characterization of chemoresistant ovarian cancer. Nature, 521 (7553). pp. 489-494. ISSN 0028-0836

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.


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Item Type: Article (Commonwealth Reporting Category C)
Refereed: Yes
Item Status: Live Archive
Additional Information: Files associated with this item cannot be displayed due to copyright restrictions.
Faculty / Department / School: No Faculty
Date Deposited: 29 Aug 2017 02:57
Last Modified: 01 Sep 2017 02:52
Uncontrolled Keywords: ovarian cancer; genome; chemotherapy
Fields of Research : 11 Medical and Health Sciences > 1112 Oncology and Carcinogenesis > 111203 Cancer Genetics
Identification Number or DOI: 10.1038/nature14410
URI: http://eprints.usq.edu.au/id/eprint/32686

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