Whole-genome characterization of chemoresistant ovarian cancer

Article


Patch, Ann-Marie, Christie, Elizabeth L., Etemadmoghadam, Dariush, Garsed, Dale W., George, Joshy, Fereday, Sian, Nones, Katia, Cowin, Prue, Alsop, Kathryn, Bailey, Peter J., Kassahn, Karin S., Newell, Felicity, Quinn, Michael C. J., Kazakoff, Stephen, Quek, Kelly, Wilhelm-Benartzi, Charlotte, Curry, Ed, Leong, Huei San, Hamilton, Anne, ..., Bowtell, David D. L.. 2015. "Whole-genome characterization of chemoresistant ovarian cancer." Nature. 521 (7553), pp. 489-494. https://doi.org/10.1038/nature14410
Article Title

Whole-genome characterization of chemoresistant ovarian cancer

ERA Journal ID17479
Article CategoryArticle
AuthorsPatch, Ann-Marie (Author), Christie, Elizabeth L. (Author), Etemadmoghadam, Dariush (Author), Garsed, Dale W. (Author), George, Joshy (Author), Fereday, Sian (Author), Nones, Katia (Author), Cowin, Prue (Author), Alsop, Kathryn (Author), Bailey, Peter J. (Author), Kassahn, Karin S. (Author), Newell, Felicity (Author), Quinn, Michael C. J. (Author), Kazakoff, Stephen (Author), Quek, Kelly (Author), Wilhelm-Benartzi, Charlotte (Author), Curry, Ed (Author), Leong, Huei San (Author), Hamilton, Anne (Author), Mileshkin, Linda (Author), Au-Yeung, George (Author), Kennedy, Catherine (Author), Hung, Jillian (Author), Chiew, Yoke-Eng (Author), Harnett, Paul (Author), Friedlander, Michael (Author), Quinn, Michael (Author), Pyman, Jan (Author), Cordner, Stephen (Author), O'Brien, Patricia (Author), Leditschke, Jodie (Author), Young, Greg (Author), Strachan, Kate (Author), Waring, Paul (Author), Azar, Walid (Author), Mitchell, Chris (Author), Traficante, Nadia (Author), Hendley, Joy (Author), Thorne, Heather (Author), Shackleton, Mark (Author), Miller, David K. (Author), Arnau, Gisela Mir (Author), Tothill, Richard W. (Author), Holloway, Timothy P. (Author), Semple, Timothy (Author), Harliwong, Ivon (Author), Nourse, Craig (Author), Nourbakhsh, Ehsan (Author), Manning, Suzanne (Author), Idrisoglu, Senel (Author), Bruxner, Timothy J. C. (Author), Christ, Angelika N. (Author), Poudel, Barsha (Author), Holmes, Oliver (Author), Anderson, Matthew (Author), Leonard, Conrad (Author), Lonie, Andrew (Author), Hall, Nathan (Author), Wood, Scott (Author), Taylor, Darrin F. (Author), Xu, Qinying (Author), Fink, J. Lynn (Author), Waddell, Nick (Author), Drapkin, Ronny (Author), Stronach, Euan (Author), Gabra, Hani (Author), Brown, Robert (Author), Jewell, Andrea (Author), Nagaraj, Shivashankar H. (Author), Markham, Emma (Author), Wilson, Peter J. (Author), Ellul, Jason (Author), McNally, Orla (Author), Doyle, Maria A. (Author), Vedururu, Ravikiran (Author), Stewart, Collin (Author), Lengyel, Ernst (Author), Pearson, John V. (Author), Waddell, Nicola (Author), deFazio, Anna (Author), Grimmond, Sean M. (Author) and Bowtell, David D. L. (Author)
Journal TitleNature
Journal Citation521 (7553), pp. 489-494
Number of Pages20
Year2015
PublisherNature Publishing Group
Place of PublicationUnited Kingdom
ISSN0028-0836
0090-0028
0300-8746
1476-4687
Digital Object Identifier (DOI)https://doi.org/10.1038/nature14410
Web Address (URL)http://www.nature.com/doifinder/10.1038/nature14410
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.

Keywordsovarian cancer; genome; chemotherapy
ANZSRC Field of Research 2020321103. Cancer genetics
Public Notes

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Byline AffiliationsUniversity of Queensland
Peter MacCallum Cancer Centre, Australia
Jackson Laboratory for Genomic Medicine, United States
Imperial College London, United Kingdom
Westmead Millennium Institute, Australia
Crown Princess Mary Cancer Centre, Australia
University of New South Wales
University of Melbourne
Department of Health, Victoria
Victorian Institute of Forensic Medicine, Australia
Victorian Life Sciences Computation Initiative, Australia
La Trobe University
Dana-Farber Cancer Institute, United States
University of Chicago, United States
University of Western Australia
University of Sydney
Institution of OriginUniversity of Southern Queensland
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