Whole–genome characterization of chemoresistant ovarian cancer

Ann-Marie Patch, Elizabeth L. 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 Mileshkin, George Au-Yeung, Catherine Kennedy, Jillian Hung, Yoke-Eng Chiew, Paul Harnett, Michael Friedlander, Michael Quinn, Jan Pyman, Stephen Cordner, Patricia O’Brien, Jodie Leditschke, Greg Young, Kate Strachan, Paul Waring, Walid Azar, Chris Mitchell, Nadia Traficante, Joy Hendley, Heather 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 McNally, Maria A. Doyle, Ravikiran Vedururu, Collin Stewart, Ernst Lengyel, John V. Pearson, Nicola Waddell, Anna deFazio, Sean M. Grimmond and David D. L. Bowtell ()
Additional contact information
Ann-Marie Patch: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
Elizabeth L. Christie: Peter MacCallum Cancer Centre
Dariush Etemadmoghadam: Peter MacCallum Cancer Centre
Dale W. Garsed: Peter MacCallum Cancer Centre
Joshy George: The Jackson Laboratory for Genomic Medicine
Sian Fereday: Peter MacCallum Cancer Centre
Katia Nones: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
Prue Cowin: Peter MacCallum Cancer Centre
Kathryn Alsop: Peter MacCallum Cancer Centre
Peter J. Bailey: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
Karin S. Kassahn: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
Felicity Newell: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
Michael C. J. Quinn: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
Stephen Kazakoff: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
Kelly Quek: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
Charlotte Wilhelm-Benartzi: Ovarian Cancer Action Research Centre, Imperial College London
Ed Curry: Ovarian Cancer Action Research Centre, Imperial College London
Huei San Leong: Peter MacCallum Cancer Centre
Anne Hamilton: Peter MacCallum Cancer Centre
Linda Mileshkin: Peter MacCallum Cancer Centre
George Au-Yeung: Peter MacCallum Cancer Centre
Catherine Kennedy: Centre for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead Hospital
Jillian Hung: Centre for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead Hospital
Yoke-Eng Chiew: Centre for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead Hospital
Paul Harnett: Crown Princess Mary Cancer Centre and University of Sydney at Westmead Hospital, Westmead
Michael Friedlander: Prince of Wales Clinical School, University of New South Wales
Michael Quinn: The University of Melbourne, and The Royal Women’s Hospital, Parkville, Victoria 3052, Australia
Jan Pyman: The Royal Women’s Hospital
Stephen Cordner: Victorian Institute of Forensic Medicine
Patricia O’Brien: Victorian Institute of Forensic Medicine
Jodie Leditschke: Victorian Institute of Forensic Medicine
Greg Young: Victorian Institute of Forensic Medicine
Kate Strachan: Victorian Institute of Forensic Medicine
Paul Waring: University of Melbourne
Walid Azar: Peter MacCallum Cancer Centre
Chris Mitchell: Peter MacCallum Cancer Centre
Nadia Traficante: Peter MacCallum Cancer Centre
Joy Hendley: Peter MacCallum Cancer Centre
Heather Thorne: Peter MacCallum Cancer Centre
Mark Shackleton: Peter MacCallum Cancer Centre
David K. Miller: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
Gisela Mir Arnau: Peter MacCallum Cancer Centre
Richard W. Tothill: Peter MacCallum Cancer Centre
Timothy P. Holloway: Peter MacCallum Cancer Centre
Timothy Semple: Peter MacCallum Cancer Centre
Ivon Harliwong: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
Craig Nourse: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
Ehsan Nourbakhsh: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
Suzanne Manning: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
Senel Idrisoglu: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
Timothy J. C. Bruxner: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
Angelika N. Christ: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
Barsha Poudel: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
Oliver Holmes: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
Matthew Anderson: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
Conrad Leonard: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
Andrew Lonie: Victorian Life Sciences Computation Initiative
Nathan Hall: La Trobe Institute for Molecular Science
Scott Wood: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
Darrin F. Taylor: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
Qinying Xu: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
J. Lynn Fink: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
Nick Waddell: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
Ronny Drapkin: Dana-Farber Cancer Institute
Euan Stronach: Ovarian Cancer Action Research Centre, Imperial College London
Hani Gabra: Ovarian Cancer Action Research Centre, Imperial College London
Robert Brown: Ovarian Cancer Action Research Centre, Imperial College London
Andrea Jewell: University of Chicago
Shivashankar H. Nagaraj: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
Emma Markham: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
Peter J. Wilson: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
Jason Ellul: Peter MacCallum Cancer Centre
Orla McNally: The University of Melbourne, and The Royal Women’s Hospital, Parkville, Victoria 3052, Australia
Maria A. Doyle: Peter MacCallum Cancer Centre
Ravikiran Vedururu: Peter MacCallum Cancer Centre
Collin Stewart: The University of Western Australia
Ernst Lengyel: University of Chicago
John V. Pearson: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
Nicola Waddell: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
Anna deFazio: Centre for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead Hospital
Sean M. Grimmond: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
David D. L. Bowtell: Peter MacCallum Cancer Centre

Nature, 2015, vol. 521, issue 7553, 489-494

Abstract: 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.

Date: 2015
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DOI: 10.1038/nature14410

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