. 2015 May 28;521(7553):489-94.

doi: 10.1038/nature14410.

Whole-genome characterization of chemoresistant ovarian cancer

Ann-Marie Patch¹, Elizabeth L Christie², Dariush Etemadmoghadam³, Dale W Garsed², Joshy George⁴, Sian Fereday², Katia Nones¹, Prue Cowin², Kathryn Alsop², Peter J Bailey⁵, Karin S Kassahn⁶, Felicity Newell⁷, Michael C J Quinn¹, Stephen Kazakoff¹, Kelly Quek⁷, Charlotte Wilhelm-Benartzi⁸, Ed Curry⁸, Huei San Leong²; Australian Ovarian Cancer Study Group; Anne Hamilton⁹, Linda Mileshkin¹⁰, George Au-Yeung², Catherine Kennedy¹¹, Jillian Hung¹¹, Yoke-Eng Chiew¹¹, Paul Harnett¹², Michael Friedlander¹³, Michael Quinn¹⁴, Jan Pyman¹⁴, Stephen Cordner¹⁵, Patricia O'Brien¹⁵, Jodie Leditschke¹⁵, Greg Young¹⁵, Kate Strachan¹⁵, Paul Waring¹⁶, Walid Azar², Chris Mitchell², Nadia Traficante², Joy Hendley², Heather Thorne², Mark Shackleton¹⁰, David K Miller⁷, Gisela Mir Arnau², Richard W Tothill¹⁰, Timothy P Holloway², Timothy Semple², Ivon Harliwong⁷, Craig Nourse⁷, Ehsan Nourbakhsh⁷, Suzanne Manning⁷, Senel Idrisoglu⁷, Timothy J C Bruxner⁷, Angelika N Christ⁷, Barsha Poudel⁷, Oliver Holmes¹, Matthew Anderson⁷, Conrad Leonard¹, Andrew Lonie¹⁷, Nathan Hall¹⁸, Scott Wood¹, Darrin F Taylor⁷, Qinying Xu¹, J Lynn Fink⁷, Nick Waddell⁷, Ronny Drapkin¹⁹, Euan Stronach⁸, Hani Gabra⁸, Robert Brown⁸, Andrea Jewell²⁰, Shivashankar H Nagaraj⁷, Emma Markham⁷, Peter J Wilson⁷, Jason Ellul², Orla McNally¹¹, Maria A Doyle², Ravikiran Vedururu², Collin Stewart²¹, Ernst Lengyel²⁰, John V Pearson¹, Nicola Waddell¹, Anna deFazio¹¹, Sean M Grimmond⁵, David D L Bowtell²²

Collaborators, Affiliations

Collaborators

Australian Ovarian Cancer Study Group:
D Bowtell, G Chenevix-Trench, A Green, P Webb, A DeFazio, D Gertig, N Traficante, S Fereday, S Moore, J Hung, K Harrap, T Sadkowsky, N Pandeya, M Malt, A Mellon, R Robertson, T Vanden Bergh, M Jones, P Mackenzie, J Maidens, K Nattress, Y E Chiew, A Stenlake, H Sullivan, B Alexander, P Ashover, S Brown, T Corrish, L Green, L Jackman, K Ferguson, K Martin, A Martyn, B Ranieri, J White, V Jayde, P Mamers, L Bowes, L Galletta, D Giles, J Hendley, K Alsop, T Schmidt, H Shirley, C Ball, C Young, S Viduka, Hoa Tran, Sanela Bilic, Lydia Glavinas, Julia Brooks, R Stuart-Harris, F Kirsten, J Rutovitz, P Clingan, A Glasgow, A Proietto, S Braye, G Otton, J Shannon, T Bonaventura, J Stewart, S Begbie, M Friedlander, D Bell, S Baron-Hay, A Ferrier, G Gard, D Nevell, N Pavlakis, S Valmadre, B Young, C Camaris, R Crouch, L Edwards, N Hacker, D Marsden, G Robertson, P Beale, J Beith, J Carter, C Dalrymple, R Houghton, P Russell, M Links, J Grygiel, J Hill, A Brand, K Byth, R Jaworski, P Harnett, R Sharma, G Wain, B Ward, D Papadimos, A Crandon, M Cummings, K Horwood, A Obermair, L Perrin, D Wyld, J Nicklin, M Davy, M K Oehler, C Hall, T Dodd, T Healy, K Pittman, D Henderson, J Miller, J Pierdes, P Blomfield, D Challis, R McIntosh, A Parker, B Brown, R Rome, D Allen, P Grant, S Hyde, R Laurie, M Robbie, D Healy, T Jobling, T Manolitsas, J McNealage, P Rogers, B Susil, E Sumithran, I Simpson, K Phillips, D Rischin, S Fox, D Johnson, S Lade, M Loughrey, N O'Callaghan, W Murray, P Waring, V Billson, J Pyman, D Neesham, M Quinn, C Underhill, R Bell, L F Ng, R Blum, V Ganju, I Hammond, Y Leung, A McCartney, M Buck, I Haviv, D Purdie, D Whiteman, N Zeps

Affiliations

¹ 1] Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia [2] QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
² Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
³ 1] Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia [2] Department of Pathology, University of Melbourne, Parkville, Victoria 3052, Australia [3] Sir Peter MacCallum Cancer Centre Department of Oncology, University of Melbourne, Parkville, Victoria 3052, Australia.
⁴ The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut 06030, USA.
⁵ 1] Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia [2] WolfsonWohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK.
⁶ 1] Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia [2] Technology Advancement Unit, Genetics and Molecular Pathology, SA Pathology, Adelaide, South Australia 5000, Australia.
⁷ Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia.
⁸ Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London W12 0HS, UK.
⁹ 1] Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia [2] Department of Medicine, University of Melbourne, Parkville, Victoria 3052, Australia [3] The Royal Women's Hospital, Parkville, Victoria 3052, Australia.
¹⁰ 1] Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia [2] Sir Peter MacCallum Cancer Centre Department of Oncology, University of Melbourne, Parkville, Victoria 3052, Australia.
¹¹ Centre for Cancer Research, University of Sydney at Westmead Millennium Institute, and Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales 2145, Australia.
¹² Crown Princess Mary Cancer Centre and University of Sydney at Westmead Hospital, Westmead, Sydney, New South Wales 2145, Australia.
¹³ Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales 2031, Australia.
¹⁴ The Royal Women's Hospital, Parkville, Victoria 3052, Australia.
¹⁵ Victorian Institute of Forensic Medicine, Southbank, Victoria 3006, Australia.
¹⁶ Department of Pathology, University of Melbourne, Parkville, Victoria 3052, Australia.
¹⁷ Victorian Life Sciences Computation Initiative, Carlton, Victoria 3053, Australia.
¹⁸ La Trobe Institute for Molecular Science, Bundoora, Victoria 3083, Australia.
¹⁹ Dana-Farber Cancer Institute, Boston, Massachusetts 02115-5450, USA.
²⁰ University of Chicago, Chicago, Illinois 60637, USA.
²¹ The University of Western Australia, Crawley, Western Australia 6009, Australia.
²² 1] Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia [2] Department of Pathology, University of Melbourne, Parkville, Victoria 3052, Australia [3] Sir Peter MacCallum Cancer Centre Department of Oncology, University of Melbourne, Parkville, Victoria 3052, Australia [4] Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London W12 0HS, UK [5] Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria 3052, Australia.

PMID: 26017449
DOI: 10.1038/nature14410

Whole-genome characterization of chemoresistant ovarian cancer

Ann-Marie Patch et al. Nature. 2015.

. 2015 May 28;521(7553):489-94.

doi: 10.1038/nature14410.

Authors

Collaborators

Australian Ovarian Cancer Study Group:
D Bowtell, G Chenevix-Trench, A Green, P Webb, A DeFazio, D Gertig, N Traficante, S Fereday, S Moore, J Hung, K Harrap, T Sadkowsky, N Pandeya, M Malt, A Mellon, R Robertson, T Vanden Bergh, M Jones, P Mackenzie, J Maidens, K Nattress, Y E Chiew, A Stenlake, H Sullivan, B Alexander, P Ashover, S Brown, T Corrish, L Green, L Jackman, K Ferguson, K Martin, A Martyn, B Ranieri, J White, V Jayde, P Mamers, L Bowes, L Galletta, D Giles, J Hendley, K Alsop, T Schmidt, H Shirley, C Ball, C Young, S Viduka, Hoa Tran, Sanela Bilic, Lydia Glavinas, Julia Brooks, R Stuart-Harris, F Kirsten, J Rutovitz, P Clingan, A Glasgow, A Proietto, S Braye, G Otton, J Shannon, T Bonaventura, J Stewart, S Begbie, M Friedlander, D Bell, S Baron-Hay, A Ferrier, G Gard, D Nevell, N Pavlakis, S Valmadre, B Young, C Camaris, R Crouch, L Edwards, N Hacker, D Marsden, G Robertson, P Beale, J Beith, J Carter, C Dalrymple, R Houghton, P Russell, M Links, J Grygiel, J Hill, A Brand, K Byth, R Jaworski, P Harnett, R Sharma, G Wain, B Ward, D Papadimos, A Crandon, M Cummings, K Horwood, A Obermair, L Perrin, D Wyld, J Nicklin, M Davy, M K Oehler, C Hall, T Dodd, T Healy, K Pittman, D Henderson, J Miller, J Pierdes, P Blomfield, D Challis, R McIntosh, A Parker, B Brown, R Rome, D Allen, P Grant, S Hyde, R Laurie, M Robbie, D Healy, T Jobling, T Manolitsas, J McNealage, P Rogers, B Susil, E Sumithran, I Simpson, K Phillips, D Rischin, S Fox, D Johnson, S Lade, M Loughrey, N O'Callaghan, W Murray, P Waring, V Billson, J Pyman, D Neesham, M Quinn, C Underhill, R Bell, L F Ng, R Blum, V Ganju, I Hammond, Y Leung, A McCartney, M Buck, I Haviv, D Purdie, D Whiteman, N Zeps

Affiliations

¹ 1] Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia [2] QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
² Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
³ 1] Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia [2] Department of Pathology, University of Melbourne, Parkville, Victoria 3052, Australia [3] Sir Peter MacCallum Cancer Centre Department of Oncology, University of Melbourne, Parkville, Victoria 3052, Australia.
⁴ The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut 06030, USA.
⁵ 1] Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia [2] WolfsonWohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK.
⁶ 1] Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia [2] Technology Advancement Unit, Genetics and Molecular Pathology, SA Pathology, Adelaide, South Australia 5000, Australia.
⁷ Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia.
⁸ Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London W12 0HS, UK.
⁹ 1] Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia [2] Department of Medicine, University of Melbourne, Parkville, Victoria 3052, Australia [3] The Royal Women's Hospital, Parkville, Victoria 3052, Australia.
¹⁰ 1] Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia [2] Sir Peter MacCallum Cancer Centre Department of Oncology, University of Melbourne, Parkville, Victoria 3052, Australia.
¹¹ Centre for Cancer Research, University of Sydney at Westmead Millennium Institute, and Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales 2145, Australia.
¹² Crown Princess Mary Cancer Centre and University of Sydney at Westmead Hospital, Westmead, Sydney, New South Wales 2145, Australia.
¹³ Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales 2031, Australia.
¹⁴ The Royal Women's Hospital, Parkville, Victoria 3052, Australia.
¹⁵ Victorian Institute of Forensic Medicine, Southbank, Victoria 3006, Australia.
¹⁶ Department of Pathology, University of Melbourne, Parkville, Victoria 3052, Australia.
¹⁷ Victorian Life Sciences Computation Initiative, Carlton, Victoria 3053, Australia.
¹⁸ La Trobe Institute for Molecular Science, Bundoora, Victoria 3083, Australia.
¹⁹ Dana-Farber Cancer Institute, Boston, Massachusetts 02115-5450, USA.
²⁰ University of Chicago, Chicago, Illinois 60637, USA.
²¹ The University of Western Australia, Crawley, Western Australia 6009, Australia.
²² 1] Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia [2] Department of Pathology, University of Melbourne, Parkville, Victoria 3052, Australia [3] Sir Peter MacCallum Cancer Centre Department of Oncology, University of Melbourne, Parkville, Victoria 3052, Australia [4] Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London W12 0HS, UK [5] Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria 3052, Australia.

PMID: 26017449
DOI: 10.1038/nature14410

Erratum in

Corrigendum: Whole-genome characterization of chemoresistant ovarian cancer.
Patch AM, Christie EL, Etemadmoghadam D, Garsed DW, George J, Fereday S, Nones K, Cowin P, Alsop K, Bailey PJ, Kassahn KS, Newell F, Quinn MC, Kazakoff S, Quek K, Wilhelm-Benartzi C, Curry E, Leong HS; Australian Ovarian Cancer Study Group; Hamilton A, Mileshkin L, Au-Yeung G, Kennedy C, Hung J, Chiew YE, Harnett P, Friedlander M, Quinn M, Pyman J, Cordner S, O'Brien P, Leditschke J, Young G, Strachan K, Waring P, Azar W, Mitchell C, Traficante N, Hendley J, Thorne H, Shackleton M, Miller DK, Arnau GM, Tothill RW, Holloway TP, Semple T, Harliwong I, Nourse C, Nourbakhsh E, Manning S, Idrisoglu S, Bruxner TJ, Christ AN, Poudel B, Holmes O, Anderson M, Leonard C, Lonie A, Hall N, Wood S, Taylor DF, Xu Q, Fink JL, Waddell N, Drapkin R, Stronach E, Gabra H, Brown R, Jewell A, Nagaraj SH, Markham E, Wilson PJ, Ellul J, McNally O, Doyle MA, Vedururu R, Stewart C, Lengyel E, Pearson JV, Waddell N, deFazio A, Grimmond SM, Bowtell DD. Patch AM, et al. Nature. 2015 Nov 19;527(7578):398. doi: 10.1038/nature15716. Epub 2015 Oct 21. Nature. 2015. PMID: 26503049 No abstract available.

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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Whole-genome characterization of chemoresistant ovarian cancer

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Whole-genome characterization of chemoresistant ovarian cancer

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