Article | Published:

Whole–genome characterization of chemoresistant ovarian cancer

Nature volume 521, pages 489494 (28 May 2015) | Download Citation

  • A Corrigendum to this article was published on 21 October 2015

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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Gene Expression Omnibus

Data deposits

The whole genome and transcriptome sequencing data have been deposited in the European Genome-phenome Archive (EGA) repository under the accession code EGAD00001000877. Genotyping, methylation and miRNA data sets have been submitted into the Gene Expression Omnibus (GEO) accession GSE65821. A complete list of the AOCS Study Group can be found at http://www.aocstudy.org.

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Acknowledgements

The AOCS gratefully acknowledge the cooperation of the participating institutions in Australia, and also acknowledge the contribution of the study nurses, research assistants and all clinical and scientific collaborators including L. Galletta, C. Emmanuel, L. Bowes and J. Hallo. The authors acknowledge assistance from C. Anderson and D. Gwynne. The CASCADE investigators would like to thank the CASCADE Management Committee, all staff at the Victorian Institute of Forensic Medicine, D. Stevens and Tobin Brothers Funerals. The investigators would like to thank the Australia New Zealand Gynaecological Oncology Group (ANZGOG) and the women, and their families, who participated in these research programs. This work was supported by the National Health and Medical Research Council of Australia (NHMRC ID631701), Worldwide Cancer Research (09-0676) and Cancer Australia (1004673). The Australian Ovarian Cancer Study was supported by the US Army Medical Research and Materiel Command under DAMD17-01-1-0729, The Cancer Council Victoria, Queensland Cancer Fund, The Cancer Council New South Wales, The Cancer Council South Australia, The Cancer Foundation of Western Australia, The Cancer Council Tasmania and the National Health and Medical Research Council of Australia (NHMRC; ID400413, ID400281). The AOCS gratefully acknowledges additional support from S. Boldeman, the Agar family, Ovarian Cancer Australia and Ovarian Cancer Action (UK). The Gynaecological Oncology Biobank at Westmead, a member of the Australasian Biospecimen Network-Oncology group, was supported by grants from the NHMRC (ID 310670, ID 628903) and the Cancer Institute of New South Wales. The CASCADE study was supported by the Peter MacCallum Cancer Centre Foundation, and in kind by the Victorian Institute of Forensic Medicine and Tobin Brothers Funerals.

Author information

Author notes

    • Ann-Marie Patch
    • , Elizabeth L. Christie
    • , Dariush Etemadmoghadam
    •  & Dale W. Garsed

    These authors contributed equally to this work.

    • Anna deFazio
    • , Sean M. Grimmond
    •  & David D. L. Bowtell

    These authors jointly supervised this work.

Affiliations

  1. Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia

    • Ann-Marie Patch
    • , Katia Nones
    • , Peter J. Bailey
    • , Karin S. Kassahn
    • , Felicity Newell
    • , Michael C. J. Quinn
    • , Stephen Kazakoff
    • , Kelly Quek
    • , David K. Miller
    • , 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
    • , Scott Wood
    • , Darrin F. Taylor
    • , Qinying Xu
    • , J. Lynn Fink
    • , Nick Waddell
    • , Shivashankar H. Nagaraj
    • , Emma Markham
    • , Peter J. Wilson
    • , John V. Pearson
    • , Nicola Waddell
    •  & Sean M. Grimmond
  2. QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia

    • Ann-Marie Patch
    • , Katia Nones
    • , Michael C. J. Quinn
    • , Stephen Kazakoff
    • , Oliver Holmes
    • , Conrad Leonard
    • , Scott Wood
    • , Qinying Xu
    • , John V. Pearson
    •  & Nicola Waddell
  3. Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia

    • Elizabeth L. Christie
    • , Dariush Etemadmoghadam
    • , Dale W. Garsed
    • , Sian Fereday
    • , Prue Cowin
    • , Kathryn Alsop
    • , Huei San Leong
    • , Anne Hamilton
    • , Linda Mileshkin
    • , George Au-Yeung
    • , Walid Azar
    • , Chris Mitchell
    • , Nadia Traficante
    • , Joy Hendley
    • , Heather Thorne
    • , Mark Shackleton
    • , Gisela Mir Arnau
    • , Richard W. Tothill
    • , Timothy P. Holloway
    • , Timothy Semple
    • , Jason Ellul
    • , Maria A. Doyle
    • , Ravikiran Vedururu
    •  & David D. L. Bowtell
  4. Department of Pathology, University of Melbourne, Parkville, Victoria 3052, Australia

    • Dariush Etemadmoghadam
    • , Paul Waring
    •  & David D. L. Bowtell
  5. Sir Peter MacCallum Cancer Centre Department of Oncology, University of Melbourne, Parkville, Victoria 3052, Australia

    • Dariush Etemadmoghadam
    • , Linda Mileshkin
    • , Mark Shackleton
    • , Richard W. Tothill
    •  & David D. L. Bowtell
  6. The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut 06030, USA

    • Joshy George
  7. WolfsonWohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK

    • Peter J. Bailey
    •  & Sean M. Grimmond
  8. Technology Advancement Unit, Genetics and Molecular Pathology, SA Pathology, Adelaide, South Australia 5000, Australia

    • Karin S. Kassahn
  9. Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London W12 0HS, UK

    • Charlotte Wilhelm-Benartzi
    • , Ed Curry
    • , Euan Stronach
    • , Hani Gabra
    • , Robert Brown
    •  & David D. L. Bowtell
  10. Department of Medicine, University of Melbourne, Parkville, Victoria 3052, Australia

    • Anne Hamilton
  11. The Royal Women’s Hospital, Parkville, Victoria 3052, Australia

    • Anne Hamilton
    •  & Jan Pyman
  12. Centre for Cancer Research, University of Sydney at Westmead Millennium Institute, and Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales 2145, Australia

    • Catherine Kennedy
    • , Jillian Hung
    • , Yoke-Eng Chiew
    •  & Anna deFazio
  13. Crown Princess Mary Cancer Centre and University of Sydney at Westmead Hospital, Westmead, Sydney, New South Wales 2145, Australia

    • Paul Harnett
  14. Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales 2031, Australia

    • Michael Friedlander
  15. Victorian Institute of Forensic Medicine, Southbank, Victoria 3006, Australia

    • Stephen Cordner
    • , Patricia O’Brien
    • , Jodie Leditschke
    • , Greg Young
    •  & Kate Strachan
  16. Victorian Life Sciences Computation Initiative, Carlton, Victoria 3053, Australia

    • Andrew Lonie
  17. La Trobe Institute for Molecular Science, Bundoora, Victoria 3083, Australia

    • Nathan Hall
  18. Dana-Farber Cancer Institute, Boston, Massachusetts 02115-5450, USA

    • Ronny Drapkin
  19. University of Chicago, Chicago, Illinois 60637, USA

    • Andrea Jewell
    •  & Ernst Lengyel
  20. The University of Western Australia, Crawley, Western Australia 6009, Australia

    • Collin Stewart
  21. Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria 3052, Australia

    • David D. L. Bowtell
  22. Department of Obstetrics and Gynaecology, The University of Melbourne, and The Royal Women’s Hospital, Parkville, Victoria 3052, Australia

    • Michael Quinn
    •  & Orla McNally

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  1. The Australian Ovarian Cancer Study Group

    A list of authors and affiliations appears in the Supplementary Information

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Contributions

Project supervision: J.V.P., Nicola.W., A.D.F., S.M.G., D.D.L.B. Study design: A.M.P., E.L.C., D.E., D.W.G., S.F., P.C., Nicola.W., A.D.F., S.M.G., D.D.L.B. Sample acquisition: S.F., K.A., A.O.C.S., A.H., L.M., O.M.N., C.K., J.H., Y.E.C., P.H., M.F., M.Q., J.P., S.C., P.O.B., J.L., P.W., N.T., H.T., M.S., R.D., E.S., H.G., A.J., O.M.N., E.L., A.D.F., D.D.L.B. Sample preparation: E.L.C., D.E., D.W.G., P.C., Y.E.C., P.H., C.M., J.H. Data acquisition: E.L.C., D.E., D.W.G., S.F., D.K.M., G.M.A., T.P.H., T.S., I.H., C.N., E.N., S.M., S.I., T.J.C.B., A.N.C. Performed patient autopsy: G.Y., K.S. Sequence data management, alignment and mutation identification: A.M.P., K.N., F.N., S.K., O.H., M.A., C.L., S.W., Q.X., J.L.F., Nick.W., S.H.N., P.J.W., J.V.P., S.M.G. Genome informatics, software tool development: A.M.P., P.J.B., K.S.K., F.N., S.K., B.P., O.H., M.A., C.L., S.W., D.F.T., Q.X., J.L.F., Nick.W., J.V.P., Nicola.W. Data analysis: A.M.P., E.L.C., D.E., D.W.G., J.G., K.N., P.J.B., K.S.K., M.C.JQ., K.Q., C.W.B., E.C., H.S.L., G.A.Y., W.A., R.W.T., A.L., N.H., R.B., J.E., M.D., R.V., C.S., J.V.P., Nicola.W., S.M.G. Perform molecular/verification analysis: E.L.C., K.N., S.M., E.M. Wrote the manuscript: A.M.P., E.L.C., D.E., D.W.G., Nicola.W., A.D.F., S.M.G., D.D.L.B.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to David D. L. Bowtell.

Extended data

Supplementary information

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  1. 1.

    Supplementary Information

    This file contains Supplementary Text, Data and Figures (see Contents list for details), a list of the AOCS Study Group Authors and Affiliations and additional references.

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    This zipped file contains Supplementary Tables 1-18.

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https://doi.org/10.1038/nature14410

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