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Whole–genome characterization of chemoresistant ovarian cancer

Author

Listed:
  • Ann-Marie Patch

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
    QIMR Berghofer Medical Research Institute)

  • Elizabeth L. Christie

    (Peter MacCallum Cancer Centre)

  • Dariush Etemadmoghadam

    (Peter MacCallum Cancer Centre
    University of Melbourne
    University of Melbourne)

  • 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
    QIMR Berghofer Medical Research Institute)

  • 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
    WolfsonWohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow)

  • Karin S. Kassahn

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
    Technology Advancement Unit, Genetics and Molecular Pathology, SA Pathology)

  • 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
    QIMR Berghofer Medical Research Institute)

  • Stephen Kazakoff

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
    QIMR Berghofer Medical Research Institute)

  • 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
    University of Melbourne
    The Royal Women’s Hospital)

  • Linda Mileshkin

    (Peter MacCallum Cancer Centre
    University of Melbourne)

  • 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
    University of Melbourne)

  • 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
    University of Melbourne)

  • 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
    QIMR Berghofer Medical Research Institute)

  • 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
    QIMR Berghofer Medical Research Institute)

  • 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
    QIMR Berghofer Medical Research Institute)

  • 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
    QIMR Berghofer Medical Research Institute)

  • 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
    QIMR Berghofer Medical Research Institute)

  • Nicola Waddell

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
    QIMR Berghofer Medical Research Institute)

  • 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
    WolfsonWohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow)

  • David D. L. Bowtell

    (Peter MacCallum Cancer Centre
    University of Melbourne
    University of Melbourne
    Ovarian Cancer Action Research Centre, Imperial College London)

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.

Suggested Citation

  • 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 & Felici, 2015. "Whole–genome characterization of chemoresistant ovarian cancer," Nature, Nature, vol. 521(7553), pages 489-494, May.
    • Handle: RePEc:nat:nature:v:521:y:2015:i:7553:d:10.1038_nature14410
    DOI: 10.1038/nature14410
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    Citations

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    Cited by:

    1. Elena Denisenko & Leanne Kock & Adeline Tan & Aaron B. Beasley & Maria Beilin & Matthew E. Jones & Rui Hou & Dáithí Ó Muirí & Sanela Bilic & G. Raj K. A. Mohan & Stuart Salfinger & Simon Fox & Khaing , 2024. "Spatial transcriptomics reveals discrete tumour microenvironments and autocrine loops within ovarian cancer subclones," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Chunyang Bao & Richard W. Tourdot & Gregory J. Brunette & Chip Stewart & Lili Sun & Hideo Baba & Masayuki Watanabe & Agoston T. Agoston & Kunal Jajoo & Jon M. Davison & Katie S. Nason & Gad Getz & Ken, 2023. "Genomic signatures of past and present chromosomal instability in Barrett’s esophagus and early esophageal adenocarcinoma," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    3. Mireia Crispin-Ortuzar & Ramona Woitek & Marika A. V. Reinius & Elizabeth Moore & Lucian Beer & Vlad Bura & Leonardo Rundo & Cathal McCague & Stephan Ursprung & Lorena Escudero Sanchez & Paula Martin-, 2023. "Integrated radiogenomics models predict response to neoadjuvant chemotherapy in high grade serous ovarian cancer," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    4. Tom Nyen & Mélanie Planque & Lilian Wagensveld & Joao A. G. Duarte & Esther A. Zaal & Ali Talebi & Matteo Rossi & Pierre-René Körner & Lara Rizzotto & Stijn Moens & Wout Wispelaere & Regina E. M. Baid, 2022. "Serine metabolism remodeling after platinum-based chemotherapy identifies vulnerabilities in a subgroup of resistant ovarian cancers," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    5. Filipe Correia Martins & Dominique-Laurent Couturier & Ines Santiago & Carolin Margarethe Sauer & Maria Vias & Mihaela Angelova & Deborah Sanders & Anna Piskorz & James Hall & Karen Hosking & Anumithr, 2022. "Clonal somatic copy number altered driver events inform drug sensitivity in high-grade serous ovarian cancer," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    6. Jennifer B. Shah & Dana Pueschl & Bradley Wubbenhorst & Mengyao Fan & John Pluta & Kurt D’Andrea & Anna P. Hubert & Jake S. Shilan & Wenting Zhou & Adam A. Kraya & Alba Llop Guevara & Catherine Ruan &, 2022. "Analysis of matched primary and recurrent BRCA1/2 mutation-associated tumors identifies recurrence-specific drivers," Nature Communications, Nature, vol. 13(1), pages 1-19, December.

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