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Whole genomes redefine the mutational landscape of pancreatic cancer

Author

Listed:
  • Nicola Waddell

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia
    QIMR Berghofer Medical Research Institute, Herston Road, Brisbane 4006, Australia)

  • Marina Pajic

    (The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia
    St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales)

  • Ann-Marie Patch

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia)

  • David K. Chang

    (The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia
    Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia
    South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales
    Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK)

  • Karin S. Kassahn

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia)

  • Peter Bailey

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia
    Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK)

  • Amber L. Johns

    (The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia)

  • David Miller

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia)

  • Katia Nones

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia)

  • Kelly Quek

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia)

  • Michael C. J. Quinn

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia)

  • Alan J. Robertson

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia)

  • Muhammad Z. H. Fadlullah

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia)

  • Tim J. C. Bruxner

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia)

  • Angelika N. Christ

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia)

  • Ivon Harliwong

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia)

  • Senel Idrisoglu

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia)

  • Suzanne Manning

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia)

  • Craig Nourse

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia
    Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK)

  • Ehsan Nourbakhsh

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia)

  • Shivangi Wani

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia)

  • Peter J. Wilson

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia)

  • Emma Markham

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia)

  • Nicole Cloonan

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia
    QIMR Berghofer Medical Research Institute, Herston Road, Brisbane 4006, Australia)

  • Matthew J. Anderson

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia)

  • J. Lynn Fink

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia)

  • Oliver Holmes

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia)

  • Stephen H. Kazakoff

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia)

  • Conrad Leonard

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia)

  • Felicity Newell

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia)

  • Barsha Poudel

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia)

  • Sarah Song

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia)

  • Darrin Taylor

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia)

  • Nick Waddell

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia)

  • Scott Wood

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia)

  • Qinying Xu

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia)

  • Jianmin Wu

    (The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia)

  • Mark Pinese

    (The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia)

  • Mark J. Cowley

    (The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia)

  • Hong C. Lee

    (The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia)

  • Marc D. Jones

    (The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia
    Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK)

  • Adnan M. Nagrial

    (The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia)

  • Jeremy Humphris

    (The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia)

  • Lorraine A. Chantrill

    (The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia)

  • Venessa Chin

    (The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia)

  • Angela M. Steinmann

    (The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia)

  • Amanda Mawson

    (The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia)

  • Emily S. Humphrey

    (The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia)

  • Emily K. Colvin

    (The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia)

  • Angela Chou

    (The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia
    St Vincent’s Hospital)

  • Christopher J. Scarlett

    (The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia
    School of Environmental & Life Sciences, University of Newcastle)

  • Andreia V. Pinho

    (The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia)

  • Marc Giry-Laterriere

    (The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia)

  • Ilse Rooman

    (The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia)

  • Jaswinder S. Samra

    (Royal North Shore Hospital, St Leonards, Sydney, New South Wales 2065, Australia
    University of Sydney)

  • James G. Kench

    (The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia
    University of Sydney
    Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital)

  • Jessica A. Pettitt

    (The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia)

  • Neil D. Merrett

    (Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia
    School of Medicine, University of Western Sydney)

  • Christopher Toon

    (The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia)

  • Krishna Epari

    (Fremantle Hospital, Alma Street, Fremantle, Western Australia 6160, Australia)

  • Nam Q. Nguyen

    (Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia)

  • Andrew Barbour

    (Princess Alexandra Hospital, Ipswich Rd, Woollongabba, Queensland 4102, Australia)

  • Nikolajs Zeps

    (School of Surgery M507, University of Western Australia, 35 Stirling Highway, Nedlands 6009, Australia
    St John of God Pathology, 12 Salvado Rd
    Bendat Family Comprehensive Cancer Centre, St John of God Subiaco Hospital)

  • Nigel B. Jamieson

    (Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK
    Academic Unit of Surgery, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow Royal Infirmary, Glasgow G4 OSF, UK
    West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G31 2ER, UK)

  • Janet S. Graham

    (Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK
    Beatson West of Scotland Cancer Centre, 1053 Great Western Road, Glasgow G12 0YN, UK)

  • Simone P. Niclou

    (Norlux Neuro-Oncology Laboratory, CRP-Santé Luxembourg, 84 Val Fleuri, L-1526, Luxembourg)

  • Rolf Bjerkvig

    (Norlux Neuro-Oncology, University of Bergen, Jonas Lies vei 91, N-5019 Bergen, Norway)

  • Robert Grützmann

    (TU Dresden, Fetscherstr. 74, 01307 Dresden, Germany)

  • Daniela Aust

    (TU Dresden, Fetscherstr. 74, 01307 Dresden, Germany)

  • Ralph H. Hruban

    (The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine)

  • Anirban Maitra

    (University of Texas MD Anderson Cancer Center)

  • Christine A. Iacobuzio-Donahue

    (Memorial Sloan Kettering Cancer Center)

  • Christopher L. Wolfgang

    (The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine)

  • Richard A. Morgan

    (The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine)

  • Rita T. Lawlor

    (ARC-NET Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona 37134, Italy
    University of Verona, Verona 37134, Italy)

  • Vincenzo Corbo

    (ARC-NET Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona 37134, Italy)

  • Claudio Bassi

    (Pancreas Institute, University and Hospital Trust of Verona, Verona 37134, Italy)

  • Massimo Falconi

    (Pancreas Institute, University and Hospital Trust of Verona, Verona 37134, Italy
    Ospedale Sacro Cuore Don Calabria Negrar, Verona 37024, Italy)

  • Giuseppe Zamboni

    (University of Verona, Verona 37134, Italy
    Ospedale Sacro Cuore Don Calabria Negrar, Verona 37024, Italy)

  • Giampaolo Tortora

    (University and Hospital Trust of Verona, Verona 37134, Italy)

  • Margaret A. Tempero

    (University of California)

  • Anthony J. Gill

    (The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia
    University of Sydney)

  • James R. Eshleman

    (The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine)

  • Christian Pilarsky

    (TU Dresden, Fetscherstr. 74, 01307 Dresden, Germany)

  • Aldo Scarpa

    (ARC-NET Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona 37134, Italy
    University of Verona, Verona 37134, Italy)

  • Elizabeth A. Musgrove

    (Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK)

  • John V. Pearson

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia
    QIMR Berghofer Medical Research Institute, Herston Road, Brisbane 4006, Australia)

  • Andrew V. Biankin

    (The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia
    Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia
    South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales
    Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK)

  • Sean M. Grimmond

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia
    Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK)

Abstract

Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded.

Suggested Citation

  • Nicola Waddell & Marina Pajic & Ann-Marie Patch & David K. Chang & Karin S. Kassahn & Peter Bailey & Amber L. Johns & David Miller & Katia Nones & Kelly Quek & Michael C. J. Quinn & Alan J. Robertson , 2015. "Whole genomes redefine the mutational landscape of pancreatic cancer," Nature, Nature, vol. 518(7540), pages 495-501, February.
    • Handle: RePEc:nat:nature:v:518:y:2015:i:7540:d:10.1038_nature14169
    DOI: 10.1038/nature14169
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    Cited by:

    1. Kakushadze, Zura & Yu, Willie, 2016. "Factor models for cancer signatures," Physica A: Statistical Mechanics and its Applications, Elsevier, vol. 462(C), pages 527-559.

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