Whole genomes redefine the mutational landscape of pancreatic cancer

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, Muhammad Z. H. Fadlullah, Tim J. C. Bruxner, Angelika N. Christ, Ivon Harliwong, Senel Idrisoglu, Suzanne Manning, Craig Nourse, Ehsan Nourbakhsh, Shivangi Wani, Peter J. Wilson, Emma Markham, Nicole Cloonan, Matthew J. Anderson, J. Lynn Fink, Oliver Holmes, Stephen H. Kazakoff, Conrad Leonard, Felicity Newell, Barsha Poudel, Sarah Song, Darrin Taylor, Nick Waddell, Scott Wood, Qinying Xu, Jianmin Wu, Mark Pinese, Mark J. Cowley, Hong C. Lee, Marc D. Jones, Adnan M. Nagrial, Jeremy Humphris, Lorraine A. Chantrill, Venessa Chin, Angela M. Steinmann, Amanda Mawson, Emily S. Humphrey, Emily K. Colvin, Angela Chou, Christopher J. Scarlett, Andreia V. Pinho, Marc Giry-Laterriere, Ilse Rooman, Jaswinder S. Samra, James G. Kench, Jessica A. Pettitt, Neil D. Merrett, Christopher Toon, Krishna Epari, Nam Q. Nguyen, Andrew Barbour, Nikolajs Zeps, Nigel B. Jamieson, Janet S. Graham, Simone P. Niclou, Rolf Bjerkvig, Robert Grützmann, Daniela Aust, Ralph H. Hruban, Anirban Maitra, Christine A. Iacobuzio-Donahue, Christopher L. Wolfgang, Richard A. Morgan, Rita T. Lawlor, Vincenzo Corbo, Claudio Bassi, Massimo Falconi, Giuseppe Zamboni, Giampaolo Tortora, Margaret A. Tempero, Anthony J. Gill, James R. Eshleman, Christian Pilarsky, Aldo Scarpa, Elizabeth A. Musgrove, John V. Pearson, Andrew V. Biankin and Sean M. Grimmond ()
Additional contact information
Nicola Waddell: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, 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
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
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
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
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
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
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
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
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
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
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
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
Nigel B. Jamieson: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, 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
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
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
Giuseppe Zamboni: University of Verona, Verona 37134, 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
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
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
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
Sean M. Grimmond: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia

Nature, 2015, vol. 518, issue 7540, 495-501

Abstract: 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.

Date: 2015
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DOI: 10.1038/nature14169

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