Whole-genome landscape of pancreatic neuroendocrine tumours

Aldo Scarpa (), David K. Chang, Katia Nones, Vincenzo Corbo, Ann-Marie Patch, Peter Bailey, Rita T. Lawlor, Amber L. Johns, David K. Miller, Andrea Mafficini, Borislav Rusev, Maria Scardoni, Davide Antonello, Stefano Barbi, Katarzyna O. Sikora, Sara Cingarlini, Caterina Vicentini, Skye McKay, Michael C. J. Quinn, Timothy J. C. Bruxner, Angelika N. Christ, Ivon Harliwong, Senel Idrisoglu, Suzanne McLean, Craig Nourse, Ehsan Nourbakhsh, Peter J. Wilson, Matthew J. Anderson, J. Lynn Fink, Felicity Newell, Nick Waddell, Oliver Holmes, Stephen H. Kazakoff, Conrad Leonard, Scott Wood, Qinying Xu, Shivashankar Hiriyur Nagaraj, Eliana Amato, Irene Dalai, Samantha Bersani, Ivana Cataldo, Angelo P. Dei Tos, Paola Capelli, Maria Vittoria Davì, Luca Landoni, Anna Malpaga, Marco Miotto, Vicki L. J. Whitehall, Barbara A. Leggett, Janelle L. Harris, Jonathan Harris, Marc D. Jones, Jeremy Humphris, Lorraine A. Chantrill, Venessa Chin, Adnan M. Nagrial, Marina Pajic, Christopher J. Scarlett, Andreia Pinho, Ilse Rooman, Christopher Toon, Jianmin Wu, Mark Pinese, Mark Cowley, Andrew Barbour, Amanda Mawson, Emily S. Humphrey, Emily K. Colvin, Angela Chou, Jessica A. Lovell, Nigel B. Jamieson, Fraser Duthie, Marie-Claude Gingras, William E. Fisher, Rebecca A. Dagg, Loretta M. S. Lau, Michael Lee, Hilda A. Pickett, Roger R. Reddel, Jaswinder S. Samra, James G. Kench, Neil D. Merrett, Krishna Epari, Nam Q. Nguyen, Nikolajs Zeps, Massimo Falconi, Michele Simbolo, Giovanni Butturini, George Van Buren, Stefano Partelli, Matteo Fassan, Kum Kum Khanna, Anthony J. Gill, David A. Wheeler, Richard A. Gibbs, Elizabeth A. Musgrove, Claudio Bassi, Giampaolo Tortora, Paolo Pederzoli, John V. Pearson, Nicola Waddell, Andrew V. Biankin () and Sean M. Grimmond ()
Additional contact information
Aldo Scarpa: ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona
David K. Chang: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate
Katia Nones: QIMR Berghofer Medical Research Institute
Vincenzo Corbo: ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona
Ann-Marie Patch: QIMR Berghofer Medical Research Institute
Peter Bailey: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate
Rita T. Lawlor: ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona
Amber L. Johns: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales
David K. Miller: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Andrea Mafficini: ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona
Borislav Rusev: ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona
Maria Scardoni: University and Hospital Trust of Verona
Davide Antonello: Pancreas Institute, University and Hospital Trust of Verona
Stefano Barbi: University and Hospital Trust of Verona
Katarzyna O. Sikora: ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona
Sara Cingarlini: Medical Oncology, University and Hospital Trust of Verona
Caterina Vicentini: ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona
Skye McKay: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales
Michael C. J. Quinn: QIMR Berghofer Medical Research Institute
Timothy J. C. Bruxner: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Angelika N. Christ: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Ivon Harliwong: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Senel Idrisoglu: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Suzanne McLean: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Craig Nourse: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate
Ehsan Nourbakhsh: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Peter J. Wilson: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Matthew J. Anderson: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
J. Lynn Fink: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Felicity Newell: QIMR Berghofer Medical Research Institute
Nick Waddell: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Oliver Holmes: QIMR Berghofer Medical Research Institute
Stephen H. Kazakoff: QIMR Berghofer Medical Research Institute
Conrad Leonard: QIMR Berghofer Medical Research Institute
Scott Wood: QIMR Berghofer Medical Research Institute
Qinying Xu: QIMR Berghofer Medical Research Institute
Shivashankar Hiriyur Nagaraj: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Eliana Amato: ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona
Irene Dalai: ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona
Samantha Bersani: University and Hospital Trust of Verona
Ivana Cataldo: ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona
Angelo P. Dei Tos: General Hospital of Treviso, University of Padua
Paola Capelli: University and Hospital Trust of Verona
Maria Vittoria Davì: Section of Endocrinology, University and Hospital Trust of Verona
Luca Landoni: Pancreas Institute, University and Hospital Trust of Verona
Anna Malpaga: Pancreas Institute, University and Hospital Trust of Verona
Marco Miotto: Pancreas Institute, University and Hospital Trust of Verona
Vicki L. J. Whitehall: QIMR Berghofer Medical Research Institute
Barbara A. Leggett: QIMR Berghofer Medical Research Institute
Janelle L. Harris: QIMR Berghofer Medical Research Institute
Jonathan Harris: Institute of Health Biomedical Innovation, Queensland University of Technology
Marc D. Jones: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate
Jeremy Humphris: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales
Lorraine A. Chantrill: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales
Venessa Chin: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales
Adnan M. Nagrial: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales
Marina Pajic: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales
Christopher J. Scarlett: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales
Andreia Pinho: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales
Ilse Rooman: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales
Christopher Toon: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales
Jianmin Wu: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales
Mark Pinese: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales
Mark Cowley: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales
Andrew Barbour: Princess Alexandra Hospital, Ipswich Rd
Amanda Mawson: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales
Emily S. Humphrey: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales
Emily K. Colvin: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales
Angela Chou: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales
Jessica A. Lovell: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales
Nigel B. Jamieson: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate
Fraser Duthie: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate
Marie-Claude Gingras: Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, MS226
William E. Fisher: Baylor College of Medicine, One Baylor Plaza
Rebecca A. Dagg: Children’s Hospital at Westmead
Loretta M. S. Lau: Children’s Hospital at Westmead
Michael Lee: Children’s Medical Research Institute, The University of Sydney
Hilda A. Pickett: Children’s Medical Research Institute, The University of Sydney
Roger R. Reddel: Children’s Medical Research Institute, The University of Sydney
Jaswinder S. Samra: Royal North Shore Hospital, St Leonards
James G. Kench: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales
Neil D. Merrett: Bankstown Hospital
Krishna Epari: Fremantle Hospital, Alma Street
Nam Q. Nguyen: Royal Adelaide Hospital, North Terrace
Nikolajs Zeps: School of Surgery M507, University of Western Australia
Massimo Falconi: Pancreas Institute, University and Hospital Trust of Verona
Michele Simbolo: ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona
Giovanni Butturini: Pancreas Institute, University and Hospital Trust of Verona
George Van Buren: Baylor College of Medicine, One Baylor Plaza
Stefano Partelli: Pancreas Institute, University and Hospital Trust of Verona
Matteo Fassan: ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona
Kum Kum Khanna: QIMR Berghofer Medical Research Institute
Anthony J. Gill: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales
David A. Wheeler: Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, MS226
Richard A. Gibbs: Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, MS226
Elizabeth A. Musgrove: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate
Claudio Bassi: Pancreas Institute, University and Hospital Trust of Verona
Giampaolo Tortora: Medical Oncology, University and Hospital Trust of Verona
Paolo Pederzoli: Pancreas Institute, University and Hospital Trust of Verona
John V. Pearson: QIMR Berghofer Medical Research Institute
Nicola Waddell: QIMR Berghofer Medical Research Institute
Andrew V. Biankin: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate
Sean M. Grimmond: University of Melbourne Centre for Cancer Research, University of Melbourne

Nature, 2017, vol. 543, issue 7643, 65-71

Abstract: Abstract The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling.

Date: 2017
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DOI: 10.1038/nature21063

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