Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes

Andrew V. Biankin, Nicola Waddell, Karin S. Kassahn, Marie-Claude Gingras, Lakshmi B. Muthuswamy, Amber L. Johns, David K. Miller, Peter J. Wilson, Ann-Marie Patch, Jianmin Wu, David K. Chang, Mark J. Cowley, Brooke B. Gardiner, Sarah Song, Ivon Harliwong, Senel Idrisoglu, Craig Nourse, Ehsan Nourbakhsh, Suzanne Manning, Shivangi Wani, Milena Gongora, Marina Pajic, Christopher J. Scarlett, Anthony J. Gill, Andreia V. Pinho, Ilse Rooman, Matthew Anderson, Oliver Holmes, Conrad Leonard, Darrin Taylor, Scott Wood, Qinying Xu, Katia Nones, J. Lynn Fink, Angelika Christ, Tim Bruxner, Nicole Cloonan, Gabriel Kolle, Felicity Newell, Mark Pinese, R. Scott Mead, Jeremy L. Humphris, Warren Kaplan, Marc D. Jones, Emily K. Colvin, Adnan M. Nagrial, Emily S. Humphrey, Angela Chou, Venessa T. Chin, Lorraine A. Chantrill, Amanda Mawson, Jaswinder S. Samra, James G. Kench, Jessica A. Lovell, Roger J. Daly, Neil D. Merrett, Christopher Toon, Krishna Epari, Nam Q. Nguyen, Andrew Barbour, Nikolajs Zeps, Nipun Kakkar, Fengmei Zhao, Yuan Qing Wu, Min Wang, Donna M. Muzny, William E. Fisher, F. Charles Brunicardi, Sally E. Hodges, Jeffrey G. Reid, Jennifer Drummond, Kyle Chang, Yi Han, Lora R. Lewis, Huyen Dinh, Christian J. Buhay, Timothy Beck, Lee Timms, Michelle Sam, Kimberly Begley, Andrew Brown, Deepa Pai, Ami Panchal, Nicholas Buchner, Richard De Borja, Robert E. Denroche, Christina K. Yung, Stefano Serra, Nicole Onetto, Debabrata Mukhopadhyay, Ming-Sound Tsao, Patricia A. Shaw, Gloria M. Petersen, Steven Gallinger, Ralph H. Hruban, Anirban Maitra, Christine A. Iacobuzio-Donahue, Richard D. Schulick, Christopher L. Wolfgang, Richard A. Morgan, Rita T. Lawlor, Paola Capelli, Vincenzo Corbo, Maria Scardoni, Giampaolo Tortora, Margaret A. Tempero, Karen M. Mann, Nancy A. Jenkins, Pedro A. Perez-Mancera, David J. Adams, David A. Largaespada, Lodewyk F. A. Wessels, Alistair G. Rust, Lincoln D. Stein, David A. Tuveson, Neal G. Copeland, Elizabeth A. Musgrove, Aldo Scarpa, James R. Eshleman, Thomas J. Hudson, Robert L. Sutherland, David A. Wheeler, John V. Pearson, John D. McPherson, Richard A. Gibbs and Sean M. Grimmond ()
Additional contact information
Andrew V. Biankin: The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia.
Nicola Waddell: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Karin S. Kassahn: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Marie-Claude Gingras: Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, MS226, Houston, Texas 77030-3411, USA.
Lakshmi B. Muthuswamy: Ontario Institute for Cancer Research
Amber L. Johns: The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia.
David K. Miller: 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
Ann-Marie Patch: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Jianmin Wu: The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia.
David K. Chang: The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia.
Mark J. Cowley: The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia.
Brooke B. Gardiner: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Sarah Song: 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
Craig Nourse: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Ehsan Nourbakhsh: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Suzanne Manning: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Shivangi Wani: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Milena Gongora: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Marina Pajic: The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia.
Christopher J. Scarlett: The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia.
Anthony J. Gill: The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia.
Andreia V. Pinho: The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia.
Ilse Rooman: The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia.
Matthew Anderson: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Oliver Holmes: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Conrad Leonard: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Darrin Taylor: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Scott Wood: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Qinying Xu: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Katia Nones: 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
Angelika Christ: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Tim Bruxner: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Nicole Cloonan: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Gabriel Kolle: Life Technologies
Felicity Newell: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Mark Pinese: The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia.
R. Scott Mead: The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia.
Jeremy L. Humphris: The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia.
Warren Kaplan: The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia.
Marc D. Jones: The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia.
Emily K. Colvin: The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia.
Adnan M. Nagrial: The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia.
Emily S. Humphrey: The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia.
Angela Chou: The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia.
Venessa T. Chin: The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia.
Lorraine A. Chantrill: The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia.
Amanda Mawson: The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia.
Jaswinder S. Samra: Royal North Shore Hospital, St Leonards
James G. Kench: The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia.
Jessica A. Lovell: The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia.
Roger J. Daly: The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, 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, 370 Victoria Street, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, 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: The University of Queensland, Princess Alexandra Hospital, Ipswich Road, Woollongabba, Queensland 4102, Australia.
Nikolajs Zeps: School of Surgery M507, University of Western Australia, 35 Stirling Hwy, Nedlands 6009, Australia and St John of God Pathology, 12 Salvado Road, Subiaco, Western Australia 6008, USA.
Nipun Kakkar: Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, MS226, Houston, Texas 77030-3411, USA.
Fengmei Zhao: Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, MS226, Houston, Texas 77030-3411, USA.
Yuan Qing Wu: Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, MS226, Houston, Texas 77030-3411, USA.
Min Wang: Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, MS226, Houston, Texas 77030-3411, USA.
Donna M. Muzny: Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, MS226, Houston, Texas 77030-3411, USA.
William E. Fisher: Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030-3411, USA.
F. Charles Brunicardi: David Geffen School of Medicine at UCLA
Sally E. Hodges: Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030-3411, USA.
Jeffrey G. Reid: Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, MS226, Houston, Texas 77030-3411, USA.
Jennifer Drummond: Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, MS226, Houston, Texas 77030-3411, USA.
Kyle Chang: Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, MS226, Houston, Texas 77030-3411, USA.
Yi Han: Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, MS226, Houston, Texas 77030-3411, USA.
Lora R. Lewis: Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, MS226, Houston, Texas 77030-3411, USA.
Huyen Dinh: Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, MS226, Houston, Texas 77030-3411, USA.
Christian J. Buhay: Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, MS226, Houston, Texas 77030-3411, USA.
Timothy Beck: Ontario Institute for Cancer Research
Lee Timms: Ontario Institute for Cancer Research
Michelle Sam: Ontario Institute for Cancer Research
Kimberly Begley: Ontario Institute for Cancer Research
Andrew Brown: Ontario Institute for Cancer Research
Deepa Pai: Ontario Institute for Cancer Research
Ami Panchal: Ontario Institute for Cancer Research
Nicholas Buchner: Ontario Institute for Cancer Research
Richard De Borja: Ontario Institute for Cancer Research
Robert E. Denroche: Ontario Institute for Cancer Research
Christina K. Yung: Ontario Institute for Cancer Research
Stefano Serra: University Health Network
Nicole Onetto: Ontario Institute for Cancer Research
Debabrata Mukhopadhyay: Mayo Clinic
Ming-Sound Tsao: University Health Network
Patricia A. Shaw: University Health Network
Gloria M. Petersen: Mayo Clinic
Steven Gallinger: University Health Network
Ralph H. Hruban: The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine
Anirban Maitra: The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine
Christine A. Iacobuzio-Donahue: The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine
Richard D. Schulick: The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine
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 center for applied research on cancer, University and Hospital Trust of Verona
Paola Capelli: University of Veron
Vincenzo Corbo: ARC-NET center for applied research on cancer, University and Hospital Trust of Verona
Maria Scardoni: University of Veron
Giampaolo Tortora: University and Hospital Trust of Verona
Margaret A. Tempero: University of California
Karen M. Mann: Cancer Research Program, The Methodist Hospital Research Institute, 6670 Bertner Avenue, Houston, Texas 77030, USA.
Nancy A. Jenkins: Cancer Research Program, The Methodist Hospital Research Institute, 6670 Bertner Avenue, Houston, Texas 77030, USA.
Pedro A. Perez-Mancera: Li Ka Shing Centre, Cambridge Research Institute, Cancer Research UK
David J. Adams: Experimental Cancer Genetics, Wellcome Trust Sanger Institute
David A. Largaespada: Masonic Cancer Center, University of Minnesota
Lodewyk F. A. Wessels: Bioinformatics and Statistics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Alistair G. Rust: Experimental Cancer Genetics, Wellcome Trust Sanger Institute
Lincoln D. Stein: Ontario Institute for Cancer Research
David A. Tuveson: Li Ka Shing Centre, Cambridge Research Institute, Cancer Research UK
Neal G. Copeland: Cancer Research Program, The Methodist Hospital Research Institute, 6670 Bertner Avenue, Houston, Texas 77030, USA.
Elizabeth A. Musgrove: The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia.
Aldo Scarpa: ARC-NET center for applied research on cancer, University and Hospital Trust of Verona
James R. Eshleman: The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine
Thomas J. Hudson: Ontario Institute for Cancer Research
Robert L. Sutherland: The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia.
David A. Wheeler: Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, MS226, Houston, Texas 77030-3411, USA.
John V. Pearson: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
John D. McPherson: Ontario Institute for Cancer Research
Richard A. Gibbs: Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, MS226, Houston, Texas 77030-3411, USA.
Sean M. Grimmond: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia

Nature, 2012, vol. 491, issue 7424, 399-405

Abstract: Abstract Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.

Date: 2012
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DOI: 10.1038/nature11547

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