Genomic analyses identify molecular subtypes of pancreatic cancer

Peter Bailey, David K. Chang, Katia Nones, Amber L. Johns, Ann-Marie Patch, Marie-Claude Gingras, David K. Miller, Angelika N. Christ, Tim J. C. Bruxner, Michael C. Quinn, Craig Nourse, L. Charles Murtaugh, Ivon Harliwong, Senel Idrisoglu, Suzanne Manning, Ehsan Nourbakhsh, Shivangi Wani, Lynn Fink, Oliver Holmes, Venessa Chin, Matthew J. Anderson, Stephen Kazakoff, Conrad Leonard, Felicity Newell, Nick Waddell, Scott Wood, Qinying Xu, Peter J. Wilson, Nicole Cloonan, Karin S. Kassahn, Darrin Taylor, Kelly Quek, Alan Robertson, Lorena Pantano, Laura Mincarelli, Luis N. Sanchez, Lisa Evers, Jianmin Wu, Mark Pinese, Mark J. Cowley, Marc D. Jones, Emily K. Colvin, Adnan M. Nagrial, Emily S. Humphrey, Lorraine A. Chantrill, Amanda Mawson, Jeremy Humphris, Angela Chou, Marina Pajic, Christopher J. Scarlett, Andreia V. Pinho, Marc Giry-Laterriere, Ilse Rooman, Jaswinder S. Samra, James G. Kench, Jessica A. Lovell, Neil D. Merrett, Christopher W. Toon, Krishna Epari, Nam Q. Nguyen, Andrew Barbour, Nikolajs Zeps, Kim Moran-Jones, Nigel B. Jamieson, Janet S. Graham, Fraser Duthie, Karin Oien, Jane Hair, Robert Grützmann, Anirban Maitra, Christine A. Iacobuzio-Donahue, Christopher L. Wolfgang, Richard A. Morgan, Rita T. Lawlor, Vincenzo Corbo, Claudio Bassi, Borislav Rusev, Paola Capelli, Roberto Salvia, Giampaolo Tortora, Debabrata Mukhopadhyay, Gloria M. Petersen, Donna M. Munzy, William E. Fisher, Saadia A. Karim, James R. Eshleman, Ralph H. Hruban, Christian Pilarsky, Jennifer P. Morton, Owen J. Sansom, Aldo Scarpa, Elizabeth A. Musgrove, Ulla-Maja Hagbo Bailey, Oliver Hofmann, Robert L. Sutherland, David A. Wheeler, Anthony J. Gill, Richard A. Gibbs, John V. Pearson, Nicola Waddell, Andrew V. Biankin () and Sean M. Grimmond ()
Additional contact information
Peter Bailey: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
David K. Chang: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate
Katia Nones: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
Amber L. Johns: The Kinghorn Cancer Centre, 370 Victoria St, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research
Ann-Marie Patch: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
Marie-Claude Gingras: Human Genome Sequencing Center, Baylor College of Medicine
David K. Miller: 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
Tim J. C. Bruxner: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
Michael C. Quinn: 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
L. Charles Murtaugh: University of Utah
Ivon Harliwong: 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
Suzanne Manning: 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
Shivangi Wani: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
Lynn Fink: 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
Venessa Chin: The Kinghorn Cancer Centre, 370 Victoria St, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research
Matthew J. Anderson: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
Stephen Kazakoff: 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
Felicity Newell: 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
Scott Wood: 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
Peter J. Wilson: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
Nicole Cloonan: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
Karin S. Kassahn: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
Darrin Taylor: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
Kelly Quek: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
Alan Robertson: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
Lorena Pantano: Harvard Chan Bioinformatics Core, Harvard T. H. Chan School of Public Health
Laura Mincarelli: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate
Luis N. Sanchez: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate
Lisa Evers: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate
Jianmin Wu: The Kinghorn Cancer Centre, 370 Victoria St, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research
Mark Pinese: The Kinghorn Cancer Centre, 370 Victoria St, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research
Mark J. Cowley: The Kinghorn Cancer Centre, 370 Victoria St, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research
Marc D. Jones: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate
Emily K. Colvin: The Kinghorn Cancer Centre, 370 Victoria St, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research
Adnan M. Nagrial: The Kinghorn Cancer Centre, 370 Victoria St, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research
Emily S. Humphrey: The Kinghorn Cancer Centre, 370 Victoria St, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research
Lorraine A. Chantrill: The Kinghorn Cancer Centre, 370 Victoria St, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research
Amanda Mawson: The Kinghorn Cancer Centre, 370 Victoria St, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research
Jeremy Humphris: The Kinghorn Cancer Centre, 370 Victoria St, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research
Angela Chou: The Kinghorn Cancer Centre, 370 Victoria St, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research
Marina Pajic: The Kinghorn Cancer Centre, 370 Victoria St, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research
Christopher J. Scarlett: The Kinghorn Cancer Centre, 370 Victoria St, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research
Andreia V. Pinho: The Kinghorn Cancer Centre, 370 Victoria St, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research
Marc Giry-Laterriere: The Kinghorn Cancer Centre, 370 Victoria St, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research
Ilse Rooman: The Kinghorn Cancer Centre, 370 Victoria St, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research
Jaswinder S. Samra: Royal North Shore Hospital, St Leonards
James G. Kench: The Kinghorn Cancer Centre, 370 Victoria St, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research
Jessica A. Lovell: The Kinghorn Cancer Centre, 370 Victoria St, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research
Neil D. Merrett: South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales
Christopher W. Toon: The Kinghorn Cancer Centre, 370 Victoria St, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research
Krishna Epari: Fiona Stanley Hospital
Nam Q. Nguyen: Royal Adelaide Hospital
Andrew Barbour: Princess Alexandra Hospital
Nikolajs Zeps: School of Surgery M507, University of Western Australia, 35 Stirling Hwy, Nedlands 6009, Australia and St John of God Pathology
Kim Moran-Jones: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate
Nigel B. Jamieson: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate
Janet S. Graham: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate
Fraser Duthie: Southern General Hospital
Karin Oien: The Kinghorn Cancer Centre, 370 Victoria St, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research
Jane Hair: GGC Bio-repository, Southern General Hospital
Robert Grützmann: Department of Surgery
Anirban Maitra: UT 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 Applied Research on Cancer Centre, University and Hospital Trust of Verona
Vincenzo Corbo: ARC-Net Applied Research on Cancer Centre, University and Hospital Trust of Verona
Claudio Bassi: Pancreas Institute, University and Hospital Trust of Verona
Borislav Rusev: ARC-Net Applied Research on Cancer Centre, University and Hospital Trust of Verona
Paola Capelli: University of Verona
Roberto Salvia: Pancreas Institute, University and Hospital Trust of Verona
Giampaolo Tortora: Comprehensive Cancer Centre, University and Hospital Trust of Verona
Debabrata Mukhopadhyay: Mayo Clinic
Gloria M. Petersen: Mayo Clinic
Donna M. Munzy: Human Genome Sequencing Center, Baylor College of Medicine
William E. Fisher: Elkins Pancreas Center, Baylor College of Medicine
Saadia A. Karim: Cancer Research UK Beatson Institute
James R. Eshleman: The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine
Ralph H. Hruban: The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine
Christian Pilarsky: Department of Surgery
Jennifer P. Morton: Cancer Research UK Beatson Institute
Owen J. Sansom: Cancer Research UK Beatson Institute
Aldo Scarpa: ARC-Net Applied Research on Cancer Centre, University and Hospital Trust of Verona
Elizabeth A. Musgrove: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate
Ulla-Maja Hagbo Bailey: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate
Oliver Hofmann: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate
Robert L. Sutherland: The Kinghorn Cancer Centre, 370 Victoria St, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research
David A. Wheeler: Human Genome Sequencing Center, Baylor College of Medicine
Anthony J. Gill: The Kinghorn Cancer Centre, 370 Victoria St, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research
Richard A. Gibbs: Human Genome Sequencing Center, Baylor College of Medicine
John V. Pearson: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
Nicola Waddell: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
Andrew V. Biankin: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate
Sean M. Grimmond: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland

Nature, 2016, vol. 531, issue 7592, 47-52

Abstract: Abstract Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.

Date: 2016
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DOI: 10.1038/nature16965

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