Article | Published:

Genomic analyses identify molecular subtypes of pancreatic cancer

Nature volume 531, pages 4752 (03 March 2016) | Download Citation

This article has been updated

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.

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Change history

  • 02 March 2016

    A present address was added for author R.G.

Accessions

Primary accessions

ArrayExpress

Gene Expression Omnibus

Data deposits

All DNA sequencing and RNA-seq data have been deposited in the European Genome-phenome Archive (EGA): accession code EGAS00001000154. All gene expression, genotyping, and methylome data used in this study has been deposited in the NCBI Gene Expression Omnibus (GEO) under accession codes GSE49149 and GSE36924. Mouse cell line expression data are available in the ArrayExpress database (http://www.ebi.ac.uk/arrayexpress) under accession number E-MTAB-4415.

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Acknowledgements

We would like to thank C. Axford, M.-A. Brancato, S. Rowe, M. Thomas, S. Simpson and G. Hammond for central coordination of the Australian Pancreatic Cancer Genome Initiative, data management and quality control; M. Martyn-Smith, L. Braatvedt, H. Tang, V. Papangelis and M. Beilin for biospecimen acquisition; and Deborah Gwynne for support at the Queensland Centre for Medical Genomics. We also thank M. Hodgins, M. Debeljak and D. Trusty for technical assistance at Johns Hopkins University. Funding support was from: National Health and Medical Research Council of Australia (NHMRC; 631701, 535903, 427601); Queensland Government (NIRAP); University of Queensland; Australian Government: Department of Innovation, Industry, Science and Research (DIISR); Australian Cancer Research Foundation (ACRF); Cancer Council NSW: (SRP06-01, SRP11-01. ICGC); Cancer Institute NSW: (10/ECF/2-26; 06/ECF/1-24; 09/CDF/2-40; 07/CDF/1-03; 10/CRF/1-01, 08/RSA/1-15, 07/CDF/1-28, 10/CDF/2-26,10/FRL/2-03, 06/RSA/1-05, 09/RIG/1-02, 10/TPG/1-04, 11/REG/1-10, 11/CDF/3-26); Garvan Institute of Medical Research; Cancer Research UK Glasgow Centre Program, A18076; Avner Nahmani Pancreatic Cancer Research Foundation; R.T. Hall Trust; Petre Foundation; Philip Hemstritch Foundation; Gastroenterological Society of Australia (GESA); American Association for Cancer Research (AACR) Landon Foundation—INNOVATOR Award; Wellcome Trust Senior Investigator Award 103721/Z/14/Z; Cancer Research UK Programme Grant C29717/A17263; Cancer Research UK Programme Grant A12481; Pancreatic Cancer UK; The Howat Foundation; University of Glasgow; European Research Council Starting Grant, 311301, Italian Ministry of University and Research (Cancer Genome Project FIRB RBAP10AHJB), Associazione Italiana Ricerca Cancro (n.12182) , Fondazione Italiana Malattie Pancreas – Ministry of Health (CUP_J33G13000210001), European Community Grant FP7 Cam-Pac, grant agreement number 602783.

Author information

Author notes

    • Robert L. Sutherland

    Deceased.

    • Robert Grützmann

    Present address: Universitätsklinikum Erlangen, Department of Surgery, 91054 Erlangen, Germany.

Affiliations

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

    • Peter Bailey
    • , Katia Nones
    • , Ann-Marie Patch
    • , David K. Miller
    • , Angelika N. Christ
    • , Tim J. C. Bruxner
    • , Michael C. Quinn
    • , Craig Nourse
    • , Ivon Harliwong
    • , Senel Idrisoglu
    • , Suzanne Manning
    • , Ehsan Nourbakhsh
    • , Shivangi Wani
    • , Lynn Fink
    • , Oliver Holmes
    • , 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
    • , John V. Pearson
    • , Nicola Waddell
    •  & Sean M. Grimmond
  2. Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK

    • Peter Bailey
    • , David K. Chang
    • , Craig Nourse
    • , Laura Mincarelli
    • , Luis N. Sanchez
    • , Lisa Evers
    • , Marc D. Jones
    • , Kim Moran-Jones
    • , Nigel B. Jamieson
    • , Janet S. Graham
    • , Elizabeth A. Musgrove
    • , Ulla-Maja Hagbo Bailey
    • , Oliver Hofmann
    • , Andrew V. Biankin
    •  & Sean M. Grimmond
  3. The Kinghorn Cancer Centre, 370 Victoria St, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia

    • David K. Chang
    • , Amber L. Johns
    • , David K. Miller
    • , Venessa Chin
    • , 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
    • , James G. Kench
    • , Jessica A. Lovell
    • , Christopher W. Toon
    • , Karin Oien
    • , Robert L. Sutherland
    • , Anthony J. Gill
    •  & Andrew V. Biankin
  4. Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia

    • David K. Chang
    •  & Andrew V. Biankin
  5. South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, New South Wales 2170, Australia

    • David K. Chang
    • , Neil D. Merrett
    •  & Andrew V. Biankin
  6. QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia

    • Katia Nones
    • , Ann-Marie Patch
    • , Michael C. Quinn
    • , Shivangi Wani
    • , Oliver Holmes
    • , Stephen Kazakoff
    • , Conrad Leonard
    • , Scott Wood
    • , Qinying Xu
    • , Nicole Cloonan
    • , John V. Pearson
    •  & Nicola Waddell
  7. Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA

    • Marie-Claude Gingras
    • , Donna M. Munzy
    • , David A. Wheeler
    •  & Richard A. Gibbs
  8. Michael DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas 77030, USA

    • Marie-Claude Gingras
    • , Donna M. Munzy
    • , David A. Wheeler
    •  & Richard A. Gibbs
  9. Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA

    • Marie-Claude Gingras
  10. Department of Human Genetics, University of Utah, Salt Lake City, Utah 84112, USA

    • L. Charles Murtaugh
  11. Genetic and Molecular Pathology, SA Pathology, Adelaide, South Australia 5000, Australia

    • Karin S. Kassahn
  12. School of Biological Sciences, The University of Adelaide, Adelaide, South Australia 5000, Australia

    • Karin S. Kassahn
  13. Harvard Chan Bioinformatics Core, Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115, USA

    • Lorena Pantano
    •  & Oliver Hofmann
  14. Macarthur Cancer Therapy Centre, Campbelltown Hospital, New South Wales 2560, Australia

    • Lorraine A. Chantrill
  15. Department of Pathology. SydPath, St Vincent’s Hospital, Sydney, NSW 2010, Australia

    • Angela Chou
  16. St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, New South Wales 2052, Australia

    • Marina Pajic
  17. School of Environmental & Life Sciences, University of Newcastle, Ourimbah, New South Wales 2258, Australia

    • Christopher J. Scarlett
  18. Department of Surgery, Royal North Shore Hospital, St Leonards, Sydney, New South Wales 2065, Australia

    • Jaswinder S. Samra
  19. University of Sydney, Sydney, New South Wales 2006, Australia

    • Jaswinder S. Samra
    • , James G. Kench
    •  & Anthony J. Gill
  20. Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown New South Wales 2050, Australia

    • James G. Kench
  21. School of Medicine, University of Western Sydney, Penrith, New South Wales 2175, Australia

    • Neil D. Merrett
  22. Fiona Stanley Hospital, Robin Warren Drive, Murdoch, Western Australia 6150, Australia

    • Krishna Epari
  23. Department of Gastroenterology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia

    • Nam Q. Nguyen
  24. Department of Surgery, Princess Alexandra Hospital, Ipswich Rd, Woollongabba, Queensland 4102, Australia

    • Andrew Barbour
  25. School of Surgery M507, University of Western Australia, 35 Stirling Hwy, Nedlands 6009, Australia and St John of God Pathology, 12 Salvado Rd, Subiaco, Western Australia 6008, Australia

    • Nikolajs Zeps
  26. Academic Unit of Surgery, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow Royal Infirmary, Glasgow G4 OSF, UK

    • Nigel B. Jamieson
  27. West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G31 2ER, UK

    • Nigel B. Jamieson
    •  & Andrew V. Biankin
  28. Department of Medical Oncology, Beatson West of Scotland Cancer Centre, 1053 Great Western Road, Glasgow G12 0YN, UK

    • Janet S. Graham
  29. Department of Pathology, Southern General Hospital, Greater Glasgow & Clyde NHS, Glasgow G51 4TF, UK

    • Fraser Duthie
    •  & Karin Oien
  30. GGC Bio-repository, Pathology Department, Southern General Hospital, 1345 Govan Road, Glasgow G51 4TY, UK

    • Jane Hair
  31. Department of Surgery, TU Dresden, Fetscherstr. 74, 01307 Dresden, Germany

    • Robert Grützmann
    •  & Christian Pilarsky
  32. Departments of Pathology and Translational Molecular Pathology, UT MD Anderson Cancer Center, Houston Texas 77030, USA

    • Anirban Maitra
  33. The David M. Rubenstein Pancreatic Cancer Research Center and Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

    • Christine A. Iacobuzio-Donahue
  34. Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA

    • Christopher L. Wolfgang
    • , Richard A. Morgan
    • , James R. Eshleman
    •  & Ralph H. Hruban
  35. Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA

    • Christopher L. Wolfgang
  36. ARC-Net Applied Research on Cancer Centre, University and Hospital Trust of Verona, Verona 37134, Italy

    • Rita T. Lawlor
    • , Vincenzo Corbo
    • , Borislav Rusev
    •  & Aldo Scarpa
  37. Department of Pathology and Diagnostics, University of Verona, Verona 37134, Italy

    • Rita T. Lawlor
    • , Paola Capelli
    •  & Aldo Scarpa
  38. Department of Surgery, Pancreas Institute, University and Hospital Trust of Verona, Verona 37134, Italy

    • Claudio Bassi
    •  & Roberto Salvia
  39. Department of Medical Oncology, Comprehensive Cancer Centre, University and Hospital Trust of Verona, Verona 37134, Italy

    • Giampaolo Tortora
  40. Mayo Clinic, Rochester, Minnesota 55905, USA

    • Debabrata Mukhopadhyay
    •  & Gloria M. Petersen
  41. Elkins Pancreas Center, Baylor College of Medicine, One Baylor Plaza, MS226, Houston, Texas 77030-3411, USA

    • William E. Fisher
  42. Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK

    • Saadia A. Karim
    • , Jennifer P. Morton
    •  & Owen J. Sansom
  43. Institute for Cancer Science, University of Glasgow, Glasgow G12 8QQ, UK

    • Owen J. Sansom
  44. University of Melbourne, Parkville, Victoria 3010, Australia

    • Sean M. Grimmond

Consortia

  1. Australian Pancreatic Cancer Genome Initiative

    A list of authors and affiliations appears in the Supplementary Information.

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Contributions

Investigator contributions are as follows: P.J.B., J.V.P., N.W., A.V.B., S.M.G. (concept and design); P.J.B., D.A.W., R.A.G., A.S., D.K.C., J.V.P., N.W., A.V.B., S.M.G. (project leaders); P.J.B., D.K.C., A.V.B., S.M.G. (writing team); D.K.M., A.N.C., T.J.C.B., C.N., K.N., S.W., D.M.M., N.W., L.E., L.M., L.S., S.M.G., I.H., S.I., S.M., E.N., K.Q., S.M.G. (genomics); P.J.B., D.K.M., K.S.K., N.W., P.J.W., O. H., A.M.P., F.N., O.H., C.L., D.T., S.W., Q.X., K.N., N.C., M.Q., M.A., A.R., M.G., S.K., K.Q., L.P., J.M., M.C., L.C.M., O.S., L.F., U.B., N.W., J.V.P., S.M.G. (data analysis); D.K.C., A.L.J., A.M.N., A.M., A.V.P., C.W.T., E.K.C., E.S.H., I.R., M.G., J.H., J.A.L., K.E., L.A.C., M.D.J., A.J.G., N.Q.N., A.B., N.Z., C.P., R.G., J.R.E., R.H.H., A.M., C.A.I., C.L.W., B.R., V.C., P.C., C.B., R.S., G.T., D.M., G.M.P., J.H., M.P., J.W., V.C., C.J.S., J.G.K., R.T.L., N.D.M., N.B.J., J.S.G., J.D.S., R.A.M., J.H., S.A.K., K.M., R.L.S., A.V.B. (sample acquisition and processing, clinical annotation, interpretation and analysis); A.J.G., A.C., R.H.H., F.D., K.O., A.S., W.F., J.G.K., C.T. (pathology assessment).

Competing interests

R.H.H. receives royalty payments from Myriad Genetics for the PALB2 invention.

Corresponding authors

Correspondence to Andrew V. Biankin or Sean M. Grimmond.

Extended data

Supplementary information

Excel files

  1. 1.

    Supplementary Tables

    This file contains Supplementary Tables 1-13

  2. 2.

    Supplementary Tables

    This file contains Supplementary Table 14

  3. 3.

    Supplementary Tables

    This file contains Supplementary Table 15

  4. 4.

    Supplementary Tables

    This file contains Supplementary Table 16

  5. 5.

    Supplementary Tables

    This file contains Supplementary Table 17

  6. 6.

    Supplementary Tables

    This file contains Supplementary Table 18

  7. 7.

    Supplementary Tables

    This file contains Supplementary Table 19

  8. 8.

    Supplementary Tables

    This file contains Supplementary Table 20

  9. 9.

    Supplementary Tables

    This file contains Supplementary Table 21

PDF files

  1. 1.

    Supplementary Information

    This file contains a list of the participants and their affiliations for the Australian Pancreatic Cancer Genome Initiative.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nature16965

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