Article | Published:

Whole genomes redefine the mutational landscape of pancreatic cancer

Nature volume 518, pages 495501 (26 February 2015) | Download Citation

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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.

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Accessions

Primary accessions

Gene Expression Omnibus

Data deposits

BAM files and associated metadata in XML format have been uploaded to the European Genome-phenome Archive (EGA; http://www.ebi.ac.uk/ega) under accession number EGAS00001000154. All SNP array data is available via GEO (GSE61502). For more information about Australian Pancreatic Cancer Genome Initiative, see (http://www.pancreaticcancer.net.au/apgi/collaborators).

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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 D. 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. N. Sperandio and D. Filippini for technical assistance at Verona University. We acknowledge the following funding support: National Health and Medical Research Council of Australia (NHMRC; 631701, 535903, 427601); Queensland Government (NIRAP); University of Queensland; Institute for Molecular Bioscience; Cancer Research UK (C596/A18076, C29717/A17263); 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; Avner Nahmani Pancreatic Cancer Research Foundation; University of Glasgow; Cancer Research UK; Howat 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; Royal Australasian College of Surgeons (RACS); Royal Australasian College of Physicians (RACP); Royal College of Pathologists of Australasia (RCPA); Italian Ministry of Research (Cancer Genome Project FIRB RBAP10AHJB); Associazione Italiana Ricerca Cancro (12182); Fondazione Italiana Malattie Pancreas – Ministero Salute (CUP_J33G13000210001); Wilhelm Sander Stiftung 2009.039.2; National Institutes of Health grant P50 CA62924.

Author information

Author notes

    • Andrew V. Biankin
    •  & Sean M. Grimmond

    These authors jointly supervised this work.

    • Robert L. Sutherland

    Deceased.

Affiliations

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

    • Nicola Waddell
    • , Ann-Marie Patch
    • , Karin S. Kassahn
    • , Peter Bailey
    • , 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
    • , John V. Pearson
    •  & Sean M. Grimmond
  2. QIMR Berghofer Medical Research Institute, Herston Road, Brisbane 4006, Australia

    • Nicola Waddell
    • , Nicole Cloonan
    •  & John V. Pearson
  3. The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia

    • Marina Pajic
    • , David K. Chang
    • , Amber L. Johns
    • , 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
    • , James G. Kench
    • , Jessica A. Pettitt
    • , Christopher Toon
    • , Anthony J. Gill
    •  & Andrew V. Biankin
  4. St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, New South Wales 2010, Australia

    • Marina Pajic
  5. Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia

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

    • David K. Chang
    •  & Andrew V. Biankin
  7. Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK

    • David K. Chang
    • , Peter Bailey
    • , Craig Nourse
    • , Marc D. Jones
    • , Nigel B. Jamieson
    • , Janet S. Graham
    • , Elizabeth A. Musgrove
    • , Andrew V. Biankin
    •  & Sean M. Grimmond
  8. Department of Anatomical Pathology, St Vincent’s Hospital, Sydney, New South Wales 2010, Australia

    • Angela Chou
  9. School of Environmental & Life Sciences, University of Newcastle, Ourimbah, New South Wales 2258, Australia

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

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

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

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

    • Neil D. Merrett
  14. Department of Surgery, Fremantle Hospital, Alma Street, Fremantle, Western Australia 6160, Australia

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

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

    • Andrew Barbour
  17. School of Surgery M507, University of Western Australia, 35 Stirling Highway, Nedlands 6009, Australia

    • Nikolajs Zeps
  18. St John of God Pathology, 12 Salvado Rd, Subiaco, Western Australia 6008, Australia

    • Nikolajs Zeps
  19. Bendat Family Comprehensive Cancer Centre, St John of God Subiaco Hospital, Subiaco, Western Australia 6008, Australia

    • Nikolajs Zeps
  20. 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
  21. West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G31 2ER, UK

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

    • Janet S. Graham
  23. Norlux Neuro-Oncology Laboratory, CRP-Santé Luxembourg, 84 Val Fleuri, L-1526, Luxembourg

    • Simone P. Niclou
  24. Norlux Neuro-Oncology, Department of Biomedicine, University of Bergen, Jonas Lies vei 91, N-5019 Bergen, Norway

    • Rolf Bjerkvig
  25. Departments of Surgery and Pathology, TU Dresden, Fetscherstr. 74, 01307 Dresden, Germany

    • Robert Grützmann
    • , Daniela Aust
    •  & Christian Pilarsky
  26. Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA

    • Ralph H. Hruban
    • , Richard A. Morgan
    •  & James R. Eshleman
  27. Departments of Pathology and Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston Texas 77030, USA

    • Anirban Maitra
  28. 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
  29. Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA

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

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

    • Rita T. Lawlor
    • , Giuseppe Zamboni
    •  & Aldo Scarpa
  32. Department of Surgery and Oncology, Pancreas Institute, University and Hospital Trust of Verona, Verona 37134, Italy

    • Claudio Bassi
    •  & Massimo Falconi
  33. Departments of Surgery and Pathology, Ospedale Sacro Cuore Don Calabria Negrar, Verona 37024, Italy

    • Massimo Falconi
    •  & Giuseppe Zamboni
  34. Department of Oncology, University and Hospital Trust of Verona, Verona 37134, Italy

    • Giampaolo Tortora
  35. Division of Hematology and Oncology, University of California, San Francisco, California 94122, USA

    • Margaret A. Tempero
  36. The Kinghorn Cancer Centre, Garvan Institute of Medical Research, 370 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia.

    • Andrew V. Biankin
    • , Amber L. Johns
    • , Amanda Mawson
    • , David K. Chang
    • , Christopher J. Scarlett
    • , Mary-Anne L. Brancato
    • , Sarah J. Rowe
    • , Skye H. Simpson
    • , Mona Martyn-Smith
    • , Michelle T. Thomas
    • , Lorraine A. Chantrill
    • , Venessa T. Chin
    • , Angela Chou
    • , Mark J. Cowley
    • , Jeremy L. Humphris
    • , Marc D. Jones
    • , R. Scott Mead
    • , Adnan M. Nagrial
    • , Marina Pajic
    • , Jessica Pettit
    • , Mark Pinese
    • , Ilse Rooman
    • , Jianmin Wu
    • , Jiang Tao
    • , Renee DiPietro
    • , Clare Watson
    • , Angela Steinmann
    • , Hong Ching Lee
    • , Rachel Wong
    • , Andreia V. Pinho
    • , Marc Giry-Laterriere
    • , Roger J. Daly
    • , Elizabeth A. Musgrove
    •  & Robert L. Sutherland
  37. Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow, Scotland G61 1BD, UK.

    • Andrew V. Biankin
    • , David K. Chang
    • , Marc D. Jones
    • , Sean M. Grimmond
    • , Elizabeth A. Musgrove
    • , Craig Nourse
    • , Nigel B. Jamieson
    • , Janet S. Graham
    •  & Karen Oien
  38. Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, St Lucia, Queensland 4072, Australia.

    • Sean M. Grimmond
    • , Nicola Waddell
    • , Karin S. Kassahn
    • , David K. Miller
    • , Peter J. Wilson
    • , Ann-Marie Patch
    • , Sarah Song
    • , Ivon Harliwong
    • , Senel Idrisoglu
    • , Craig Nourse
    • , Ehsan Nourbakhsh
    • , Suzanne Manning
    • , Shivangi Wani
    • , Milena Gongora
    • , Matthew Anderson
    • , Oliver Holmes
    • , Conrad Leonard
    • , Darrin Taylor
    • , Scott Wood
    • , Christina Xu
    • , Katia Nones
    • , J. Lynn Fink
    • , Angelika Christ
    • , Tim Bruxner
    • , Nicole Cloonan
    • , Felicity Newell
    • , John V. Pearson
    • , Peter Bailey
    • , Michael Quinn
    • , Shivashankar Nagaraj
    • , Stephen Kazakoff
    • , Nick Waddell
    • , Keerthana Krisnan
    • , Kelly Quek
    • , David Wood
    •  & Muhammad Z. H. Fadlullah
  39. Royal North Shore Hospital, Westbourne Street, St Leonards, New South Wales 2065, Australia.

    • Jaswinder S. Samra
    • , Anthony J. Gill
    • , Nick Pavlakis
    • , Alex Guminski
    •  & Christopher Toon
  40. Bankstown Hospital, Eldridge Road, Bankstown, New South Wales 2200, Australia.

    • Ray Asghari
    • , Neil D. Merrett
    • , Darren Pavey
    •  & Amitabha Das
  41. Liverpool Hospital, Elizabeth Street, Liverpool, New South Wales 2170, Australia.

    • Peter H. Cosman
    • , Kasim Ismail
    •  & Chelsie O’Connnor
  42. Westmead Hospital, Hawkesbury and Darcy Roads, Westmead, New South Wales 2145, Australia.

    • Vincent W. Lam Duncan McLeod
    • , Henry C. Pleass
    • , Arthur Richardson
    •  & Virginia James
  43. Royal Prince Alfred Hospital, Missenden Road, Camperdown, New South Wales 2050, Australia.

    • James G. Kench
    • , Caroline L. Cooper
    • , David Joseph
    • , Charbel Sandroussi
    • , Michael Crawford
    •  & James Gallagher
  44. Fremantle Hospital, Alma Street, Fremantle, Western Australia 6959, Australia.

    • Michael Texler
    • , Cindy Forest
    • , Andrew Laycock
    • , Krishna P. Epari
    • , Mo Ballal
    • , David R. Fletcher
    •  & Sanjay Mukhedkar
  45. Sir Charles Gairdner Hospital, Hospital Avenue, Nedlands, Western Australia 6009, Australia.

    • Nigel A. Spry
    • , Bastiaan DeBoer
    •  & Ming Chai
  46. St John of God Healthcare, 12 Salvado Road, Subiaco, Western Australia 6008, Australia.

    • Nikolajs Zeps
    • , Maria Beilin
    •  & Kynan Feeney
  47. Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia.

    • Nan Q. Nguyen
    • , Andrew R. Ruszkiewicz
    • , Chris Worthley
    • , Chuan P. Tan
    •  & Tamara Debrencini
  48. Flinders Medical Centre, Flinders Drive, Bedford Park, South Australia 5042, Australia.

    • John Chen
    • , Mark E. Brooke-Smith
    •  & Virginia Papangelis
  49. Greenslopes Private Hospital, Newdegate Street, Greenslopes, Queensland 4120, Australia.

    • Henry Tang
    •  & Andrew P. Barbour
  50. Envoi Pathology, 1/49 Butterfield Street, Herston, Queensland 4006, Australia.

    • Andrew D. Clouston
    •  & Patrick Martin
  51. Princess Alexandria Hospital, 237 Ipswich Road, Woolloongabba, Queensland 4102, Australia.

    • Thomas J. O’Rourke
    • , Amy Chiang
    • , Jonathan W. Fawcett
    • , Kellee Slater
    • , Shinn Yeung
    • , Michael Hatzifotis
    •  & Peter Hodgkinson
  52. Austin Hospital, 145 Studley Road, Heidelberg, Victoria 3084, Australia.

    • Christopher Christophi
    • , Mehrdad Nikfarjam
    •  & Angela Mountain
  53. Victorian Cancer Biobank, 1 Rathdown Street, Carlton, Victoria 3053, Australia.

  54. Johns Hopkins Medical Institute, 600 North Wolfe Street, Baltimore, Maryland 21287, USA.

    • James R. Eshleman
    • , Ralph H. Hruban
    • , Anirban Maitra
    • , Christine A. Iacobuzio-Donahue
    • , Richard D. Schulick
    • , Christopher L. Wolfgang
    • , Richard A Morgan
    •  & Mary Hodgin
  55. ARC-NET Center for Applied Research on Cancer, University of Verona, Via dell’Artigliere, 19 37129 Verona, Province of Verona, Italy.

    • Aldo Scarpa
    • , Rita T. Lawlor
    • , Stefania Beghelli
    • , Vincenzo Corbo
    • , Maria Scardoni
    •  & Claudio Bassi
  56. University of California, San Francisco, 500 Parnassus Avenue, San Francisco, California 94122, USA.

    • Margaret A. Tempero
  57. Greater Glasgow and Clyde National Health Service, 1053 Great Western Road, Glasgow G12 0YN, UK.

    • Andrew V. Biankin
    • , David K. Chang
    • , Nigel B. Jamieson
    • , Janet S. Graham
    • , Karen Oien
    •  & Jane Hair

Consortia

  1. Australian Pancreatic Cancer Genome Initiative

    (Participants are arranged by institution.)

    Garvan Institute of Medical Research

    Queensland Centre for Medical Genomics / Institute for Molecular Biosciences

    Royal North Shore Hospital

    Bankstown Hospital

    Liverpool Hospital

    Westmead Hospital

    Royal Prince Alfred Hospital

    Fremantle Hospital

    Sir Charles Gairdner Hospital

    St John of God Healthcare

    Royal Adelaide Hospital

    Flinders Medical Centre

    Greenslopes Private Hospital

    Envoi Pathology

    Princess Alexandria Hospital

    Austin Hospital

    Victorian Cancer Biobank

    Johns Hopkins Medical Institutes

    ARC-Net Centre for Applied Research on Cancer

    University of California, San Francisco

    University of Glasgow

    Greater Glasgow & Clyde National Health Service

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Contributions

Biospecimens were collected at affiliated hospitals and processed at each biospecimen core resource centre. Data generation and analyses were performed by the Queensland Centre for Medical Genomics. Investigator contributions are as follows: A.V.B. and S.M.G. (concept and design); S.M.G., J.V.P. N.W., A.V.B. (project leaders); N.W., S.M.G., D.K.C., A.V.B. (writing team); J.V.P., S.M.G., N.W., A.L.J., P.B., S.S., K.S.K., Nk.W., P.J.W., A.M.P., F.N., B.P., E.M., O.H., J.L.F., C.L., D.T., S.W., Q.X., K.N., N.C., M.C.J.Q., M.J.A., M.Z.H.F., A.J.R., S.K., K.Q., M.Pi., H.C.L., M.J.C. and J.W. (bioinformatics); M.Pa., C.J.S., D.K.C., E.S.H., A.M.N., A.C., A.S., C.S., A.V.P., I.R., A.M.S., S.P.N., R. B. (preclinical testing); A.L.J., M.D.J., M.P., C.J.S., C.T., A.M.N., V.T.C., L.A.C., J.S.S., D.K.C., V.C., A.S., C.S., A.J.G., J.A.L., I.R., A.V.P., E.A.M. (sample processing and quality control); A.J.G., J.G.K., C.T., G.Z., A.S., D.A. R.H.H., A.M., C.A.I-D., A.S. (pathology assessment); A.L.J., L.A.C., A.J.G., A.C., R.S.M., C.B., M.F., G.T., J.S.S., J.G.K., C.T., K.E., N.Q.N., N.Z., H.W., N.B.J., J.S.G, R.G., C.P., R.G., C.L.W., R.A.M., R.T.L., M.F., G.Z., G.T., M.A.T., A.P.G.I., J.R.E., R.H.H., A.M., C.A.I-D., A.S. (sample collection and clinical annotation); D.M., T.J.C.B., A.N.C., I.H., S.I., S.M., C.N., E.N., S.W. (sequencing). All authors have read and approved the final manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Sean M. Grimmond or Sean M. Grimmond.

Extended data

Supplementary information

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  1. 1.

    Supplementary Tables

    This zipped file contains Supplementary Tables 1-12.

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DOI

https://doi.org/10.1038/nature14169

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