Article | Published:

Whole-genome landscape of pancreatic neuroendocrine tumours

Nature volume 543, pages 6571 (02 March 2017) | Download Citation

  • A Corrigendum to this article was published on 27 September 2017

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.

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Acknowledgements

We thank E. Missiaglia, S. Beghelli, N. Sperandio, G. Bonizzato, S. Grimaldi, F. Pisani, C. Cantù, G. Zamboni and P. Merlini for assistance at the ARC-Net Research Centre and Verona University; 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; D. Gwynne and D. Stetner for support at the Queensland Centre for Medical Genomics; and The Kinghorn Centre for Clinical Genomics for genome sequencing of validation samples. Funding support was from: Italian Ministry of Research (Cancer Genome Project FIRB RBAP10AHJB); Associazione Italiana Ricerca Cancro (AIRC n. 12182); Fondazione Italiana Malattie Pancreas – Ministero Salute (CUP_J33G13000210001); National Health and Medical Research Council of Australia (NHMRC; 631701, 535903, CDF 1112113, PRF 1025427, SRF 455857, 535903); The Queensland State Government Smart State National and International Research Alliances Program (NIRAP); Institute for Molecular Bioscience/University of Queensland; The Royal Australasian College of Physicians, Sidney Catalyst, NHMRC, Pancare Australia; 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; R.T. Hall Trust; Petre Foundation; Philip Hemstritch Foundation; Gastroenterological Society of Australia (GESA Senior Research Fellowship); Royal Australasian College of Surgeons (RACS); Royal Australasian College of Physicians (RACP); Royal College of Pathologists of Australasia (RCPA); QIMR Berghofer Medical Research; The Keith Boden Fellowship (K.N.); NHGRI U54 HG003273; CPRIT grant RP101353-P7; Wellcome Trust Senior Investigator Award (103721/Z/14/Z); CRUK Programme (C29717/A17263 and C29717/A18484); CRUK Glasgow Centre (C596/A18076); CRUK Clinical Training Award (C596/A20921); Pancreatic Cancer UK Future Research Leaders Fund; The Howat Foundation; and the University of Glasgow.

Author information

Author notes

    • Ilse Rooman
    •  & Amanda Mawson

    Present addresses: Oncology Research Centre, Vrije Universiteit Brussel, Brussels, Belgium (I.R.); Pancreatic Cancer Translational Research Group, Adult Cancer Program, Prince of Wales Clinical School, Lowy Cancer Research Centre, UNSW, Sydney, Australia (A.M.).

    • Aldo Scarpa
    • , David K. Chang
    • , Katia Nones
    •  & Vincenzo Corbo

    These authors contributed equally to this work.

    • Aldo Scarpa
    • , Nicola Waddell
    • , Andrew V. Biankin
    •  & Sean M. Grimmond

    These authors jointly supervised this work.

Affiliations

  1. ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona 37134, Italy

    • Aldo Scarpa
    • , Vincenzo Corbo
    • , Rita T. Lawlor
    • , Andrea Mafficini
    • , Borislav Rusev
    • , Katarzyna O. Sikora
    • , Caterina Vicentini
    • , Eliana Amato
    • , Irene Dalai
    • , Ivana Cataldo
    • , Michele Simbolo
    •  & Matteo Fassan
  2. Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona 37134, Italy

    • Aldo Scarpa
    • , Vincenzo Corbo
    • , Rita T. Lawlor
    • , Maria Scardoni
    • , Stefano Barbi
    • , Eliana Amato
    • , Irene Dalai
    • , Samantha Bersani
    • , Ivana Cataldo
    •  & Paola Capelli
  3. Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1QH, UK

    • David K. Chang
    • , Peter Bailey
    • , Craig Nourse
    • , Marc D. Jones
    • , Nigel B. Jamieson
    • , Fraser Duthie
    • , Elizabeth A. Musgrove
    •  & Andrew V. Biankin
  4. West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G31 2ER, UK

    • David K. Chang
    • , Nigel B. Jamieson
    •  & Andrew V. Biankin
  5. 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

    • David K. Chang
    • , Amber L. Johns
    • , Skye McKay
    • , 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
    • , Amanda Mawson
    • , Emily S. Humphrey
    • , Emily K. Colvin
    • , Angela Chou
    • , Jessica A. Lovell
    • , James G. Kench
    • , Anthony J. Gill
    •  & Andrew V. Biankin
  6. Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia

    • David K. Chang
    • , Neil D. Merrett
    •  & Andrew V. Biankin
  7. 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
  8. QIMR Berghofer Medical Research Institute, Herston Road, Brisbane 4006, Australia

    • Katia Nones
    • , Ann-Marie Patch
    • , Michael C. J. Quinn
    • , Felicity Newell
    • , Oliver Holmes
    • , Stephen H. Kazakoff
    • , Conrad Leonard
    • , Scott Wood
    • , Qinying Xu
    • , Vicki L. J. Whitehall
    • , Barbara A. Leggett
    • , Janelle L. Harris
    • , Kum Kum Khanna
    • , John V. Pearson
    •  & Nicola Waddell
  9. Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia

    • Katia Nones
    • , Ann-Marie Patch
    • , Peter Bailey
    • , David K. Miller
    • , 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
    • , John V. Pearson
    •  & Nicola Waddell
  10. Department of Surgery, Pancreas Institute, University and Hospital Trust of Verona, Verona 37134, Italy

    • Davide Antonello
    • , Luca Landoni
    • , Anna Malpaga
    • , Marco Miotto
    • , Massimo Falconi
    • , Giovanni Butturini
    • , Stefano Partelli
    • , Claudio Bassi
    •  & Paolo Pederzoli
  11. Medical Oncology, University and Hospital Trust of Verona, Verona, Italy

    • Sara Cingarlini
    •  & Giampaolo Tortora
  12. Department of Pathology, General Hospital of Treviso, Department of Medicine, University of Padua, Italy

    • Angelo P. Dei Tos
  13. Department of Medicine, Section of Endocrinology, University and Hospital Trust of Verona, Verona, Italy

    • Maria Vittoria Davì
  14. The University of Queensland, School of Medicine, Brisbane 4006, Australia

    • Vicki L. J. Whitehall
    •  & Barbara A. Leggett
  15. Pathology Queensland, Brisbane 4006, Australia

    • Vicki L. J. Whitehall
  16. Royal Brisbane and Women’s Hospital, Department of Gastroenterology and Hepatology, Brisbane 4006, Australia

    • Barbara A. Leggett
  17. Institute of Health Biomedical Innovation, Queensland University of Technology, Brisbane, Australia

    • Jonathan Harris
  18. School of Environmental & Life Sciences, University of Newcastle, Ourimbah, New South Wales 2258, Australia

    • Christopher J. Scarlett
  19. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Centre for Cancer Bioinformatics, Peking University Cancer Hospital & Institute, Beijing 100142, China

    • Jianmin Wu
  20. Department of Surgery, Princess Alexandra Hospital, Ipswich Rd, Woollongabba, Queensland 4102, Australia

    • Andrew Barbour
  21. Department of Anatomical Pathology. St Vincent’s Hospital, Sydney, New South Wales 2010, Australia

    • Angela Chou
  22. 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
  23. Department of Pathology, Queen Elizabeth University Hospital, Greater Glasgow & Clyde NHS, Glasgow G51 4TF, UK

    • Fraser Duthie
  24. Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, MS226, Houston, Texas 77030-3411, USA

    • Marie-Claude Gingras
    • , David A. Wheeler
    •  & Richard A. Gibbs
  25. Michael E. DeBakey Department of Surgery and The Elkins Pancreas Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030-3411, USA

    • Marie-Claude Gingras
    • , William E. Fisher
    •  & George Van Buren
  26. Children’s Hospital at Westmead, Westmead, New South Wales 2145, Australia

    • Rebecca A. Dagg
    •  & Loretta M. S. Lau
  27. Children’s Medical Research Institute, The University of Sydney, Westmead, New South Wales 2145, Australia

    • Michael Lee
    • , Hilda A. Pickett
    •  & Roger R. Reddel
  28. Department of Surgery, Royal North Shore Hospital, St Leonards, Sydney, New South Wales 2065, Australia

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

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

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

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

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

    • Nam Q. Nguyen
  34. School of Surgery M507, University of Western Australia, 35 Stirling Highway, Nedlands, Western Australia 6009, Australia

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

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

    • Nikolajs Zeps
  37. University of Melbourne Centre for Cancer Research, University of Melbourne, Melbourne, 3010, Victoria, Australia

    • Sean M. Grimmond

Consortia

  1. Australian Pancreatic Cancer Genome Initiative

    A list of participants and their affiliations is provided in the Supplementary Information.

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Contributions

Biospecimens were collected at affiliated hospitals and processed at each biospecimen core resource centre. Investigator contributions are as follows: A.S., D.K.C., Nicola W., A.V.B., S.M.G. (concept and design); A.S., D.K.C., Nicola W., A.V.B., S.M.G. (project leaders); A.S., D.K.C., K.N., V.Co., Nicola W., A.V.B., S.M.G. (writing team); K.N., A.-M.P., P.B., R.T.L., A.L.J., B.R., S.C., M.C.J.Q, P.J.W., S.H.N., I.D., A.P.D.T, M.V.D., L.L., A.Mal., M.M., M.D.J., J.Hu., L.A.C., V.Ch., A.M.N., M.Pa., M.Pi., C.J.S., A.P., I.R., C.T., V.Ch, A.Maw., E.S.H., E.K.C., A.C., J.A.L., N.B.J., F.D., M.C.G., J.S.S., N.D.M., K.E., N.Q.N., N.Z., M.Fal., M.Fas., G.B., S.P., W.E.F., A. Malp., A. Maw., G.V.B., D.A.W., R.A.G., E.A.M., A.B., C.B., G.T., P.P., A.V.B. (sample collection, processing, quality control & clinical annotation); A.S., D.K.C., J.G.K., A.J.G, A.V.B. (clinico-pathological analyses and interpretation); V.L.J.W., B.A.L. (colon sample collection and clinical annotation); A.S., B.R., I.C., P.C., J.G.K., M.Fas., A.J.G (pathology assessment); V.Co., D.K.M., M.Sc., M.Si., D.A., C.V., T.J.C.B., A.N.C., I.H., S.I., S.McL., C.N., E.N., E.A., S.Be., M.Si. (sequencing); O.H., R.A.D., L.M.S.L., M.L., H.A.P., R.R.R., J.V.P. (telomere analysis); K.N., A.M.P., P.B., R.T.L., A.L.J., A.Maf., S.Ba., K.O.S., S.S., M.C.J.Q., P.J.W., M.J.A., J.L.F., F.N., Nick W., O.H., S.H.K., C.L., S.W., Q.X., J.W., M.Pi., M.C., J.V.P., Nicola W., S.M.G. (bioinformatics); K.K.K, J.Ha. (protein modelling); JLH., K.K.K (functional validation of CHEK2 variants); A.P.D.T. (revision of fusion cases and FISH analysis); A.S., D.K.C., K.N., V.Co., P.B., P.P., N.B.J., F.D., Nicola W., S.M.G., A.V.B. (data interpretation). All authors have read and approved the final manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

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

Reviewer Information Nature thanks S. Chanock and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Extended data

Supplementary information

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    Supplementary Information

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

Excel files

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    Supplementary Data

    This file contains Supplementary Tables 1-16.

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DOI

https://doi.org/10.1038/nature21063

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