Abstract

Melanoma of the skin is a common cancer only in Europeans, whereas it arises in internal body surfaces (mucosal sites) and on the hands and feet (acral sites) in people throughout the world. Here we report analysis of whole-genome sequences from cutaneous, acral and mucosal subtypes of melanoma. The heavily mutated landscape of coding and non-coding mutations in cutaneous melanoma resolved novel signatures of mutagenesis attributable to ultraviolet radiation. However, acral and mucosal melanomas were dominated by structural changes and mutation signatures of unknown aetiology, not previously identified in melanoma. The number of genes affected by recurrent mutations disrupting non-coding sequences was similar to that affected by recurrent mutations to coding sequences. Significantly mutated genes included BRAF, CDKN2A, NRAS and TP53 in cutaneous melanoma, BRAF, NRAS and NF1 in acral melanoma and SF3B1 in mucosal melanoma. Mutations affecting the TERT promoter were the most frequent of all; however, neither they nor ATRX mutations, which correlate with alternative telomere lengthening, were associated with greater telomere length. Most melanomas had potentially actionable mutations, most in components of the mitogen-activated protein kinase and phosphoinositol kinase pathways. The whole-genome mutation landscape of melanoma reveals diverse carcinogenic processes across its subtypes, some unrelated to sun exposure, and extends potential involvement of the non-coding genome in its pathogenesis.

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Acknowledgements

This work was supported by Melanoma Institute Australia, Bioplatforms Australia, the New South Wales Ministry of Health, Cancer Council NSW, National Health and Medical Research Council of Australia (NHMRC), Cancer Institute NSW, Australian Cancer Research Foundation and the National Collaborative Research Infrastructure Strategy. N.K.H., Nicola W., R.A.S., J.S.W. and K.D.-R. were supported by NHMRC Fellowships, K.N. by a Keith Boden Fellowship, G.V.L. by the University of Sydney Medical Foundation, M.S. by Pfizer Australia, the Victorian Endowment for Knowledge, Science and Innovation and NHMRC, L.B.A. by a J. Robert Oppenheimer Fellowship at Los Alamos National Laboratory, and N.L.-B. by the European Research Council (Consolidator Grant 682398). Biobanking was supported by Melanoma Institute Australia, the Victorian Cancer Agency, Victorian Cancer Biobank, Victorian State Government Operational Infrastructure Support Program, Melanoma Research Alliance and the Melbourne Melanoma Project, and the efforts of patients, clinicians and other staff at health services across Australia. Cell lines were provided via the ABN-Oncology group, supported by NHMRC. Research at Los Alamos National Laboratory was under the auspices of the National Nuclear Security Administration of the US Department of Energy; the Los Alamos National Laboratory Institutional Computing Program was supported by contract DE-AC52-06NA25396. We acknowledge the support of colleagues at Melanoma Institute Australia, Royal Prince Alfred Hospital, NSW Health Pathology, Westmead Institute for Medical Research, Peter MacCallum Cancer Centre and Olivia Newton-John Cancer Research Institute. We thank D. Stetner for computing assistance.

Author information

Author notes

    • Nicholas K. Hayward
    • , James S. Wilmott
    • , Nicola Waddell
    •  & Peter A. Johansson

    These authors contributed equally to this work.

    • Nicholas K. Hayward
    • , John V. Pearson
    • , John F. Thompson
    • , Richard A. Scolyer
    •  & Graham J. Mann

    These authors jointly supervised this work.

Affiliations

  1. Melanoma Institute Australia, The University of Sydney, North Sydney, Sydney, New South Wales 2065, Australia

    • Nicholas K. Hayward
    • , James S. Wilmott
    • , Hazel Burke
    • , Valerie Jakrot
    • , Jonathan R. Stretch
    • , Richard F. Kefford
    • , Peter Hersey
    • , Georgina V. Long
    • , Andrew J. Spillane
    • , Robyn P. M. Saw
    • , John F. Thompson
    • , Richard A. Scolyer
    •  & Graham J. Mann
  2. QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia

    • Nicholas K. Hayward
    • , Nicola Waddell
    • , Peter A. Johansson
    • , Katia Nones
    • , Ann-Marie Patch
    • , Stephen Kazakoff
    • , Oliver Holmes
    • , Conrad Leonard
    • , Scott Wood
    • , Qinying Xu
    • , Antonia Pritchard
    • , Ken Dutton-Regester
    • , Felicity Newell
    •  & John V. Pearson
  3. Discipline of Pathology, Sydney Medical School, The University of Sydney, Sydney, New South Wales 2006, Australia

    • James S. Wilmott
    • , Hojabr Kakavand
    • , Ricardo De Paoli-Iseppi
    • , Ricardo E. Vilain
    • , Ping Shang
    •  & Richard A. Scolyer
  4. Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia

    • Nicola Waddell
    • , Katia Nones
    • , Ann-Marie Patch
    • , Stephen Kazakoff
    • , Oliver Holmes
    • , Conrad Leonard
    • , Scott Wood
    • , Qinying Xu
    • , Nick Waddell
    •  & John V. Pearson
  5. Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Queensland 4878, Australia

    • Matthew A. Field
  6. Los Alamos National Laboratory, Los Alamos, New Mexico 87545, USA

    • Ludmil B. Alexandrov
  7. Research Program on Biomedical Informatics, IMIM Hospital del Mar Medical Research Institute, Universitat Pompeu Fabra, 08003 Barcelona, Catalonia, Spain

    • Radhakrishnan Sabarinathan
    • , Loris Mularoni
    •  & Núria López-Bigas
  8. Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain

    • Radhakrishnan Sabarinathan
    • , Loris Mularoni
    •  & Núria López-Bigas
  9. Centre for Cancer Research, Westmead Institute for Medical Research, The University of Sydney, Westmead, Sydney, New South Wales 2145, Australia

    • Varsha Tembe
    • , Gulietta M. Pupo
    • , Sarah-Jane Schramm
    •  & Graham J. Mann
  10. Children’s Medical Research Institute, The University of Sydney, Westmead, Sydney, New South Wales 2145, Australia

    • Loretta M. S. Lau
    •  & Hilda A. Pickett
  11. Children’s Hospital at Westmead, The University of Sydney, Westmead, New South Wales Sydney, 2145, Australia

    • Rebecca A. Dagg
  12. Bioplatforms Australia, North Ryde, Sydney, New South Wales 2109, Australia

    • Anna Fitzgerald
    •  & Catherine A. Shang
  13. University of Melbourne Centre for Cancer Research, University of Melbourne, Parkville, Melbourne, Victoria 3052, Australia

    • Sean M. Grimmond
  14. School of Mathematics and Statistics, The University of Sydney, Sydney, New South Wales 2006, Australia

    • Jean Y. Yang
  15. Olivia Newton-John Cancer Research Institute, La Trobe University, Austin Health, Heidelberg, Melbourne, Victoria 3084, Australia

    • Andreas Behren
    •  & Jonathan Cebon
  16. Macquarie University, North Ryde, Sydney, New South Wales 2109, Australia

    • Richard F. Kefford
  17. Centenary Institute, The University of Sydney, Sydney, New South Wales 2006, Australia

    • Peter Hersey
  18. Department of Medical Oncology, Royal North Shore Hospital, St Leonards, Sydney, New South Wales 2065, Australia

    • Georgina V. Long
  19. Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, Victoria 3000, Australia

    • Mark Shackleton
  20. Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain

    • Núria López-Bigas
  21. Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, Sydney, New South Wales 2050, Australia

    • Richard A. Scolyer

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Contributions

P.A.J., M.A.F., K.N., A.-M.P., L.B.A., A.P., S.K., O.H., C.L., S.W., Q.X., Nick W. K.D.-R. and F.N. analysed genomic data; V.J., P.S., H.K., R.D.P.-I., V.T., G.M.P. and H.B. collected, prepared and analysed samples and data; L.M.S.L., R.A.D. and H.A.P. validated telomere length; L.M., R.S. and N.L.-B. analysed selection on coding and non-coding mutations; A.F., C.A.S., J.Y.Y. and S.-J.S. supported design and planning; J.V.P., Nicola W. and S.M.G. developed and directed the analysis pipeline; J.F.T., M.S., A.B., J.C., J.R.S., R.F.K., P.H., G.V.L., A.J.S., R.P.M.S. and R.E.V. collected samples and data; N.K.H., J.S.W., P.A.J., Nicola W., R.A.S. and G.J.M. designed and directed the study, analysed data and wrote the manuscript, which all authors reviewed.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Graham J. Mann.

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

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Supplementary information

Excel files

  1. 1.

    Supplementary Table 1

    This file contains clinical and mutation data.

  2. 2.

    Supplementary Table 3

    This file contains structural rearrangements in melanoma.

  3. 3.

    Supplementary Table 4

    This file contains gene promoters frequently mutated in melanoma.

  4. 4.

    Supplementary Table 5

    This file contains recurrent 5’ UTR mutations in melanoma.

  5. 5.

    Supplementary Table 6

    This file contains recurrent 3’ UTR mutations in melanoma.

  6. 6.

    Supplementary Table 7

    This file contains significantly mutated genes.

  7. 7.

    Supplementary Table 8

    This file contains the key to Fig 3b: Significantly mutated genes and selected published melanoma driver genes.

  8. 8.

    Supplementary Table 9

    This file contains perturbed pathways in melanoma.

Zip files

  1. 1.

    Supplementary Table 2

    This file contains coding mutations (SNV and indel) in melanoma (MAF). This file corrupted and was replaced by a zipped version on the 5 June 2017 to fix the corruption error.

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DOI

https://doi.org/10.1038/nature22071

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