Whole-genome landscapes of major melanoma subtypes

Nicholas K. Hayward, James S. Wilmott, Nicola Waddell, Peter A. Johansson, Matthew A. Field, Katia Nones, Ann-Marie Patch, Hojabr Kakavand, Ludmil B. Alexandrov, Hazel Burke, Valerie Jakrot, Stephen Kazakoff, Oliver Holmes, Conrad Leonard, Radhakrishnan Sabarinathan, Loris Mularoni, Scott Wood, Qinying Xu, Nick Waddell, Varsha Tembe, Gulietta M. Pupo, Ricardo De Paoli-Iseppi, Ricardo E. Vilain, Ping Shang, Loretta M. S. Lau, Rebecca A. Dagg, Sarah-Jane Schramm, Antonia Pritchard, Ken Dutton-Regester, Felicity Newell, Anna Fitzgerald, Catherine A. Shang, Sean M. Grimmond, Hilda A. Pickett, Jean Y. Yang, Jonathan R. Stretch, Andreas Behren, Richard F. Kefford, Peter Hersey, Georgina V. Long, Jonathan Cebon, Mark Shackleton, Andrew J. Spillane, Robyn P. M. Saw, Núria López-Bigas, John V. Pearson, John F. Thompson, Richard A. Scolyer and Graham J. Mann ()
Additional contact information
Nicholas K. Hayward: Melanoma Institute Australia, The University of Sydney
James S. Wilmott: Melanoma Institute Australia, The University of Sydney
Nicola Waddell: QIMR Berghofer Medical Research Institute
Peter A. Johansson: QIMR Berghofer Medical Research Institute
Matthew A. Field: Australian Institute of Tropical Health and Medicine, James Cook University
Katia Nones: QIMR Berghofer Medical Research Institute
Ann-Marie Patch: QIMR Berghofer Medical Research Institute
Hojabr Kakavand: Discipline of Pathology, Sydney Medical School, The University of Sydney
Ludmil B. Alexandrov: Los Alamos National Laboratory
Hazel Burke: Melanoma Institute Australia, The University of Sydney
Valerie Jakrot: Melanoma Institute Australia, The University of Sydney
Stephen Kazakoff: QIMR Berghofer Medical Research Institute
Oliver Holmes: QIMR Berghofer Medical Research Institute
Conrad Leonard: QIMR Berghofer Medical Research Institute
Radhakrishnan Sabarinathan: Research Program on Biomedical Informatics, IMIM Hospital del Mar Medical Research Institute, Universitat Pompeu Fabra
Loris Mularoni: Research Program on Biomedical Informatics, IMIM Hospital del Mar Medical Research Institute, Universitat Pompeu Fabra
Scott Wood: QIMR Berghofer Medical Research Institute
Qinying Xu: QIMR Berghofer Medical Research Institute
Nick Waddell: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland
Varsha Tembe: Centre for Cancer Research, Westmead Institute for Medical Research, The University of Sydney
Gulietta M. Pupo: Centre for Cancer Research, Westmead Institute for Medical Research, The University of Sydney
Ricardo De Paoli-Iseppi: Discipline of Pathology, Sydney Medical School, The University of Sydney
Ricardo E. Vilain: Discipline of Pathology, Sydney Medical School, The University of Sydney
Ping Shang: Discipline of Pathology, Sydney Medical School, The University of Sydney
Loretta M. S. Lau: Children’s Medical Research Institute, The University of Sydney
Rebecca A. Dagg: Children’s Hospital at Westmead, The University of Sydney
Sarah-Jane Schramm: Centre for Cancer Research, Westmead Institute for Medical Research, The University of Sydney
Antonia Pritchard: QIMR Berghofer Medical Research Institute
Ken Dutton-Regester: QIMR Berghofer Medical Research Institute
Felicity Newell: QIMR Berghofer Medical Research Institute
Anna Fitzgerald: Bioplatforms Australia
Catherine A. Shang: Bioplatforms Australia
Sean M. Grimmond: University of Melbourne Centre for Cancer Research, University of Melbourne
Hilda A. Pickett: Children’s Medical Research Institute, The University of Sydney
Jean Y. Yang: School of Mathematics and Statistics, The University of Sydney
Jonathan R. Stretch: Melanoma Institute Australia, The University of Sydney
Andreas Behren: Olivia Newton-John Cancer Research Institute, La Trobe University, Austin Health
Richard F. Kefford: Melanoma Institute Australia, The University of Sydney
Peter Hersey: Melanoma Institute Australia, The University of Sydney
Georgina V. Long: Melanoma Institute Australia, The University of Sydney
Jonathan Cebon: Olivia Newton-John Cancer Research Institute, La Trobe University, Austin Health
Mark Shackleton: Peter MacCallum Cancer Centre and University of Melbourne
Andrew J. Spillane: Melanoma Institute Australia, The University of Sydney
Robyn P. M. Saw: Melanoma Institute Australia, The University of Sydney
Núria López-Bigas: Research Program on Biomedical Informatics, IMIM Hospital del Mar Medical Research Institute, Universitat Pompeu Fabra
John V. Pearson: QIMR Berghofer Medical Research Institute
John F. Thompson: Melanoma Institute Australia, The University of Sydney
Richard A. Scolyer: Melanoma Institute Australia, The University of Sydney
Graham J. Mann: Melanoma Institute Australia, The University of Sydney

Nature, 2017, vol. 545, issue 7653, 175-180

Abstract: 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.

Date: 2017
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DOI: 10.1038/nature22071

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