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Nature. 2017 May 11;545(7653):175-180. doi: 10.1038/nature22071. Epub 2017 May 3.

Whole-genome landscapes of major melanoma subtypes.

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Melanoma Institute Australia, The University of Sydney, North Sydney, Sydney, New South Wales 2065, Australia.
QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
Discipline of Pathology, Sydney Medical School, The University of Sydney, Sydney, New South Wales 2006, Australia.
Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia.
Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Queensland 4878, Australia.
Los Alamos National Laboratory, Los Alamos, New Mexico 87545, USA.
Research Program on Biomedical Informatics, IMIM Hospital del Mar Medical Research Institute, Universitat Pompeu Fabra, 08003 Barcelona, Catalonia, Spain.
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain.
Centre for Cancer Research, Westmead Institute for Medical Research, The University of Sydney, Westmead, Sydney, New South Wales 2145, Australia.
Children's Medical Research Institute, The University of Sydney, Westmead, Sydney, New South Wales 2145, Australia.
Children's Hospital at Westmead, The University of Sydney, Westmead, New South Wales Sydney, 2145, Australia.
Bioplatforms Australia, North Ryde, Sydney, New South Wales 2109, Australia.
University of Melbourne Centre for Cancer Research, University of Melbourne, Parkville, Melbourne, Victoria 3052, Australia.
School of Mathematics and Statistics, The University of Sydney, Sydney, New South Wales 2006, Australia.
Olivia Newton-John Cancer Research Institute, La Trobe University, Austin Health, Heidelberg, Melbourne, Victoria 3084, Australia.
Macquarie University, North Ryde, Sydney, New South Wales 2109, Australia.
Centenary Institute, The University of Sydney, Sydney, New South Wales 2006, Australia.
Department of Medical Oncology, Royal North Shore Hospital, St Leonards, Sydney, New South Wales 2065, Australia.
Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, Victoria 3000, Australia.
Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain.
Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, Sydney, New South Wales 2050, Australia.


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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