Whole-genome landscapes of major melanoma subtypes - PubMed (original) (raw)

. 2017 May 11;545(7653):175-180.

doi: 10.1038/nature22071. Epub 2017 May 3.

James S Wilmott 1 3, Nicola Waddell 2 4, Peter A Johansson 2, Matthew A Field 5, Katia Nones 2 4, Ann-Marie Patch 2 4, Hojabr Kakavand 3, Ludmil B Alexandrov 6, Hazel Burke 1, Valerie Jakrot 1, Stephen Kazakoff 2 4, Oliver Holmes 2 4, Conrad Leonard 2 4, Radhakrishnan Sabarinathan 7 8, Loris Mularoni 7 8, Scott Wood 2 4, Qinying Xu 2 4, Nick Waddell 4, Varsha Tembe 9, Gulietta M Pupo 9, Ricardo De Paoli-Iseppi 3, Ricardo E Vilain 3, Ping Shang 3, Loretta M S Lau 10, Rebecca A Dagg 11, Sarah-Jane Schramm 9, Antonia Pritchard 2, Ken Dutton-Regester 2, Felicity Newell 2, Anna Fitzgerald 12, Catherine A Shang 12, Sean M Grimmond 13, Hilda A Pickett 10, Jean Y Yang 14, Jonathan R Stretch 1, Andreas Behren 15, Richard F Kefford 1 16, Peter Hersey 1 17, Georgina V Long 1 18, Jonathan Cebon 15, Mark Shackleton 19, Andrew J Spillane 1, Robyn P M Saw 1, Núria López-Bigas 7 8 20, John V Pearson 2 4, John F Thompson 1, Richard A Scolyer 1 3 21, Graham J Mann 1 9

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Whole-genome landscapes of major melanoma subtypes

Nicholas K Hayward et al. Nature. 2017.

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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