Whole-genome landscapes of major melanoma subtypes

Hayward, Nicholas K., Wilmott, James S., Waddell, Nicola, Johansson, Peter A., Field, Matthew A., Nones, Katia, Patch, Ann-Marie, Kakavand, Hojabr, Alexandrov, Ludmil B., Burke, Hazel, Jakrot, Valerie, Kazakoff, Stephen, Holmes, Oliver, Leonard, Conrad, Sabarinathan, Radhakrishnan, Mularoni, Loris, Wood, Scott, Xu, Qinying, Waddell, Nick, Tembe, Varsha, Pupo, Gulietta M., De Paoli-Iseppi, Ricardo, Vilain, Ricardo E., Shang, Ping, Lau, Loretta M.S., Dagg, Rebecca A., Schramm, Sarah-Jane, Pritchard, Antonia, Dutton-Regester, Ken, Newell, Felicity, Fitzgerald, Anna, Shang, Catherine A., Grimmond, Sean M., Pickett, Hilda A., Yang, Jean Y., Stretch, Jonathan R., Behren, Andreas, Kefford, Richard F., Hersey, Peter, Long, Georgina V., Cebon, Jonathan, Shackleton, Mark, Spillane, Andrew J., Saw, Robyn P.M., López-Bigas, Núria, Pearson, John V., Thompson, John F., Scolyer, Richard A., and Mann, Graham J. (2017) Whole-genome landscapes of major melanoma subtypes. Nature, 545. pp. 175-180.

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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.

Item ID: 48898
Item Type: Article (Research - C1)
ISSN: 1476-4687
Funders: Melanoma Institute Australia (MIA), Bioplatoforms Australia (BA), New South Wales Ministry of Health, Cancer Council NSW (CC), National Health and Medical Research Council (NHMRC), Cancer Institute NSW (CI), Australian Cancer Research Foundation, National Collaborative Research Infrastructure Strategy Australia, University of Sydney Medical Foundation, Pfizer Australia, Victorian Endowment for Science Knowledge and Innovation, Los Alamos National Laboratory (LANL), European Research Council (ERC), National Nuclear Security Administration, USA
Projects and Grants: LANL J. Robert Oppenheimer Fellowship, ERC Consolidator Grant 682398
Date Deposited: 03 Aug 2017 06:35
FoR Codes: 06 BIOLOGICAL SCIENCES > 0601 Biochemistry and Cell Biology > 060102 Bioinformatics @ 50%
11 MEDICAL AND HEALTH SCIENCES > 1112 Oncology and Carcinogenesis > 111203 Cancer Genetics @ 50%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920102 Cancer and Related Disorders @ 100%
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