Whole-genome landscapes of major melanoma subtypes

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.

Frequent Genetic Aberrations in the CDK4 Pathway in Acral Melanoma Indicate the Potential for CDK4/6 Inhibitors in Targeted Therapy

“…Large-scale sequencing of both DNA and RNA of acral melanoma samples in future may help to provide unabridged molecular profile for acral melanoma and may contribute to resolve the question why acral melanoma cells do not respond equally and effectively to CDK4/6 inhibitors. Recently, a large, high-coverage wholegenome sequencing study of 183 cases of melanomas with differential subtypes (including 35 acral melanomas) is published, proving an excellent profile for genetic aberrations in acral melanoma (46). The data showed that acral and mucosal melanomas were dominated by structural changes and mutation signatures of unknown etiology, and they also found that greater proportions of the acral and mucosal melanoma genomes showed CNV than in cutaneous melanomas.…”

Precision Oncology: The Promise of Big Data and the Legacy of Small Data

“…While establishing the clonal structure of tumors is very important for predicting its evolution (Rosenthal et al, 2017), the detection of very early cancer stages will depend on the examination of healthy samples and will allow the definition of molecular hallmarks of premalignant conditions (Ryan and Faupel-Badger, 2016), and even the foreseen achievement of a precancer genome atlas (Campbell et al, 2016;Kensler et al, 2016). Examples are already available, for instance with a series of recent studies centered on melanoma: one in which mutations were examined from precursor to invasive lesions (Shain et al, 2015), another in which single-cell RNA-Seq was employed to profile a multitude of cell types (Tirosh et al, 2016), and then one focusing on subtypes from multiple sites (Hayward et al, 2017).…”

Defining the Molecular Genetics of Dermoscopic Naevus Patterns

“…Acral and mucosal melanomas often lack a UVR mutational signature but harbour alternate mutational signatures not commonly identified in cutaneous melanoma [40]. Furthermore, approximately 50% of acral and mucosal melanomas lacked BRAF , RAS or NF1 mutations (i.e., triple-WT) but loss-of-function mutations in CDKN2A , TP53 and ARID2 , and activating hotspot mutations in GNAQ and SF3B1, were more common [40]. …”

“…In contrast to cutaneous melanoma, acral and mucosal melanomas demonstrate a markedly different genomic landscape with a lower mutation burden dominated by large-scale copy number aberrations and structural rearrangements [40]. Acral and mucosal melanomas often lack a UVR mutational signature but harbour alternate mutational signatures not commonly identified in cutaneous melanoma [40].…”

“…The genomic landscape of cutaneous melanoma has been studied most extensively and is characterised by driver mutations, ultraviolet radiation (UVR) mutational signature and copy number aberrations [39, 40]. Cutaneous melanomas have been classified into 4 genomic subtypes based on the pattern of the most prevalent significantly mutated genes: BRAF subtype, RAS family ( NRAS / HRAS / KRAS ) subtype, NF1 subtype and triple-WT (wild-type) subtype (i.e., non- BRAF / NRAS / NF1 mutant) [39].…”