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.

Prediction of outcome for melanoma patients with surgically resected macroscopic nodal metastases is very imprecise. We performed a comprehensive clinico-pathologic assessment of fresh-frozen macroscopic nodal metastases and the preceding primary melanoma, somatic mutation profiling, and gene expression profiling to identify determinants of outcome in 79 melanoma patients. In addition to disease stage 4 years, 90% confidence interval): the presence of a nodular component in the primary melanoma (6.8, 0.6-76.0), and small cell size (11.1, 0.8-100.0) or low pigmentation (3.0, 0.8-100.0) in the nodal metastases. Absence of BRAF mutation (20.0, 1.0-1000.0) or NRAS mutation (16.7, 0.6-1000.0) were both favorable prognostic factors. A 46-gene expression signature with strong overrepresentation of immune response genes was predictive of better survival (10.9, 0.4-325.6); in the full cohort, median survival was >100 months in those with the signature, but 10 months in those without. This relationship was validated in two previously published independent stage III melanoma data sets. We conclude that the presence of BRAF mutation, NRAS mutation, and the absence of an immune-related expressed gene profile predict poor outcome in melanoma patients with macroscopic stage III disease.