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Melanoma represents just 1% of skin cancer but is responsible for the vast majority of skin cancer deaths. Given its implications for therapeutic advancement, the field of melanoma genomics has dramatically expanded in recent years. At one time classified mainly by anatomical location-non-acral cutaneous melanoma (NACM), acral cutaneous melanoma (ACM), mucosal melanoma (MuM), or uveal melanoma (UM) are now further sub-classified based on the mutated genes that drive their initiation, progression, and survival. BRAF gene mutations in NACM are the most frequently occurring and the best-studied, giving rise to the successful use of BRAF inhibitors in clinical practice for the last decade. This development has opened the door for many promising clinical trials and countless investigations into melanoma's genetic underpinnings. In this review, we offer an overview of melanoma genomics and discuss the most relevant somatic mutations such as BRAF, NRAS, and NF1 in NACM, KIT in ACM and MuM, and GNAQ, GNA11, and BAP1 in UM. Particular emphasis is placed on the biochemical pathways driven by each mutation, their associated clinical manifestations, and their role as current and future therapeutic targets.

Although TERT promoter mutations have been associated with a worsened prognosis in melanoma, the relationship between mutation status and downstream telomerase activity and telomere length remains convoluted. Using Sanger sequencing and techniques based on quantitative reverse transcriptase in real time, we evaluated 60 melanoma cell lines for TERT promoter mutational status, copy number, gene expression, and telomere length to provide a comprehensive analysis of the TERT/telomere pathway and establish a classification system whereby the associations between TERT mutations and their downstream molecular manifestations can more easily be ascertained. Mutations at positions -124/125 and -146 were associated with the highest levels of TERT gene expression but had no appreciable impact on absolute telomere length. In contrast, the common variant rs2853669 (at position -245) was significantly associated with longer telomere length via a recessive model in our cohort (P ¼ 0.003). Our results, which are from assays performed on purified melanoma cell lines, suggest that the TERT promoter harbors a more complex mutational landscape than previously thought. Furthermore, the failure of TERT promoter mutations to consistently correlate with TERT expression and telomere length suggests an alternative method whereby tumor cells escape the critical shortening of telomeres.