BRAF targets in melanoma. Biological mechanisms, resistance, and drug discovery. Cancer drug discovery and development. Volume 82. Ed. Ryan J. Sullivan. Springer (2015)

Although melanoma is a highly heterogeneous disease with respect to clinical behavior, histology, and underlying genomic aberrations and mutations, several themes have emerged in our understanding of its molecular pathogenesis. The MAPK pathway is the key signaling pathway, with activating mutations in BRAF, NRAS, KIT, GNAQ, or GNA11 found in almost all melanomas. The RB and p53 pathways are also frequently dysregulated in melanoma and are implicated in many familial cases. Given the important role of MAPK, RB, and p53 signaling in other malignancies, understanding abnormalities of these pathways may have broad implications for research and treatment of many cancers.

Lineage-specific activity is known to contribute to melanomagenesis as well, with amplification and dysregulation of MITF found in 20% of melanomas. Other genes, which are less commonly affected, have been identified by analysis of large exome sequence datasets and other methods. In the future, intron and UTR sequence data from whole-genome sequencing will allow further refinement of algorithms and increased statistical power to find low frequency driver mutations in melanoma.

Despite substantial progress in our understanding of melanoma pathogenesis, several important observations remain unexplained. Sun exposure is the leading environmental risk factor for melanoma, but the most common oncogenic mutations (in BRAF and NRAS) are not caused by known UV-related mechanisms. Sunscreens confer protection against cutaneous squamous cell carcinoma and have been shown to diminish melanoma incidence in certain contexts, but less so (or not at all) in other studies, suggesting a complexity that is poorly understood [117, 118]. Moreover, a recent study reported that the red hair/fair skin pigmentation phenotype is associated with elevated melanoma risk independent of UV exposure [18]. Elucidating the molecular basis for UV-independent melanoma susceptibility and genetic lesions will provide the framework for progress in melanoma prevention.

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