BRAF targets in melanoma. Biological mechanisms, resistance, and drug discovery. Cancer drug discovery and development. Volume 82. Ed. Ryan J. Sullivan. Springer (2015)
Melanoma pathogenesis is driven by both environmental and genetic factors. Epidemiologic studies have linked melanoma to geographic location and sun (UV) exposure, which is believed to be the most important environmental risk factor. In particular, severe sunburns early in life are associated with the highest risk for melanoma [5, 6]. Melanomas occur more frequently on sun-exposed regions of the body. However, unlike most keratinocyte skin cancers which are known to be products of UVR, melanoma primary tumors are not restricted to sun-exposed skin. Although individuals with fair skin are more susceptible, melanomas also arise in darkly pigmented individuals, most often at acral or mucosal sites. These observations suggest that sun exposure does not account for all melanoma risk.
Increased melanoma susceptibility is associated with family history, fair pigmentation phenotypes, and higher numbers of melanocytic nevi. A family history of melanoma confers an estimated twofold increase in melanoma risk, and approximately 10% of melanoma patients have a family history of the disease . Melanoma is considered familial if two first-degree relatives or three individuals in a family, irrespective of relationship, are diagnosed with melanoma. Familial melanoma is most often associated with dysregulation of cell cycle checkpoints due to mutations in cell cycle regulatory genes such as cyclin-dependent kinase 4 (CDK4)  and cyclin-dependent kinase inhibitor 2A (CDKN2A), which accounts for 40% of cases and is the most common high-penetrance melanoma susceptibility locus . Germline CDKN2A mutations are responsible for familial atypical multiple mole melanoma (FAMM) syndrome, an autosomal dominant genodermatosis characterized by increased incidence of melanocytic nevi and melanoma, and elevated risk of other malignancies such as pancreatic cancer in some FAMM kindreds [10, 11]. A less common cause of familial melanoma is the recently reported E318K variant of MITF [12, 13]. This variant exhibited gain-of-function activity for MITF, which is a previously described amplified melanoma oncogene. Individuals carrying the allele exhibited elevated nevus counts and non-blue eye colors, together with increased melanoma risk. The risk was intermediate in nature in the general population (sporadic) and also segregated among many studied melanoma families in multiple continents. The E318K coding variant disrupts a sumoylation site on MITF , thereby inhibiting a functionally suppressive post-translational modification on MITF.
Heritable physical characteristics such as fair skin complexion, inability to tan, and blue eyes are associated with elevated melanoma susceptibility. Germline variants of pigmentation genes such as MC1R, agouti signaling protein (ASIP), and tyrosinase (TYR) confer lowor moderate-penetrance melanoma risk [15, 16]. Individuals with non-signaling variants of MC1R have the red hair/fair skin phenotype, characterized by fair pigmentation, freckling, and sun sensitivity, that is associated with the highest risk of melanoma of all pigmentation phenotypes . MC1R coding variants are found in 80% of individuals with red hair, less than 20% of individuals with brown or black hair, and less than 4% of individuals with a robust tanning response . Comparison of melanomas in murine models of different pigmentation phenotypes has demonstrated that the synthesis pathway of the red pigment pheomelanin contributes to melanomagenesis via a UV-independent mechanism .
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