Abstract
BACKGROUND: Although a role for ultraviolet radiation (UVR) in cutaneous malignant melanoma (CMM) development is accepted, there is debate over the magnitude and mechanisms given its association with intermittent but not chronic exposure. OBJECTIVES: To assess new ideas and data on the subject, review some debated topics, bringing a molecular view to epidemiological observations. METHODS: We reviewed some recent advances in the field of epidemiology and genetics, including phenome-wide association studies, evolutionary genetics related to skin cancer, and mechanisms of UVR-induced DNA adduct formation. RESULTS: High rates of CMM are strongly correlated with light colored skin across the globe. CMM shares risk factors associated with UVR sensitivity with keratinocyte cancer (KC). CMM risk is dominated by MC1R, a gene regulating the proportions of black and red melanin produced. An emerging mutagenic mechanism involves reactive melanin, particularly red pheomelanin, that can itself induce DNA adducts. CONCLUSION: Demographically, epidemiologically, and mechanistically, pigmentation status is central to CMM risk and a shared genetic susceptibility, comprising several pigmentation genes, between CMM and KCs. In the general population, CMM risk is associated with pale skin and poor tanning ability, mechanistically due to a relative lack of protection against UVR adduct formation, or perhaps via an alternate manner in individuals with abundant pheomelanin. Overall, evidence suggests that UVR exposure impacts CMM risk.