Background: Population-based studies have identified several clinical variables associated with an increased risk of developing cutaneous melanoma that include phenotype, amount of and response to sun exposure, and family history. However, these observations are of limited relevance to clinical practice as the risk associated with each factor is individually modest and the characteristics of these variables lack precision when applied to a particular individual.
Objective: To review the literature regarding recent advances made in the understanding of the genes and genetics of clinical variables associated with an increased risk of melanoma.
Conclusion: Variants of the MC1R (melanocortin-1 receptor) have been identified as major determinants of high-risk phenotypes, such as red hair and pale skin, and the ability to tan in response to UV exposure. Several studies also suggest that such variants may increase melanoma risk independent of their contribution to phenotype. A strong genetic basis for both nevus density and size has been demonstrated and the link between nevi and the development of MM has become better defined. Finally, germline defects in several genes involved in cell cycle regulation, namely, p16 and CDK4, have been demonstrated in many familial melanoma kindreds. This progress has introduced the prospect of genetic testing as a means of identifying a limited number of high-risk individuals who can be targeted with regular screening and education regarding UV exposure and skin self-examination. Ultimately, through rational genetic therapy targeted to correcting the underlying molecular defect, altering the natural history of melanoma development may be possible.