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Pigmentation genes and melanoma susceptibility

Fargnoli, M.C.

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doi: 10.1097/01.cmr.0000382757.85871.8b
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Human pigmentation is a strong risk factor for melanoma and incidence of melanoma is higher in individuals with fair skin complexion than in those with dark skin complexion. A number of recent studies, including genome-wide association studies, have identified numerous polymorphisms in both known pigmentation pathways and previously unknown genes controlling human hair, eye and skin color. Among more than 120 genes being implicated in human pigmentation, the melanocortin-1 receptor (MC1R) gene, which encodes the melanocyte-stimulating hormone receptor, is the only clearly characterized low-penetrance melanoma susceptibility gene. Association studies have indeed shown that the R142H, R151C, R160W and D294H MC1R variants, known as red hair color (RHC) variants, increase melanoma risk. In addition, coinheritance of MC1R variants increases the penetrance of CDKN2A in melanoma families and predisposes to development of multiple melanomas in CDKN2A-mutation carriers. MC1R variants have also been shown to increase the risk of developing melanomas harboring BRAF mutations. Polymorphic variants in other pigmentation genes, such as OCA2, ASIP, TYR and TYRP1, have been associated with increased melanoma risk in European populations. On the other hand, another key pigmentation gene, SCL45A2/MATP, appeared to have a strong protective effect for melanoma. Therefore, several evidences show that pigmentation genes are of potential importance in melanoma susceptibility. Genetic information combined with clinical examination may help define specific high-risk groups targeting melanoma prevention programs.

© 2010 Lippincott Williams & Wilkins, Inc.