The melanocortin-1 receptor gene polymorphism and association with human skin cancer.

The melanocortin-1 receptor (MC1R) is a key gene involved in the regulation of melanin synthesis and encodes a G-protein coupled receptor expressed on the surface of the melanocyte in the skin and hair follicles. MC1R activation after ultraviolet radiation exposure results in the production of the dark eumelanin pigment and the tanning process in humans, providing physical protection against DNA damage. The MC1R gene is highly polymorphic in Caucasian populations with a number of MC1R variant alleles associated with red hair, fair skin, freckling, poor tanning, and increased risk of melanoma and nonmelanoma skin cancer. Variant receptors have shown alterations in biochemical function, largely due to intracellular retention or impaired G-protein coupling, but retain some signaling ability. The association of MC1R variant alleles with skin cancer risk remains after correction for pigmentation phenotype, indicating regulation of nonpigmentary pathways. Notably, MC1R activation has been linked to DNA repair and may also contribute to the regulation of immune responses.