• MC1R
• melanoma
• pigmentation
• ultraviolet radiation

• MM, malignant melanoma
• FAM, familial melanoma
• MPM, multiple primary melanoma
• NPIM, non-photo induced melanoma
• ALM, acral lentiginous melanoma
• MC1R, melanocortin1 receptor
• α-MSH, alpha melanocyte stimulating hormone
• PAR, population attributable risk
• AMS, atypical mole syndrome
• ASP, agouti signalling protein
• RHC, red hair characteristics
• NMSC, non-melanoma skin cancer

Malignant melanoma (MM) is increasing in most Caucasian populations, the incidence doubling every 10 years.¹ Multiple phenotypic risk factors, including the number of melanocytic naevi (moles), freckling, dysplastic naevi, propensity to sunburn, and the number of severe sunburn episodes during youth, have been identified in the aetiology and pathogenesis of this disease.²

Approximately 10% of MM cases occur in kindreds, suggesting hereditary predisposition to melanoma, often in association with the atypical mole syndrome (AMS) phenotype. Germline mutations affecting two highly penetrant genes predisposing to melanoma, CDKN2A and Cdk4, have been associated with an increased risk for the development of familial cutaneous melanoma.^3–6 However, these mutations are found in only 30 to 40% of kindreds, indicating that other genes may predispose to MM.

In addition to the major predisposition to melanoma caused by these genes, polygenic inheritance determining the development of melanoma has been shown to depend upon polymorphisms located on genes controlling different cellular pathways such as DNA repair,⁷ pigmentation,⁸ and reactive oxygen detoxification.^9,10 Among these, loss of function variants of the human melanocortin 1 receptor gene (MC1R), which plays a crucial role in pigmentation,^11,12 seems important in determining MM risk.^8,13

MC1R maps to chromosome 16q24.3 and encodes a G protein coupled receptor with seven transmembrane domains expressed on many cell types,¹⁴ including melanocytes. MC1R is the receptor of two melanocortin peptides synthesised in the pituitary gland, alpha melanocyte stimulating hormone (α-MSH) and ACTH. These have the same affinity for MC1R, and are cleavage products of the large precursor peptide propiomelanocortin. Their binding to this receptor activates adenylate cyclase, increases intracellular c-AMP production, then leads to enhanced tyrosinase transcription and traduction, and, ultimately, to production of photoprotective eumelanin and melanocyte proliferation. Regulation of melanogenesis also …