ReviewSkin colour and skin cancer –MC1R, the genetic linkSturm, R. A.Author Information Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia. Tel: (+61) 7 3365 1831; Fax: (+61) 7 3365 4388; Email: [email protected] (Received 2 January 2002; accepted in revised form 2 April 2002) Melanoma Research: September 2002 - Volume 12 - Issue 5 - p 405-416 Buy Abstract Pigmentary traits such as red hair, fair skin, lack of tanning ability and propensity to freckle (the RHC phenotype) have been identified as genetic risk factors for both melanoma and non-melanocytic skin cancers when combined with the environmental risk factor of high ultraviolet light exposure. The human melanocortin-1 receptor (MC1R) is a key determinant of the pigmentation process and can account in large part for the diverse range of variation in human pigmentation phenotypes and skin phototypes. The MC1R coding sequence is highly polymorphic in human populations, with several of these variant forms of the receptor now known to be associated with the RHC phenotype. We have examined MC1R variant allele frequencies in the general population and in a collection of adolescent dizygotic and monozygotic twins with defined pigmentation characteristics. Variant allele frequencies have also been determined in several case-control studies of sporadic melanoma, basal cell carcinoma and squamous cell carcinoma, and in familial melanoma kindreds collected within Australia. These studies have shown that three RHC alleles – Arg151Cys, Arg160Trp and Asp294His – were associated with increased risk in all forms of skin cancer and with penetrance and age of onset in familial melanoma in CDKN2A mutation carriers. There is a significant RHC allele heterozygote carrier effect on skin phototype and skin cancer risk, which indicates that variant MC1R alleles do not behave in a strictly recessive manner. Ultimately, the genetic and chemical assessment of melanin synthesis rather than skin colour will be the best indicator for skin cancer risk, and such genetic association studies combined with functional analysis of MC1R variant alleles should provide the link to understanding skin phototypes. © 2002 Lippincott Williams & Wilkins, Inc.