Skin colour and skin cancer - MC1R, the genetic link

• Published in: Melanoma research Vol. 12; no. 5; pp. 405 - 416
• Main Author: Sturm, R A
• Format: Journal Article
• Language: English
• Published: England 01-09-2002
• Subjects: Alleles; Amino Acid Sequence; Arginine - chemistry; Aspartic Acid - chemistry; Base Sequence; Case-Control Studies; Cystine - chemistry; Genotype; Histidine - chemistry; Humans; Models, Genetic; Molecular Sequence Data; Phenotype; Polymorphism, Genetic; Receptors, Corticotropin - biosynthesis; Receptors, Corticotropin - genetics; Receptors, Melanocortin; Signal Transduction; Skin Neoplasms - metabolism; Skin Pigmentation - genetics; Tryptophan - chemistry; Twins; Twins, Dizygotic; Twins, Monozygotic; Ultraviolet Rays
• ISSN: 0960-8931
• DOI: 10.1097/00008390-200209000-00001

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 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 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 mutation carriers. There is a significant RHC allele heterozygote carrier effect on skin phototype and skin cancer risk, which indicates that variant 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 variant alleles should provide the link to understanding skin phototypes.