The Role of Melanocortin-1 Receptor Polymorphism in Skin Cancer Risk Phenotypes RICHARD A. STURM 1 , DAVID L. DUFFY 2 , NEIL F. BOX 1 , WEI CHEN 1 , DARREN J. SMIT 1 , DARREN L. BROWN 1 , JENNIFER L. STOW 1 , J. HELEN LEONARD 2 and NICHOLAS G. MARTIN 2 1 Institute for Molecular Bioscience, University of Queensland; 2 Queensland Institute of Medical Research, Brisbane, Queensland, Australia *Address reprint requests to Dr Richard A. Sturm, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia. E-mail: r.sturm@imb.uq.edu.au Received 21 January 2003; in final form 21 February 2003 We have examined melanocortin-1 receptor (MC1R) variant allelefrequenciesinthegeneralpopulationandinacollectionof adolescent dizygotic and monozygotic twins to determine statistical associations of pigmentation phenotypes with increased skin cancer risk. This included hair and skin color, freckling, mole count and sun exposed skin reflectance. Nine variants were studied and designated as either strong R (OR = 63; 95% CI 32–140) or weak r (OR = 5; 95% CI 3– 11) red hair alleles. Penetrance of each MC1R variant allele was consistent with an allelic model where effects were multiplicative for red hair but additive for skin reflectance. To assesstheinteractionofthebrowneyecolorgeneBEY2 ⁄ OCA2 on the phenotypic effects of variant MC1R alleles we imputed OCA2 genotype in the twin collection. A modifying effect of OCA2 on MC1R variant alleles was seen on constitutive skin color,frecklingandmolecount.Inordertostudytheindividual effects of these variants on pigmentation phenotype we have established a series of human primary melanocyte strains genotyped for the MC1R receptor. These include strains which are MC1R wild-type consensus, variant heterozygotes, and homozygotes for strong R alleles Arg151Cys and Arg160Trp. Ultrastructural analysis demonstrated that only consensus strains contained stage III and IV melanosomes in their terminal dendrites whereas Arg151Cys and Arg160Trp homo- zygous strains contained only immature stage I and II melanosomes. Such genetic association studies combined with the functional analysis of MC1R variant alleles in melanocytic cells should provide a link in understanding the association between pigmentary phototypes and skin cancer risk. Key words: MC1R, OCA2, Freckle, Mole, Melanocyte INTRODUCTION Although there are complex mutagenic actions of ultraviolet (UV) radiation on the different skin cells that give rise to basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and melanoma it is clear that each is causally related to the degree or intensity of sun exposure. Epidemiological studies of these skin cancers have shown that SCC is strongly associated with an individual’s total or occupational UV exposure while the incidence of BCC is less strongly related with sun exposure, and is only weakly associated with pigmentation characteristics. In contrast, recreational sun exposure, history of sunburn, pigmentation phenotype and number of benign nevi are more predictive factors of melanoma (1). The incidence rate of each tumor is greatest in fair-skinned sun-sensitive individuals, indicating the importance of the innate ability to respond to UV light through the increased synthesis of melanin and a skin tanning response. However, the absolute amount and differ- ential light-absorbing properties of the melanin biopolymer within the epidermal melanocytes must be considered in response to sun exposure, leaving the idea of a protective tanning response in question. Melanin can be viewed as either photoprotective or photosensitizing, depending on the type and composition of the pigment itself (2). Of central importance in determining an individual’s risk for skin Abbreviations – BCC, basal cell carcinoma; BEY2, brown eye color-2; MC1R, melanocortin-1 receptor; MSH, a-melanocyte-stimulating hormone; OCA2, oculocutaneous albinism-2; OR, odds ratio; QF, Queensland foreskin; RHC, red hair color; SCC, squamous cell carcinoma; TYR, tyrosinase; TYRP1, tyrosinase related protein-1; UV, ultraviolet PIGMENT CELL RES 16: 266–272. 2003 Copyright Ó Blackwell Munksgaard 2003 Printed in UK—all rights reserved ISSN 0893-5785 266 Pigment Cell Res. 16, 2003