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Population-Based Study of Natural Variation in the Melanocortin-1 Receptor Gene and Melanoma

¹ Department of Biostatistics and Epidemiology and Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania; ² Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York; ³ University of Sydney, Sydney, New South Wales, Australia; ⁴ Cancer Care Ontario; ⁵ Women's College Hospital, Toronto, Ontario, Canada; ⁶ University of North Carolina, Chapel Hill, North Carolina; ⁷ University of Michigan, Ann Arbor, Michigan; ⁸ University of California, Irvine, California; ⁹ Centro per la Prevenzione Oncologia Torino, Piemonte, Italy; ¹⁰ British Columbia Cancer Agency, Vancouver, British Columbia, Canada; ¹¹ Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia; ¹² New Jersey Department of Health and Senior Services, Trenton, New Jersey; and ¹³ Department of Epidemiology, University of New Mexico, Albuquerque, New Mexico

Requests for reprints: Peter A. Kanetsky, Center for Clinical Epidemiology and Biostatistics and Epidemiology, University of Pennsylvania, 903 Blockley Hall, Philadelphia, PA 19104-6021. Phone: 215-573-3282; Fax: 215-573-2260; E-mail: pkanetsk{at}cceb.med.upenn.edu.

Natural variation in the coding region of the melanocortin-1 receptor (MC1R) gene is associated with constitutive pigmentation phenotypes and development of melanoma and nonmelanoma skin cancers. We investigated the effect of MC1R variants on melanoma using a large, international population-based study design with complete determination of all MC1R coding region variants. Direct sequencing was completed for 2,202 subjects with a single primary melanoma (controls) and 1,099 subjects with second or higher-order primary melanomas (cases) from Australia, the United States, Canada, and Italy. We observed 85 different MC1R variants, 10 of which occurred at a frequency >1%. Compared with controls, cases were more likely to carry two previously identified red hair ("R") variants [D84E, R151C, R160W, and D294H; odds ratio (OR), 1.6; 95% confidence interval (95% CI), 1.1-2.2]. This effect was similar among individuals carrying one R variant and one r variant (defined as any non-R MC1R variant; OR, 1.6; 95% CI, 1.3-2.2) and among those carrying only one R variant (OR, 1.5; 95% CI, 1.1-1.9). There was no statistically significant association among those carrying only one or two r variants. Effects were similar across geographic regions and categories of pigmentation characteristics or number of moles. Our results confirm that MC1R is a low-penetrance susceptibility locus for melanoma, show that pigmentation characteristics may not modify the relationship of MC1R variants and melanoma risk, and suggest that associations may be smaller than previously reported in part due to the study design. (Cancer Res 2006; 66(18): 9330-7)