title: Population-based study of natural variation in the melanocortin-1 receptor gene and melanoma.
abstract: 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.
authors.affiliation: Department of Biostatistics and Epidemiology and Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6021, USA. pkanetsk@cceb.med.upenn.edu
authors.forename: Peter A
authors.initials: PA
authors.lastname: Kanetsky
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Rebbeck
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Hummer
authors.forename: Saarene
authors.initials: S
authors.lastname: Panossian
authors.forename: Bruce K
authors.initials: BK
authors.lastname: Armstrong
authors.forename: Anne
authors.initials: A
authors.lastname: Kricker
authors.forename: Loraine D
authors.initials: LD
authors.lastname: Marrett
authors.forename: Robert C
authors.initials: RC
authors.lastname: Millikan
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Gruber
authors.forename: Hoda Anton
authors.initials: HA
authors.lastname: Culver
authors.forename: Roberto
authors.initials: R
authors.lastname: Zanetti
authors.forename: Richard P
authors.initials: RP
authors.lastname: Gallagher
authors.forename: Terence
authors.initials: T
authors.lastname: Dwyer
authors.forename: Klaus
authors.initials: K
authors.lastname: Busam
authors.forename: Lynn
authors.initials: L
authors.lastname: From
authors.forename: Urvi
authors.initials: U
authors.lastname: Mujumdar
authors.forename: Homer
authors.initials: H
authors.lastname: Wilcox
authors.forename: Colin B
authors.initials: CB
authors.lastname: Begg
authors.forename: Marianne
authors.initials: M
authors.lastname: Berwick
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics*; D008875:Middle Aged; D044102:Receptor, Melanocortin, Type 1 / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D044102:Receptor, Melanocortin, Type 1