3058

Candidate Risk Genes: Melanoma, Hereditary Cancer Syndromes, and Rare and Childhood Cancers

MC1R variants as genetic markers of increased risk of melanoma in persons with protective phenotype

Tuesday, Apr 21, 2009, 8:00 AM -12:00 PM

Hall B-F, Poster Section 4

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Peter A. Kanetsky, Saarene Panossian, David E. Elder, DuPont Guerry IV, Michael E. Ming, Lynn Schuchter, Timothy R. Rebbeck. Univ. of Pennsylvania, Philadelphia, PA

Natural variation in the melanocortin-1 receptor gene (MC1R) is a robust genetic marker of increased melanoma risk. The risk conferred by MC1R variants may be greater in those individuals with protective phenotypic characteristics such as darker skin complexion. From the Pigmented Lesion Clinic of the University of Pennsylvania, we recruited to this case-control study patients with incident melanoma and otherwise healthy persons referred by enrolled cases. All study participants self-reported phenotypic characteristics via a structured questionnaire and underwent a skin examination. MC1R genotyping was determined by direct sequencing of germline DNA, and variants were categorized as high [R] or low [r] risk. Carriage of MC1R [R] variants was associated with a 2-fold age- and sex-adjusted increase in melanoma risk (OR= 2.2, 95% CI 1.5, 3.0). However, risk was stronger in or limited to those with protective phenotypes. Carriage of MC1R [R] variants increased risk among participants with dark hair (OR=2.4, 95% CI 1.5, 3.6), while no increased risk was evident among those with blond (OR=1.0, 95% CI 0.43, 2.4) or red (OR=0.78, 95% CI 0.16, 3.8) hair. The pattern of elevated risk associated with MC1R [R] variants was seen in persons with dark eye color (OR=3.2, 95% CI 1.8, 5.8), who did not freckle (OR=8.0, 95% CI 2.0, 32), who moderately or deeply tanned after repeated sun exposure (OR=2.4, 95% CI 1.6, 3.6) and who tanned after exposure to first strong summer sun without or with initial mild burning (OR=9.5, 95% CI 1.8, 50; OR=2.4, 95% CI 1.4, 3.9, respectively). Meta-analysis of published articles that presented stratified results of MC1R-melanoma associations by a third phenotypic variable supported these findings. High risk MC1R variants increase risk of melanoma primarily in individuals who have phenotypes that would otherwise put them at low risk for melanoma. These data indicate that MC1R genotypes provide information about melanoma risk in those individuals who would not be identified as high risk based on their phenotypes alone.