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Increased risk of developing cutaneous malignant melanoma is associated with variation in pigmentation genes and VDR, and may involve epistatic effects

Kosiniak-Kamysz, Agnieszkaa; Marczakiewicz-Lustig, Annab; Marcińska, Magdalenad; Skowron, Małgorzataa; Wojas-Pelc, Annaa; Pośpiech, Ewelinac; Branicki, Wojciechc,d

doi: 10.1097/CMR.0000000000000095

Cutaneous malignant melanoma (CMM) is a malicious human skin cancer that primarily affects individuals with light pigmentation and heavy sun exposure, but also has a known familial association. Multiple genes and polymorphisms have been reported as low-penetrance susceptibility loci for CMM. Here, we examined 33 candidate polymorphisms located in 11 pigmentation genes and the vitamin D receptor gene (VDR) in a population of 130 cutaneous melanoma patients and 707 healthy controls. The genotypes obtained were evaluated for main association effects and potential gene–gene interactions. MC1R, TYR, VDR and SLC45A2 genes were found to be associated with CMM in our population. The results obtained for major function MC1R mutations were the most significant [with odds ratio (OR)=1.787, confidence interval (CI)=1.320–2.419 and P=1.715−4], followed by TYR (rs1393350) (with OR=1.569, CI=1.162–2.118, P=0.003), VDR (GCCC haplotype in rs2238136–rs4516035–rs7139166–rs11568820 block) (with OR=5.653, CI=1.794–17.811, P=0.003) and SLC45A2 (rs16891982) (with OR=0.238, CI=0.057–0.987, P=0.048). The study also detected significant intermolecular epistatic effects between MC1R and TYR, SLC45A2 and VDR, HERC2 and VDR, OCA2 and TPCN2, as well as intramolecular interactions between variants within the genes MC1R and VDR. In the final multivariate logistic regression model for CMM development, only the gene–gene interactions discovered remained significant, showing that epistasis may be an important factor in the risk of melanoma.

aDepartment of Dermatology, Collegium Medicum of the Jagiellonian University

bDepartment of Analytical Biochemistry, Jagiellonian University Medical College

cDepartment of Genetics and Evolution, Institute of Zoology, Jagiellonian University

dSection of Forensic Genetics, Institute of Forensic Research, Kraków, Poland

All supplementary digital content is available directly from the corresponding author.

Correspondence to Ewelina Pośpiech, PhD, Department of Genetics and Evolution, Institute of Zoology, Jagiellonian University, Gronostajowa 9, 30–384 Kraków, Poland Tel: +48 126 645 087; fax: +48 126 645 101; e-mail:

Received January 20, 2014

Accepted May 8, 2014

© 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins