Genetic determinants of UV-susceptibility in non-melanoma skin cancer

• Published in: PloS one Vol. 6; no. 7; p. e20019
• Main Authors: Welsh, Marleen M, Karagas, Margaret R, Kuriger, Jacquelyn K, Houseman, Andres, Spencer, Steven K, Perry, Ann E, Nelson, Heather H
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 08.07.2011; Public Library of Science (PLoS)
• Subjects: Adult; Aged; Antigens; Basal cell carcinoma; Biomarkers; Burns; Cancer; Cytokines; Demography; Deoxyribonucleic acid; Development and progression; Disease susceptibility; DNA; Etiology; Female; Gender differences; Gene expression; Genetic aspects; Genetic diversity; Genetic Predisposition to Disease; Genetic research; Genetic testing; Genetic variance; Haplotypes; Haplotypes - genetics; Health risks; Hepatitis; Humans; Immune Tolerance - genetics; Immunosuppression; Immunotherapy; Interleukin 1; Interleukin 10; Interleukin 4; Interleukin 4 receptors; Ionizing radiation; Logistic Models; Male; Medicine; Melanoma; Middle Aged; Polymorphism, Single Nucleotide - genetics; Population studies; Preventive medicine; Regression analysis; Risk analysis; Risk factors; Signaling; Skin cancer; Skin diseases; Skin Neoplasms - etiology; Skin Neoplasms - genetics; Skin Neoplasms - pathology; Squamous cell carcinoma; Studies; Tumor necrosis factor; Ultraviolet radiation; Ultraviolet Rays - adverse effects; Lebanon; Rhode Island; Minnesota; United States > US; New Hampshire
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0020019

A milieu of cytokines and signaling molecules are involved in the induction of UV-induced immune suppression and thus the etiology of non-melanoma skin cancer (NMSC). Targeting the UV-induced immunosuppression pathway, and using a large population based study of NMSC, we have investigated the risk associated with functional variants in 10 genes (IL10, IL4, IL4R, TNF, TNFR2, HTR2A, HRH2, IL12B, PTGS2, and HAL). The most prominent single genetic effect was observed for IL10. There was increasing risk for both basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) with increasing number of variant IL10 haplotypes (BCC: p(trend) = 0.0048; SCC: p(trend) = 0.031). Having two IL10 GC haplotypes was associated with increased odds ratios of BCC and SCC (OR(BCC) = 1.5, 95% CI 1.1-1.9; OR(SCC) = 1.4, 95% CI 1.0-1.9), and these associations were largely confined to women (OR(BCC) = 2.2, 95% CI 1.4-3.4; SCC: OR(SCC) = 1.8, 95% CI 1.1-3.0). To examine how combinations of these variants contribute to risk of BCC and SCC, we used multifactor dimensionality reduction (MDR) and classification and regression trees (CART). Results from both of these methods found that in men, a combination of skin type, burns, IL10, IL4R, and possibly TNFR2 were important in both BCC and SCC. In women, skin type, burns, and IL10 were the most critical risk factors in SCC, with risk of BCC involving these same factors plus genetic variants in HTR2A, IL12B and IL4R. These data suggest differential genetic susceptibility to UV-induced immune suppression and skin cancer risk by gender.