Genetic Determinants of UV-Susceptibility in Non-Melanoma Skin Cancer

Abstract

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: ptrend = 0.0048; SCC: ptrend = 0.031). Having two IL10 GC haplotypes was associated with increased odds ratios of BCC and SCC (ORBCC = 1.5, 95% CI 1.1–1.9; ORSCC = 1.4, 95% CI 1.0–1.9), and these associations were largely confined to women (ORBCC = 2.2, 95% CI 1.4–3.4; SCC: ORSCC = 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.

Characterization of a Human Skin Equivalent Model to Study the Effects of Ultraviolet B Radiation on Keratinocytes

“…Chronic, unprotected exposure to high levels of UVR and predisposing genetic risk factors have been shown to increase the likelihood of skin cancer development. [1][2][3] Consequently, populations in countries that experience extreme levels of solar UVR experience the highest rates of skin cancers. 4 In Australia, for example, nonmelanoma skin cancers (NMSC), resulting from the carcinogenic transformation of epidermal keratinocytes, represent the most frequently diagnosed cancer type.…”

The role of analysis of EVER2 haplotypes in actinic keratosis

“…W SCC zlokalizowanych w obrębie skóry badano haplotypy genów mających znaczenie w melanogenezie, m.in. gen MC1R, ASIP AH, TYR, OCA2, SLC45A2, wśród których silną zależność opisano pomiędzy haplotypem genu ASIP AH oraz haplotypem genu dla IL-10 a ryzykiem wystąpienia SCC [21,22]. Badano też haplotypy licznej grupy genów odpowiedzialnych za naprawę uszkodzeń DNA, wśród których wykazano niekorzystną rolę haplotypu genu XPA w kancerogenezie skórnej [23].…”

Associations Between Three Polymorphisms in the Interleukin-4 Receptor Gene and Risk of Cancer: a Meta-analysis

“…Single nucleotide polymorphisms of IL-4R that have been identified included I75V (rs1805010), S503P (rs1805015), Q576R (rs1801275), Ser752Ala (rs1805016), -29429 >T (rs2057768), 49359G >A (rs3024656) and so on (Ruan et al, 2011;Sarpatwari et al, 2011;Welsh et al, 2011). The most extensively studied polymorphisms for their implications in cancer risk are three polymorphic sites: I75V (rs1805010), Q576R (rs1801275) and S503P (rs1805015).…”