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Immunity and inflammatory pathways are important in the genesis of non-melanoma skin cancers (NMSC). Functional genetic variation in immune modulators has the potential to affect disease etiology. We investigated associations between common variants in two key regulators,  MIR146A  and  RNASEL , and their relation to NMSCs. Using a large population-based case-control study of basal cell (BCC) and squamous cell carcinoma (SCC), we investigated the impact of  MIR146A  SNP rs2910164 on cancer risk, and interaction with a SNP in one of its putative targets ( RNASEL , rs486907). To examine associations between genotype and BCC and SCC, occurrence odds ratios (OR) and 95% confidence intervals (95%CI) were calculated using unconditional logistic regression, accounting for multiple confounding factors. We did not observe an overall change in the odds ratios for SCC or BCC among individuals carrying either of the  RNASEL  or  MIR146A  variants compared with those who were wild type at these loci. However, there was a sex-specific association between BCC and  MIR146A  in women (OR GC  = 0.73, [95%CI = 0.52–1.03]; OR CC  = 0.29, [95% CI = 0.14–0.61], p-trend<0.001), and a reduction in risk, albeit not statistically significant, associated with  RNASEL  and SCC in men (OR AG  = 0.88, [95%CI = 0.65–1.19]; OR AA  = 0.68, [95%CI = 0.43–1.08], p-trend = 0.10). Most striking was the strong interaction between the two genes. Among individuals carrying variant alleles of both rs2910164 and rs486907, we observed inverse relationships with SCC (OR SCC  = 0.56, [95%CI = 0.38–0.81], p-interaction = 0.012) and BCC (OR BCC  = 0.57, [95%CI = 0.40–0.80], p-interaction = 0.005). Our results suggest that genetic variation in immune and inflammatory regulators may influence susceptibility to NMSC, and novel SNP-SNP interaction for a microRNA and its target. These data suggest that RNASEL, an enzyme involved in RNA turnover, is controlled by miR-146a and may be important in NMSC etiology.

RNASEL and MIR146A SNP-SNP Interaction as a Susceptibility Factor for Non-Melanoma Skin Cancer