Genetic susceptibility to UV-induced immunosuppression in the etiology of non-melanoma skin cancer

Ultraviolet radiation (UVR) is the most widely studied exposure for non-melanoma skin cancers (NMSCs) due to its mutagenic capacity. However, UVR also contributes to disease etiology through suppression of immune response and tumor surveillance. In both mice and humans, distinct phenotypes of differing susceptibility to UV-induced immunosuppression occur, indicating there is a strong genetic component to how UV affects the immune system. Experiments in mice have demonstrated that much of the curbed immune response can be attributed to the production of a UV-B absorbing compound in the stratum corneum, urocanic acid (UCA). The enzyme histidase (HAL), synthesized by keratinocytes, catalyzes the non-oxidative deamination of histidine to trans-UCA, which is then photoisomerized to a cis-isomer. This isomer mediates immune suppression via expansion of Th2-type cells and concomitant development of T regulatory cells. Studies in humans and mice have linked this immunosuppression to increased occurrence of non-melanoma skin cancers. Therefore, we have investigated the interaction between genetic variation in mediators of the immune suppression and exposures to steroids, hormones, and UV exposure in the development of NMSCs. In Chapter 2, we examined the role of coding polymorphism HAL I439V in the etiology of NMSC and found that in response to innate and environmental exposures, such as UV light, glucocorticoids, and estrogen, the variant allele is associated with increased risk of NMSC, particularly SCC. In Chapter 3, we explored the relationship between functional polymorphisms in the UV immune signaling pathway and environmental exposures such as UV light and observed many high-order interactions particularly between skin type, sunburns, IL10 haplotypes, and IL4R haplotypes, as well as gender-specific effects. In Chapter 4, we found that the functional variant CT60 in CTLA4, but not haplotypes, altered risk for NMSC, particularly BCC. Together, these results further our understanding of the genetic susceptibility to the most prevalent type of cancer, non-melanoma skin cancer, and provide evidence of gender disparities in risk.