Molecular Epidemiological Studies of Arsenical Skin Cancer: Effect of Gwas-Derived Snp Variants and Their Gene Expression on Cancer Risk

Skin cancer has been the models of two-stage carcinogenesis in cancer research and cancer risk assessment in chemical carcinogenicity. In Taiwan, an endemic occurrence of arsenic-related diseases, including non-melanoma skin cancer, has been reported since the 1960s. Skin abnormalities, ranging from hyperkeratosis, Bowen’s disease (BD, a carcinoma in situ) to invasive skin cancer (SC) are the typical early indicators of chronic arsenic intoxication. Skin cancer is not among the list of cancers with high case fatality; however, internal cancers occur at a high frequency in patients with arsenical skin cancer. The lifetime risk from cancer mortality remains high even after cessation of arsenic exposure for decades. Although arsenic is the strongest predictor for the skin cancer, the facts that only a small proportion of arsenic-exposed persons afflicted with cancer and a wide range of individual variation in arsenic metabolism via methylation pathway suggesting the roles of genetically susceptible factors and arsenic methylation efficiency in individual in cancer development. The goal of our full-range study project in 5 years is to develop a panel of SNP genetic variants identified from genome-wide association study (GWAS) in arsenic-induced BD/SC for the prediction for cancer risk in individuals after arsenic exposure. To reach the goal, we propose this 3-year study project with the following 3 specific aims. (1) To identify the independent SNPs for BD/SC risk by the method of GWAS. The GWAS was done previously. We plan to continue to validate systematically using the most updated bioinformatics toolsets, including linkage disequilibrium analysis and eSNP/eQTL analysis. Resulting SNP-expression association will be examined on tissue samples. (2) To evaluate the effect of leading independent SNPs on the development of BD/SC after adjusting for individual methylation capacity. To avoid residual confounding and reverse causality between methylation capacity and BD/SC risk, we will include AS3MT genetic variants as instrumental variables in this association estimation. (3) To investigate the biological effect of the leading SNPs/associated genes on the development of BD/SC. By the method of in vitro transfection experiments, cancer potential such as cell growth, migratory and invasive behavior of transfected cells will be examined for changes in response to ectopic gene expression.The results of this study may provide information not only the genetic architecture of skin cancer and risk prediction from arsenic exposure, but also potentially be exploited for the development of intervention to prevent large number of deaths caused by arsenic exposure.