Arsenic Methylation, Cigarette Smoking Exposure, Individual DNA Susceptibility Factors and Urothelial Carcinoma

Urothelial carcinoma (UC) arises exclusively from the urothelium including the renal pelvis,ureter, bladder and urethra, with bladder transitional cell carcinoma (TCC) being the most common form. Arsenic is a well-established human carcinogen of the skin and lung. Recent studies have well documented that the long-term exposure to inorganic arsenic through ingestion and inhalation is associated with an increased risk of bladder cancer, especially TCC.

However, the carcinogenic mechanism of arsenic-induced UC is still unclear. Recently our study found that cigarette smoking interacts with the urinary arsenic profile in modifying the UC risk. In addition, we also found that DNA damage marker 8-hydroxydeoxyguanine (8-OHdG) levels significantly higher in UC patients compared to healthy controls. The mechanism of the interaction between arsenic methylation and cigarette on UC risk is unknown. In addition, whether 8-OHdG is related to DNA repair enzymes or to inflammatory factors or not does need to explore, therefore the specific aims of this project are:

1. To investigate the relationship between arsenic methylation enzymes (AS3MT, PNP, GSTO1, and GSTO2) genetic polymorphism and UC risk.
2. To explore the relationship between cigarettes metabolites (NNK, NNAL, HBA, NNAL-Gluc, O6-Methylguanine, and N7-Methylguanine) and UC risk.
3. To examine the relationship between cigarette metabolic enzymes (CYP2A6, CYP2A13, and UGT2B7) genetic polymorphism and UC risk.
4. To elucidate the relationship between DNA repair enzymes (MGMT, XPD, XRCC1, and XRCC3) gene polymorphism and 8-OHdG or between DNA repair enzymes and UC risk.
5. To examine relationship between COX-2 (-1195G/A、-765G/C 和 8473C/T), IL-6, IL-8, and TNF-α gene polymorphism and 8-OHdG or between COX-2, IL-6, IL-8, and TNF-α gene polymorphism and UC risk.
6. To examine the risk factors of the environment-environment, gene-environment, and gene-gene interaction on the risk of UC.