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
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.
Observational Model: Case Control, Time Perspective: Retrospective
Yeong-Shiau Pu, M.D.PhD.
National Taiwan University Hospital
Taiwan: Department of Health