Polymorphisms in cell cycle regulatory genes, urinary arsenic profile and urothelial carcinoma

• Published in: Toxicology and applied pharmacology 2008-10, Vol.232 (2), p.203-209
• Main Authors: Chung, Chi-Jung, Huang, Chi-Jung, Pu, Yeong-Shiau, Su, Chien-Tien, Huang, Yung-Kai, Chen, Ying-Ting, Hsueh, Yu-Mei
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; 8-hydroxydeoxyguanine; ABSORPTION SPECTROSCOPY; ARSENIC; Arsenic - urine; Biological and medical sciences; CARCINOGENESIS; Carcinogenesis, carcinogens and anticarcinogens; Carcinoma, Transitional Cell - genetics; Carcinoma, Transitional Cell - metabolism; Carcinoma, Transitional Cell - urine; CARCINOMAS; Case-Control Studies; CCND1; CELL CYCLE; Chemical agents; Chemical and industrial products toxicology. Toxic occupational diseases; Cyclin D; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclins - genetics; Deoxyguanosine - analogs & derivatives; Deoxyguanosine - urine; DOSE-RESPONSE RELATIONSHIPS; ENZYME IMMUNOASSAY; Female; GENES; Genes, cdc - physiology; Genetic Variation - genetics; GENOTYPE; HEALTH HAZARDS; HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY; Humans; HYDRIDES; Male; Medical sciences; Metals and various inorganic compounds; Middle Aged; MONOCLINIC LATTICES; p21; p53; POLYMERASE CHAIN REACTION; POLYMERASES; Polymorphism; Polymorphism, Genetic - genetics; SENSITIVITY; Toxicology; Tumor Suppressor Protein p53 - genetics; Tumors; Urinary arsenic profile; Urinary Bladder Neoplasms - genetics; Urinary Bladder Neoplasms - metabolism; Urinary Bladder Neoplasms - urine; Urothelial carcinoma
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2008.06.011

Polymorphisms in p53, p21 and CCND1 could regulate the progression of the cell cycle and might increase the susceptibility to inorganic arsenic-related cancer risk. The goal of our study was to evaluate the roles of cell cycle regulatory gene polymorphisms in the carcinogenesis of arsenic-related urothelial carcinoma (UC). A hospital-based case-controlled study was conducted to explore the relationships among the urinary arsenic profile, 8-hydroxydeoxyguanosine (8-OHdG) levels, p53 codon 72, p21 codon 31 and CCND1 G870A polymorphisms and UC risk. The urinary arsenic profile was determined using high-performance liquid chromatography (HPLC) and hydride generator-atomic absorption spectrometry (HG-AAS). 8-OHdG levels were measured by high-sensitivity enzyme-linked immunosorbent assay (ELISA) kits. Genotyping was conducted using polymerase chain reaction-restriction fragment length polymerase (PCR-RFLP). Subjects carrying the p21 Arg/Arg genotype had an increased UC risk (age and gender adjusted OR = 1.53; 95% CI, 1.02–2.29). However, there was no association of p53 or CCND1 polymorphisms with UC risk. Significant effects were observed in terms of a combination of the three gene polymorphisms and a cumulative exposure of cigarette smoking, along with the urinary arsenic profile on the UC risk. The higher total arsenic concentration, monomethylarsonic acid percentage (MMA%) and lower dimethylarsinic acid percentage (DMA%), possessed greater gene variant numbers, had a higher UC risk and revealed significant dose–response relationships. However, effects of urinary 8-OHdG levels combined with three gene polymorphisms did not seem to be important for UC risk. The results showed that the variant genotype of p21 might be a predictor of inorganic arsenic-related UC risk.