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


METHODS
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).


RESULTS
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.


CONCLUSIONS
The results showed that the variant genotype of p21 might be a predictor of inorganic arsenic-related UC risk.
Chung
Chi-Jung
CJ
Graduate Institute of Public Health, Taipei Medical University, Taipei, Taiwan.
Huang
Chi-Jung
CJ
Pu
Yeong-Shiau
YS
Su
Chien-Tien
CT
Huang
Yung-Kai
YK
Chen
Ying-Ting
YT
Hsueh
Yu-Mei
YM
D000080242:8-Hydroxy-2'-Deoxyguanosine; D001151:Arsenic / Q000652:urine*; D002295:Carcinoma, Transitional Cell / Q000235:genetics* / Q000378:metabolism / Q000652:urine*; D016022:Case-Control Studies; D056741:Cyclin D; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D016213:Cyclins / Q000235:genetics; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000652:urine; D005260:Female; D018816:Genes, cdc / Q000502:physiology*; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000652:urine*
C493956:CDKN1A protein, human; D056741:Cyclin D; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine; D001151:Arsenic