title: Polymorphisms in cell cycle regulatory genes, urinary arsenic profile and urothelial carcinoma.
abstract: 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.
authors.affiliation: Graduate Institute of Public Health, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chi-Jung
authors.initials: CJ
authors.lastname: Chung
authors.forename: Chi-Jung
authors.initials: CJ
authors.lastname: Huang
authors.forename: Yeong-Shiau
authors.initials: YS
authors.lastname: Pu
authors.forename: Chien-Tien
authors.initials: CT
authors.lastname: Su
authors.forename: Yung-Kai
authors.initials: YK
authors.lastname: Huang
authors.forename: Ying-Ting
authors.initials: YT
authors.lastname: Chen
authors.forename: Yu-Mei
authors.initials: YM
authors.lastname: Hsueh
mesh_terms: 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*
chemical_list: 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