192R allele of paraoxanase 1 (PON1) gene as a new marker for susceptibility to bladder cancer.

BACKGROUND: The human body has a number of endogenous free-radical scavenging systems. Paraoxonase1 (PON1) is one of the enzymes involved in such systems. The purpose of this study was to investigate the relationship between bladder cancer and the polymorphism of PON1 which results in Q/R substitution at codon 192. This is the first report of this polymorphism in bladder cancer.

PATIENTS AND METHODS: Seventy-six bladder cancer patients and 135 healthy controls took part in the study. DNA from paraffin-embedded tissues for patients and from blood cells for controls was extracted. The distribution of PON1(192) polymorphism was determined by Polymerase Chain Reaction (PCR) and Restriction Fragment Length Polymorphism (RFLP) techniques.

RESULTS: There was significant difference in PON1 genotype frequencies (patients/controls QQ: 8/37, QR: 53/84, RR: 15/14, p=0.007) between the control and bladder cancer patients. Moreover, in patients there was significant association of the RR genotype of PON1 with invasive growth pattern (p=0.027), perineural invasion (p=0.016), distant metastasis (p<0.001), radical cystectomy (p=0.016) and death (p=0.005).

CONCLUSION: In patients, the QQ genotype was statistically less frequent, while the RR genotype frequency was somewhat less than in controls. QQ type PON1 enzyme activity might be protective for bladder carcinogenesis. These findings support that genotypical differences of PON1 might contribute to prognosis and pathogenesis of bladder cancer. Arylamines are well-known bladder carcinogens, especially after a sulfate or an acetate esterification and PON1 has arylesterase activity. We hypothesize that arylesterase activity of PON1 would help the formation of free-radical type arylamine derivates on the bladder epithelial surface, so that secondary metabolites of paraoxon or related chemicals and biotransformed intermediates of arylamines might be involved in formation of bladder carcinoma.