Implication du polymorphisme génétique (NAT2 et XPC) dans le cancer de la vessie.

Abstract

Bladder cancer is a multifactorial disease due to the interaction between genetic factors and environmental factors. The individual susceptibility to the risk of bladder cancer is modulated by genetic polymorphisms carried by certain genes including the genes encoding the detoxifying enzymes. Among these genes, the N-acetyltransferases (NAT) involved in the detoxification phase II of several xenobiotics and whose variations represent risk factors incriminated in several cancers. Another rs2228001 polymorphism has recently been implicated in the etiology of bladder cancer. It is focused on the XPC gene (Xeroderma pigmentosum complementation group C), responsible for the synthesis of a protein involved in the initiation of the DNA repair process by the nucleotide excision repair system (NER). Objectives: Our work aims to analyze firstly the impact of tobacco consumption and the professional environment at risk on the occurrence of bladder cancer. In a second step, to look for a possible association between the risk of this type of cancer and the different SNPs of the NAT2 detoxification gene. This association was also sought for the different NAT2 acetylation profiles. We also explored the involvement of the allele at risk of rs2228001 polymorphism in bladder carcinogenesis. The combined effect of the studied polymorphisms as well as the stratification of genotypes and acetylation phenotypes according to smoking status, occupational exposure and clinico-pathological parameters were tested. Methods: This case-control study included 175 patients with bladder cancer and 189 controls matched to patients by age, sex and ethnicity. The genotypes of the different SNPs of the NAT2 gene are determined by sequencing using DNA extracted from peripheral blood. The genotypes of the rs2228001 polymorphism are determined by the TaqMan technique and sequencing. The comparison of allelic and genotypic frequencies between the two groups was established by calculating the odds ratio with a 95% confidence interval. Results: 13 previously described SNPs were identified in this study, only those in position T341C and G590A showed a statistically significant association with the risk of bladder cancer (p <0.05). The slow acetylator phenotype represents a high risk for bladder carcinogenesis (p = 0.0009), with an increased risk for the NAT2 *5 allele. For these same polymorphisms, the risk of bladder cancer remains higher for smokers compared to non-smokers and for workers in risk sectors compared to those working in non-risk sectors. Our study showed a strong interaction between the NAT2 phenotype slow acetylator and smoking (p = 7.20e⁻⁶) similarly for the professional sector at risk (p = 1.58e-9). However, the rs2228001 polymorphism showed a significant association with bladder cancer only for heterozygotes (OR = 1.64, 95% CI = 1.01- 2.68, p = 0.04), whereas for mutated homozygotes the association is present but not significant (OR = 1.35, 95% CI = 0.71-2.56, p = 0.3). This risk is increased in heterozygous smokers (p = 0.002) or in those occupying risky activity sectors (p = 3.60e-7). Conclusion : This study shows that smoking, occupational exposure, T341C and G590A variants of the NAT2 gene, the NAT2 slow acetylator phenotype, and the heterozygous genotype of the rs2228001 polymorphism individually represent a risk factor for bladder cancer in the Algerian population. The gene-tobacco or gene-profession interaction greatly increases this risk. No interaction was found between the studied polymorphisms and clinicalpathological parameters.