Étude génétique du cancer de la vessie.

Abstract

Bladder cancer is the ninth most common cancer in the world and the second urological malignancy in men after prostate cancer. It 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 the genetic polymorphism carried by certain genes including genes coding for detoxifying enzymes. Among these genes Glutathione S-transferase mu1 (GSTM1) and Glutathione S-transferase theta1 (GSTT1) involved in phase II of detoxification of several xenobiotics. Deletions of these genes are associated with increased risk of several cancers. Another polymorphism rs798766 has been recently implicated in the etiology of bladder cancer. It is located on the TACC3 gene (transforming acidic coiled-coil-containing protein 3), which emerged as an important factor in mitotic spindles organization and stability during cell divisions. Objectives: Our work aims to analyze first the impact of tobacco consumption with its two forms (smoked or sniffed) on the occurrence of bladder cancer. Then, to investigate the relationship between the risk of bladder cancer and the null genotypes of GSTM1 and GSTT1 and smoking status in Algerian population. Finally, to explore the involvement of the mutated allele of rs798766 polymorphism in bladder carcinogenesis. The combined effect of all studied polymorphisms as well as the stratification of the genotypes according to the smoking status, the clinicopathological parameters and the recurrence was also tested. Methods: This case-control study included 175 patients with bladder cancer and 188 controls matched for age, sex, and ethnicity. The GSTM1 and GSTT1 genotypes were determined by multiplex PCR using blood genomic DNA. The genotypes of the rs798766 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: A significant association were observed between bladder cancer risk and tobacco smoke (p=1.21E-08), GSTM1 null genotype (p=0.018), GSTT1 null genotype (p=0.009) and both null GSTM1 and GSTT1 genotypes (p=0.001). The risk increases significantly among smokers carrying both null GSTM1 and GSTT1 genotypes (p=1.09E-05).The combined effect of smoking status, GSTM1null/GSTT1null genotype and the mutated allele of rs798766 polymorphism confers the most increased risk of bladder cancer. However, no significant association was shown between bladder cancer and rs798766 polymorphism alone or between stage, grade and bladder cancer recurrence and the testing genotypes. Conclusion: This study indicated that smoking, GSTM1 null, GSTT1 null genotypes and combined GSTM1null/GSTT1null individually represent a risk factor of bladder cancer in Algerian population. The interaction smoking-gene increased the risk considerably. The combined GSTM1null/GSTT1null with cigarette smoking habit is a most important risk factor for bladder cancer found in our study. Smokers with a double deletion of the detoxification genes and the T allele of the rs798766 polymorphism present an increased risk of this cancer.