Polymorphic deletions of theGSTT1andGSTM1genes and susceptibility to bladder cancer
Authors: Salinas‐Sánchez Antonio S. , Sánchez‐Sánchez Francisco , Donate‐Moreno María J. , Rubio‐del‐Campo Antonio , Gimenez‐Bachs José M. , Lorenzo‐Romero Juan G. , Serrano‐Oviedo Leticia , Escribano Julio 
Published: October 2010

What’s known on the subject? and What does the study add?

Bladder cancer susceptibility may be determined by genetic differences in the activity of glutathione S‐transferases, enzymes that regulate the conversion of exogenous carcinogens to excretable hydrophilic metabolites by glutathione conjugation. The discrepancy of results regarding the association of common genetic polymorphisms and complex diseases such as cancer has raised scepticism in this area of research. Although the evidence generally supports the implication of GSTM1 and GSTT1 polymorphisms in bladder cancer, there is still some debate, with some studies in favour and some against.

This study shows a greater risk of bladder cancer in individuals with GSTM1 null genotype, particularly women. This relationship is less evident with GSTT1 null genotypes. Null genotypes in both genes appear to be synergistic, particularly among smokers, and to increase the predisposition to more aggressive tumours. Nevertheless, the role of GSTM1 and GSTT1 polymorphisms in predisposition to bladder cancer should be viewed with caution, due to the multifactorial genetic origin of this condition and the need for long‐term longitudinal studies to confirm these results.

OBJECTIVE

• To estimate the prevalence and importance ofGSTT1andGSTM1genotypes (implicated in glutathioneS‐transferase activity) in bladder cancer, to determine whether smoking and occupational factors influence this relationship, and to identify the value ofGSTT1andGSTM1genotypes as prognostic factors.

PATIENTS AND METHODS

• A cross‐sectional study was conducted with a group of patients with bladder carcinoma and a control group with benign conditions and no history of tumours. The controls were selected and paired as subjects were recruited.

• Sociodemographic variables, smoking, professional occupation, histological features and the presence ofGSTT1andGSTM1polymorphisms by multiplex PCR techniques were assessed.

RESULTS

• GSTM1genotypes were investigated in 201 patients and 193 controls andGSTT1genotypes in 190 patients and 163 controls.

• In the patients group,GSTT1null genotype was observed in 22.1% (not significant) andGSTM1null genotype in 54.2% (P= 0.008) (odds ratio, OR, 1.7); when considered together, 15.5% (P< 0.05; OR, 3.5) of patients had both null genotypes. In the multivariate analysis, the presence ofGSTM1null genotype remained in the model (OR, 2.1) in addition to smoking and age.

• Subjects with bladder tumour andGSTM1null genotype were younger than patients without gene deletion (P= 0.049).

• Women withGSTM1null genotype presented a higher OR than men (P= 0.024). When stratified by smoking habit, smokers with both null genotypes showed an OR of 4.7.

• The percentage of patients with G3 tumours was higher in patients withGSTT1null genotype (P= 0.013) and in patients with both null genotypes (P= 0.002).

• A higher percentage of infiltrating tumours was also observed in patients with both null genotypes (P= 0.035).

CONCLUSIONS

• The data obtained in the present study suggest a higher risk of bladder cancer in individuals with theGSTM1null genotype.

• This risk is twofold higher whenGSTM1andGSTT1null genotypes are both present and is also higher in smokers.

• A greater predisposition for more aggressive tumours appears to exist, particularly when both null genotypes are combined.

• Longer‐term longitudinal studies are needed to confirm these results.