Susceptibility genes: GSTM1 and GSTM3 as genetic risk factors in bladder cancer

Abstract

Glutathione S-transferase (GST, E.C. 2.5.1.18) comprises a family of isoenzymes that play a key role in the detoxification of such exogenous substrates as xenobiotics, environmental substances, and carcinogenic compounds. At least five mammalian GST gene families have been identified to be polymorphic, and mutations or deletions of these genes contribute to the predisposition for several diseases, including cancer. The gene cluster of GSTM1–GSTM5 has been reported to be localized on chromosome 1p and spans a length of nearly 100 kb. One mutation of the GSTM3 gene generates a recognition site for the transcription factor yin yang 1. As a result of this mutation, the expression of GSTM3 can be influenced. The mutated GSTM3 gene has been reported to be involved in increased susceptibility for the development of cancer, but no information is available concerning its role in bladder cancer. We have identified patients with a heterozygous GSTM3 geno- type who carry a significantly increased risk for the development of bladder cancer. Here we report that the mutation of intron 6 of GSTM3 increases the risk for bladder cancer (odds ratio: 2.31; 95% confidence interval [CI], 1.79–2.82). We developed a procedure to identify heterozygous or homozygous carriers of the GSTM1 alleles. Heterozygous carriers of the GSTM1 null genotype have a significantly elevated risk of developing bladder cancer. We calculated an odds ratio of 3.54 (95% CI, 2.99–4.11) for this genotype. These observations lead to the assumption that the lack of detoxification by glutathione conjugation predispose to bladder cancer when at least one of two alleles is affected. Furthermore, individuals presenting the homozygous wild type of GSTM1 and GSTM3 are significantly protected against bladder cancer.

Role of GSTM3 Polymorphism in the Risk of Developing Esophageal Cancer

“…Heterozygous carriers of the mutated allele GSTM3*B were more frequent and at risk in the group of esophageal cancer patients. This is similar to the other studies on larynx (5), colorectal (13), bladder (6), and breast cancer (14). In contrast, GSTM3 AA genotype has been a risk factor in oral cancer (12).…”

“…As a result of this mutation, the expression of GSTM3 can be influenced. The functional consequence of this is unclear, but both negative and positive regulatory effects have been suggested (6)(7)(8). However, possible influence of GSTM3 has not been studied in esophageal cancer.…”

GSTM1,GSTM3andGSTT1Gene Variants and Risk of Benign Prostate Hyperplasia in North India

“…The null allele of GSTM1 has also been reported to be associated with prostate cancer in different ethnic groups like North Indians, Chilean population and Japanese [10,15,16]. GSTM3 variant (B) allele is also known to be associated with prostate, larynx, colorectal, bladder and breast cancer [9,[17][18][19][20]. It is well documented that GSTM3*B allele induces YY1 transcription factor which in turn suppresses the expression of various cytokines or stress response genes like IFN-c [21].…”

Association between polymorphisms in glutathione S-transferase Mu3 and IgG titer levels in serum against Helicobacter pylori

“…A recent metaanalysis study, however, reported a minor increase in the risk of gastric cancer in GST-T1-null genotypes. 5 The association between GST-M3 polymorphisms and risk of cancer was studied in the prostate, 30 esophagus, 31 larynx, 32 colorectal, 33 bladder, 34 breast 35 and basal cell carcinomas. 36 A study on a Polish population, however, reported insufficient evidence of an association between GST-M3 polymorphisms and gastric cancer.…”