Effects of Polymorphism of Genes related to Metabolism of Xenobiotics on Bladder Tumor Occurrence

Kim, Wun Jae; Kim, Heon; Kim, Yong Tae; Lee, Hyung Lae

Abstract

PURPOSE: Cancer development depends on activities of enzymes involved in metabolisms of various carcinogenic xenobiotics. N-acetyltransferase(NAT) and glutathione S-transferases(GST) are enzymes, reducing the toxicity of activated carcinogenic metabolites. Carcinogens of bladder cancer can not be fully explained by single risk factor and many kinds of enzymes would be involved in the metabolism of carcinogens excreted in urine. This study was performed to investigate whether the polymorphisms of NAT2, GSTM1, and GSTT1 were risk factors of bladder cancer and to evaluate the effects of their interaction on bladder cancer occurrence.
MATERIALS AND METHODS
One hundred and thirteen bladder cancer and 221 non-cancer patients hospitalized in the Chungbuk National University Hospital participated in the present case-control study. Questionnaire interview was performed and the genotypes of NAT2, GSTM1 and GSTT1 were identified using PCR methods with DNA extracted from venous blood. Effects of the polymorphism of NAT2, GSTM1 and GSTT1 and their interaction on bladder cancer were statistically analyzed after controlling other risk factors.
RESULTS
The frequencies of slow, intermediate, and rapid acetylators were 7.1%, 37.5%, and 55.4% for the cases, and 11.0%, 43.4%, and 45.7% for the controls, respectively. The risk of bladder cancer was not associated with the increase of NAT2 activity(x2trend=3.16, p>0.05). GSTM1 was deleted in 69.6% of the cases and 55.9% of the controls(x2=5.86, P<0.05), and the mean odds ratio(95% CI) was 1.81 (1.12 - 2.93). The GSTT1 deletion, the rate of which were 42.0% for the bladder cancer patients and 45.9% for the controls, showed the protective effect against bladder cancer, but was not statistically significant. Smoking history turned out to be insignificant as a risk factor of bladder cancer(OR=1.34, 95%CI: 0.78 - 2.31), and occupation was not analyzed due to the extremely small number of occupational history related to the increase of bladder cancer. Medical histories of tuberculosis and bronchial asthma were significant risk factors for bladder cancer, and their average ORs(95% CI) were 3.61(1.57-8.26) and 4.15(1.61-10.75), respectively. In multiple logistic analysis controlling the effects of other risk factors, GSTM1 deletion (OR: 1.80, 95% CI: 1.07-3.05), and histories of tuberculosis(OR: 2.99, 95% CI: 1.22-7.32) and of bronchial asthma(OR: 3.38, 95% CI: 1.24-9.22) were the significant risk factors for bladder cancer, but slow acetylation and GSTT1 deletion were not.
CONCLUSIONS
These results suggest that GSTM1 deletion may be a significant risk factor of bladder cancer, and GSTT1 deletion may have the protective effect against bladder tumor development. Since tuberculosis and bronchial asthma, in the present study, appeared to be involved in the development of bladder tumor, possible associated relationships are under experimental investigation in every aspect.