Cancer Letters

Cancer Letters

Volume 177, Issue 2, 28 March 2002, Pages 173-179
Cancer Letters

Combined effect of glutathione S-transferase M1 and T1 genotypes on bladder cancer risk

https://doi.org/10.1016/S0304-3835(01)00820-5Get rights and content

Abstract

To evaluate the association between genetic polymorphism of GSTM1, GSTT1 and development of bladder cancer, a hospital-based case-control study was conducted in South Korea. The study population consisted of 232 histologically confirmed male bladder cancer cases and 165 male controls enrolled from urology departments with no previous history of cancer or systemic diseases in Seoul during 1997–1999. The GSTM1 null genotype was significantly associated with bladder cancer (OR: 1.6, 95% CI: 1.0–2.4), whereas the association observed for GSTT1 null genotype did not reach statistical significance (OR: 1.3, 95% CI: 0.9–2.0). There was a statistically significant multiple interaction between GSTM1 and GSTT1 genotype for risk of bladder cancer (P=0.04); the risk associated with the concurrent lack of both of the genes (OR: 2.2, 95% CI: 1.2–4.3) was greater than the product of risk in men with GSTM1 null/GSTT1 present (OR: 1.3, 95% CI: 0.7–2.5) or GSTM1 present/GSTT1 null (OR: 1.1, 95% CI: 0.6–2.2) genotype combinations.

Introduction

Bladder cancer ranks fourth in incidence of cancer in the United States [1]. Its incidence among non-Hispanic white men in US was 33.1/100 000 in 1988–1992 [1], which is similar to that found in most European countries [2]. In contrast, the incidence of bladder cancer appears to be much lower in Korean men, being 7.8/100 000 in 1989 [3]. These differences may be explained by environmental or dietary factors or by genetic backgrounds. A large difference also exists between sexes in both countries; this malignancy is three to four times more frequent in men than in women [1], [3].

Exposure to chemicals in tobacco smoke and other environmental and occupational chemicals has been described as risk factors for bladder cancer in numerous epidemiological and laboratory studies (e.g. 2-naphthylamine, benzidine, 4-aminobiphenyl) [1], [4]. Genetic differences in the metabolism of these chemicals have been recently suggested as modifiers of individual susceptibility to environmentally-induced bladder cancer. Glutathione S-transferases (GSTs) detoxify reactive chemical species, such as polycyclic aromatic hydrocarbon (PAH) epoxides present in tobacco smoke, by conjugating them with glutathione. The GST multigene family consists of at least four enzyme classes: the alpha, mu, theta, and pi with partially overlapping substrate specificities [5].

Subsequent to the first report by Bell et al. [6] that GSTM1 deficiency increased risk of bladder cancer in a hospital-based case control study, a number of studies appeared with supporting findings [7], [8], [9], [10], [11], [12], [13], [14]. In contrast to GSTM1, studies exploring the potential role of GSTT1 genotype in individual susceptibility to bladder cancer have reported inconsistent results. A few studies showed non-significantly decreased risk of bladder cancer with GSTT1 null genotype [15], [16], [17], whereas others showed increased bladder cancer risk with GSTT1 null genotype [13], [18]. Inconsistent results have also emerged from the recent studies exploring the potential combined effect of GSTM1 and GSTT1 genotypes in development of this malignancy [13], [16], [19], [20].

In this study, the potential role of GSTM1 and GSTT1 genotypes in bladder cancer risk was examined further in a Korean study population.

Section snippets

Study subjects and selection

The study population consisted of 232 histologically confirmed male bladder cancer cases admitted for treatment to urology departments of three teaching hospitals in Seoul during February 1997–May 1999 (Seoul National University Hospital, Boramae Hospital, and Samsung Medical Center) and 165 male controls with no present or previous history of cancer or systemic illnesses admitted to the same departments. Approximately 95% of cases diagnosed at these hospitals were asked to participate in the

Results

Selected characteristics of bladder cancer cases and controls are presented in Table 1. The mean age of bladder cancer patients and controls was 63.9 years (SD 10.6 years) and 62.8 years (SD 12.1 years), respectively. There was a statistically significant dose-dependent increase in risk of bladder cancer associated with smoking (P for trend=0.009). Although a slightly higher percentage of cases than controls had ever worked in high-risk occupations (31 and 27%, respectively), no significant

Discussion

We observed an increased risk for bladder cancer associated with the GSTM1 null genotype, in agreement with several previous studies (summarized in [25], [26], [27]). A tendency of increased risk was also observed for the GSTT1 null genotype (OR: 1.3, 95% CI: 0.9–2.3), although this difference was not statistically significant. Our findings agree with two previous studies, one of which showed a significantly increased risk (OR: 2.1, 95% CI: 1.1–3.9) for the GSTT1 null genotype [13], and the

Acknowledgements

This research was supported in part by a grant of the 1996 (96-1-4-14) Korean National Cancer Control Program, Ministry of Health & Welfare, R.O.K., by NONDIRECTED RESEARCH FUND, Korean Research Foundation, 1998 (003-F00084), by 1999 BK21 project for Medicine, Dentistry and Pharmacy, and by the Finnish Academy.

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