|Year : 2018 | Volume
| Issue : 12 | Page : 993-997
Glutathione S-transferase M1 and T1 null genotypes and bladder cancer risk: A meta-analysis in a single ethnic group
Da-Ke Chen, Wei-Wen Huang, Lin-Jin Li, Qiang-Wei Pan, Wen-Shuo Bao
Department of Urology, Wenzhou People's Hospital, Wenzhou, Zhejiang, China
|Date of Web Publication||11-Dec-2018|
Department of Urology, Wenzhou People's Hospital, No. 57 Canghou Road, Ouhai District, Wenzhou 325000, Zhejiang
Source of Support: None, Conflict of Interest: None
Aim of Study: To further evaluate the influence of glutathione S-transferase M1 (GSTM1) and glutathione S-transferase T1 (GSTT1) null genotypes on bladder cancer risk, we conducted a meta-analysis in the Chinese population.
Materials and Methods: PubMed and Chinese databases were electronically searched through April 2016.
Results: Nine studies were included for our meta-analysis, involving 1646 bladder cancer cases and 1938 controls. In general, our findings indicated that a significant association existed between GSTM1-null genotype and the risk of bladder cancer in the studied Chinese population (odds ratio = 1.56, 95% confidence interval: 1.36–1.79). However, no significant association between GSTT1 polymorphism and bladder cancer was found. After stratification of the subgroup analyses by source of controls and geographical areas, a substantially elevated risk was revealed between GSTM1-null genotype and bladder cancer in the population-based studies and those conducted in South China and North China.
Conclusion: Our meta-analysis suggested that GSTM1-null genotype is associated with an increased bladder cancer risk in the Chinese individuals.
Keywords: Bladder cancer, glutathione S-transferase M1, glutathione S-transferase T1, meta-analysis
|How to cite this article:|
Chen DK, Huang WW, Li LJ, Pan QW, Bao WS. Glutathione S-transferase M1 and T1 null genotypes and bladder cancer risk: A meta-analysis in a single ethnic group. J Can Res Ther 2018;14, Suppl S5:993-7
|How to cite this URL:|
Chen DK, Huang WW, Li LJ, Pan QW, Bao WS. Glutathione S-transferase M1 and T1 null genotypes and bladder cancer risk: A meta-analysis in a single ethnic group. J Can Res Ther [serial online] 2018 [cited 2019 Sep 20];14:993-7. Available from: http://www.cancerjournal.net/text.asp?2018/14/12/993/191067
| > Introduction|| |
Bladder cancer is one of the most common urinary system tumors, with an increasing incidence and death rate nowadays., An estimated 386,300 new cases of bladder cancer and 150,200 deaths occurred in 2008 worldwide, as well as 429,800 new cases and 165,100 deaths in 2012. In China, according to the 2015 National Central Cancer Registry of China, the incidence of bladder cancer ranked sixth in male cancers. Currently, several main risk factors have been identified as risk factors for bladder cancer, including exposure to certain chemicals, smoking, chronic urinary tract infections, and genetic susceptibility. In recent years, many candidate genes have been identified as potential bladder cancer susceptibility loci. One important gene is glutathione S-transferases (GSTs), which are involved in the metabolism of many xenobiotics in mammals, including an array of environmental carcinogens and endogenously derived reactive oxygen species. GSTs comprise multiple isoenzymes, of which the most extensively studied in humans are the polymorphisms of GSTM1 and GSTT1. The most common variant of GSTM1 and GSTT1 genes is homozygous deletion (null genotype), which has been suggested to be associated with the loss of enzyme activity, increased vulnerability to cytogenetic damage, and resulted in the increased susceptibility to cancer.,
Several previous studies have explored the association between the GSTM1 and GSTT1 polymorphisms and bladder cancer susceptibility; however, existing results are inconsistent. Differences in findings may be due to race and clinical heterogeneity in patients who have been studied, as well as a limited number of patients in each study. Moreover, bladder cancer incidence rates presented with significant geographic and racial differences,, and individual genetic differences may influence the activity level of GSTs. Therefore, we performed this meta-analysis to assess the relationship between GSTM1 and GSTT1 polymorphisms and bladder cancer in the Chinese population.
| > Materials and Methods|| |
Search strategy and selection criteria
PubMed and Chinese databases were used to retrieve studies with an association between GSTM1 and/or GSTT1 status and bladder cancer published before April 2016. The search terms were as follows: Bladder cancer AND glutathione S-transferase T1 or glutathione S-transferase M1 or GSTT1 or GSTM1 AND China or Chinese or Taiwan. Data search was conducted with no restriction on language.
Inclusion criteria: (1) They were case–control or cohort studies describing the association of GSTM1 and/or GSTT1 status and bladder cancer, (2) they provided the null and nonnull genotypes in cases and controls, and (3) participants were Chinese population. Exclusion criteria: (1) Repeated literature, (2) incomplete data, (3) case-only articles, and (4) review articles and abstracts.
We conducted this meta-analysis in accordance with the guidelines provided by the preferred reporting items for systematic reviews and meta-analyses statement. Information was extracted carefully from all eligible publications independently by two authors, based on the inclusion criteria above. Disagreements were resolved through a discussion between the two authors. Titles and abstracts of all identified studies were screened first. Full articles were scrutinized if the title and abstract were ambiguous. Data extracted from identified studies included first author's name, publication year, source of controls, geographic areas, sample size, GSTM1/GSTT1 null/nonnull genotypes, and GSTM1–GSTT1 interaction data.
The strength of the association between GSTM1/GSTT1 null genotype and bladder cancer risk was measured using the pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs). The significance of the pooled OR was determined by a Z-test. The between-study heterogeneity was assessed by Chi-square based Q-test. Depending on the results of the heterogeneity test among individual studies, the fixed effects model (Mantel–Haenszel) or random effects model (DerSimonian and Laird) was selected to summarize the combined ORs and their 95% CIs. Sensitivity analysis was evaluated by comparing the results of fixed effects model and random effects model. Publication bias was investigated using funnel plots, wherein the standard errors of the log OR of each study were plotted against its OR. Funnel plot asymmetry was further assessed by Egger's linear regression test. All statistical analyses were performed using Stata, version 12 (StataCorp LP, College Station, TX, USA). A P < 0.05 was considered statistically significant.
| > Results|| |
[Figure 1] illustrates the literature search process in the form of a flowchart. We identified 41 articles that examined the association between GSTM1 and/or GSTT1 polymorphisms and bladder cancer in various databases. According to the inclusion and exclusion criteria, nine studies,,,,,,,, were included and 32 articles were excluded. The publication year of involved studies ranged from 2002 to 2014. In total, 1646 bladder cancer cases and 1938 controls were contained in this meta-analysis, which evaluated the relationship between GSTM1 and/or GSTT1 status and bladder cancer risk. The source of controls in eight studies was population-based (PB). The characteristics of the included studies are summarized in [Table 1].
There was no evidence of between-study heterogeneity among all included studies (GSTM1: χ2 = 7.34; P = 0.394; GSTT1: χ2 = 2.34; P = 0.673). Therefore, the fixed effects model was used in the overall analyses. The results showed that the pooled ORs for bladder cancer were 1.56 (95% CI: 1.36–1.79) and 1.00 (95% CI: 0.83–1.21) in Chinese patients with GSTM1-null genotype and GSTT1-null genotype [Table 2] and [Table 3], [Figure 2] and [Figure 3].
|Table 2: Main results of the total and subgroup analyses on glutathione S-transferase M1 and bladder cancer|
Click here to view
|Table 3: Main results of the total and subgroup analyses on glutathione S-transferase T1 and bladder cancer|
Click here to view
|Figure 2: Forest plots on the association between glutathione S-transferase M1 polymorphism and bladder cancer risk|
Click here to view
|Figure 3: Forest plots on the association between glutathione S-transferase T1 polymorphism and bladder cancer risk|
Click here to view
In the subgroup analysis, based on source of controls, the results showed that the GSTM1-null genotype was significantly related to bladder cancer risk in PB studies (OR = 1.69, 95% CI = 1.45–1.99) [Table 2]. With respect to geographic areas, significant risk was found between GSTM1-null genotype and bladder cancer both in South and North China.
Glutathione S-transferase M1–glutathione S-transferase T1 interaction analysis
Bladder cancer risk was calculated based on GSTM1–GSTT1 genotype interactions. Relevant data were extracted from three studies.,, The nonnull genotypes were designated as the reference. There was no significant interaction for Chinese individuals with combined deletion mutations of GSTT1 and GSTM1 with respect to bladder cancer risk (OR = 0.93, 95% CI = 0.45–1.91).
Sensitivity analysis and publication bias
For comparison of differences and evaluation of sensitivity, we used fixed effects and random effects models to evaluate meta-analysis stability. No result was materially altered in overall and subgroup analyses [Table 2] and [Table 3]. Hence, sensitivity analysis results suggest the data in this meta-analysis to be relatively stable and credible. Begg's funnel plot and Egger's test were performed to access publication bias. As shown in [Figure 4], funnel plot shapes did not reveal any obvious asymmetry. Furthermore, the Egger's test indicated no evidence of obvious publication bias in the eight reviewed studies for GSTM1 (t = 1.71, P = 0.138).
| > Discussion|| |
At present, it is accepted that bladder cancer is a multifactorial disease, and one major possible mechanism is molecular alteration. Individual genetic differences may influence the activity level of GSTs and susceptibility to cancer, particularly in cases of higher exposure to toxic and carcinogenic agents., The first association between the GSTM1 or GSTT1 null genotype and the risk of bladder cancer was reported by Zhong et al. 1993 and Kempkes et al. in 1996, respectively. Following these initial reports, many studies had investigated the association between polymorphism of GSTM1 or GSTT1 and the susceptibility of bladder cancer during the past decades, but the findings were inconsistent and controversial. Regional and racial differences are one likely reason for the conflict results. Therefore, we performed this meta-analysis to assess the effect of GSTM1 and GSTT1 polymorphisms on risk for bladder cancer in the Chinese population specifically, to reduce the impacts of genetic background and regional difference.
A total of nine studies with 1646 bladder cancer cases and 1938 controls were included to systematically explore the association between GSTM1 and GSTT1 polymorphisms and bladder cancer risk in this meta-analysis. From the combined statistical results, we found a significant association between GSTM1-null genotype with the risk of bladder cancer in the overall analysis. To further explain environmental factors can modulate the risk, subgroup analyses stratified by geographical areas and sources of controls were performed. We found that GSTM1-null genotype had an increased risk of bladder cancer in PB studies, in South and North China. This result suggested that the same gene polymorphism may have different roles in bladder cancer susceptibility among different geographical areas. Therefore, further studies of bladder cancer-related genes should be on the basis of region and nationality. Because of insufficient data, we were unable to perform subgroup analysis for other environment factors.
As the effect of any single gene likely has a limited impact on bladder cancer risk, it is possible that combinations of certain genotypes may be more discriminatory. Thus, the possible interaction between GSTM1 and GSTT1 status and bladder cancer risk was investigated in this meta-analysis. Three of the included studies investigated the interaction of GSTM1–GSTT1 polymorphisms. Results of the meta-analysis showed that there was no significant interaction for bladder cancer in individuals null for both genotypes compared with those with the positive genotypes.
As compared to the previous meta-analyses,,,,, they only included a smaller number of studies which were conducted in Chinese populations, and most of them did not search Chinese databases. Xu et al.'s meta-analysis was conducted in the Chinese Han population, however, which included reduplicate studies such as Shao (2008) and Shao et al. and Cash (2012) and Shao et al. This current meta-analysis is strengthened by excluding the reduplicate studies and including several new studies. The effect of geographical areas and sources for controls was determined by subgroup analyses. We were able to explore the association between GSTM1 and GSTT1 polymorphisms and bladder cancer may not be influenced by genetic backgrounds and living environment. Sensitivity analyses and publication bias test confirmed the reliability and stability of the meta-analysis. Therefore, our results indicated that GSTM1-null genotype is associated with bladder cancer in individuals from China.
| > Conclusion|| |
This meta-analysis suggested that GSTM1 polymorphism is associated with an increased risk of developing bladder cancer in individuals from China. Further studies are needed to determine if GSTM1 polymorphism confers a risk of bladder cancer in other ethnic groups, and studies analyzing gene–gene and gene–environment interactions are required to confirm our results.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61:69-90.
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin 2015;65:87-108.
Pang C, Guan Y, Li H, Chen W, Zhu G. Urologic cancer in China. Jpn J Clin Oncol 2016;46:497-501.
Malats N, Real FX. Epidemiology of bladder cancer. Hematol Oncol Clin North Am 2015;29:177-89, vii.
Hayes JD, Flanagan JU, Jowsey IR. Glutathione transferases. Annu Rev Pharmacol Toxicol 2005;45:51-88.
McIlwain CC, Townsend DM, Tew KD. Glutathione S-transferase polymorphisms: Cancer incidence and therapy. Oncogene 2006;25:1639-48.
Rebbeck TR. Molecular epidemiology of the human glutathione S-transferase genotypes GSTM1 and GSTT1 in cancer susceptibility. Cancer Epidemiol Biomarkers Prev 1997;6:733-43.
Cochran WG. The combination of estimates from different experiments. Biometrics 1954;10:101-29.
Hao G, Xu C, Zhang H, Ge N, Meng Y, Yang M. GSTM1 genetic polymorphism and bladder cancer susceptibility. Chin J Urol 2002;23:344-6.
Zhou CZ. The Research on the Polymorphism of CYP2E1, GSTM1 and the Susceptibility of Bladder Cancer. Master Thesis, of Jilin University, China; 2007.
Wang RJ. Association of Genetic Polymorphism of GSTM1 and PSCA with Bladder Cancer Risk. Master Thesis of Tianjin Medical University, China; 2014.
Shao JF, Qian L, Wu H, Gu M, Hua L, Zhou J, et al
. Genetic polymorphisms of GSTM1 and susceptibility to bladder cancer. Tumor 2006;26:352-4.
Shao C, Xiang Y, Zhang W, Fang R, Cheng J. Polymorphisms of GSTM1 and GSTT1 with smoking and bladder cancer risk: A population-based case control study. Tumor 2006;26:346-51.
Fu J. Relationship Between Genetic Polymorphisms of CYP1A1, NQO1, EPHX1 and GSTs and Susceptibility to Bladder Cancer. Master Thesis, of Wenzhou Medical School, China; 2009.
Song DK, Xing DL, Zhang LR, Li ZX, Liu J, Qiao BP. Association of NAT2, GSTM1, GSTT1, CYP2A6, and CYP2A13 gene polymorphisms with susceptibility and clinicopathologic characteristics of bladder cancer in Central China. Cancer Detect Prev 2009;32:416-23.
Ma QW, Lin GF, Chen JG, Shen JH. Polymorphism of glutathione S-transferase T1, M1 and P1 genes in a Shanghai population: Patients with occupational or non-occupational bladder cancer. Biomed Environ Sci 2002;15:253-60.
Chen YC, Xu L, Guo YL, Su HJ, Smith TJ, Ryan LM, et al.
Polymorphisms in GSTT1 and p53 and urinary transitional cell carcinoma in south-western Taiwan: A preliminary study. Biomarkers 2004;9:386-94.
Strange RC, Fryer AA. The glutathione S-transferases: Influence of polymorphism on cancer susceptibility. IARC Sci Publ 1999;148:231-49.
Zhong S, Wyllie AH, Barnes D, Wolf CR, Spurr NK. Relationship between the GSTM1 genetic polymorphism and susceptibility to bladder, breast and colon cancer. Carcinogenesis 1993;14:1821-4.
Kempkes M, Golka K, Reich S, Reckwitz T, Bolt HM. Glutathione S-transferase GSTM1 and GSTT1 null genotypes as potential risk factors for urothelial cancer of the bladder. Arch Toxicol 1996;71:123-6.
Xu W, Wang F, Ying L, Wang HH. Association between glutathione S-transferase M1 null variant and risk of bladder cancer in Chinese Han population. Tumour Biol 2014;35:773-7.
Gong M, Dong W, An R. Glutathione S-transferase T1 polymorphism contributes to bladder cancer risk: A meta-analysis involving 50 studies. DNA Cell Biol 2012;31:1187-97.
Jiang Z, Li C, Wang X. Glutathione S-transferase M1 polymorphism and bladder cancer risk: A meta-analysis involving 33 studies. Exp Biol Med (Maywood) 2011;236:723-8.
Zhang R, Xu G, Chen W, Zhang W. Genetic polymorphisms of glutathione S-transferase M1 and bladder cancer risk: A meta-analysis of 26 studies. Mol Biol Rep 2011;38:2491-7.
Zeng FF, Liu SY, Wei W, Yao SP, Zhu S, Li KS, et al.
Genetic polymorphisms of glutathione S-transferase T1 and bladder cancer risk: A meta-analysis. Clin Exp Med 2010;10:59-68.
Shao J, Gu M, Zhang Z, Xu Z, Hu Q, Qian L. Genetic variants of the cytochrome p450 and glutathione S-transferase associated with risk of bladder cancer in a south-eastern Chinese population. Int J Urol 2008;15:216-21.
Cash HL, Tao L, Yuan JM, Marsit CJ, Houseman EA, Xiang YB, et al
. Line-1 hypomethylation is associated with bladder cancer risk among nonsmoking Chinese. Int J Cancer 2012;130:1151-9.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3]