RESEARCH ARTICLE

An updated meta-analysis of the association between GSTM1polymorphism and colorectal cancer in Asians

Xiang Cai & Lie Yang & Haining Chen & Cun Wang

Received: 26 July 2013 /Accepted: 16 August 2013 /Published online: 8 September 2013# International Society of Oncology and BioMarkers (ISOBM) 2013

Abstract Glutathione S-transferases (GSTs) are a large fam-ily of phase II detoxification enzymes that are expressed inmany tissues and play critical roles in protecting hosts againstcancer. The association of glutathione S-transferase M1(GSTM1) polymorphism with susceptibility to colorectal can-cer in Asians has not been well established. We performed ameta-analysis to quantitatively assess the association be-tween GSTM1 polymorphism and colorectal cancer inAsians. We systematically searched the PubMed andEmbase databases to identify the eligible studies. Finally,17 eligible studies with 5,907 cases and 9,726 controlswere included into the meta-analysis. The pooled oddsratio (OR) with its 95 % confidence intervals (95 %CI)was used to assess the association. The meta-analysis ofthose included studies suggests that GSTM1 null genotypewas significantly associated with colorectal cancer risk inAsians (OR=1.14, 95 %CI=1.013–1.29, P=0.03). Thecumulative meta-analyses showed a trend of an obviousassociation between the GSTM1 null genotype and risk ofcolorectal cancer in Asians as information accumulated byyear. Thus, there is an obvious association between theGSTM1 null genotype and risk of colorectal cancer inAsians.

Keywords Colorectal cancer . GSTM1 . Asians

Introduction

Colorectal cancer is a major cause of cancer-related deaths inthe world [1]. There is obvious difference in the incidence ratesof colorectal cancer in different countries, which indicates thatthe influence of genetic factors and local environmental factorsboth play important roles in the development of colorectalcancer [2, 3]. It is clear that the proposed etiological pathwayof colorectal cancer involves a series of steps in which envi-ronmental carcinogens and genetic factors play important roles[2–4]. Glutathione S-transferases (GSTs) are a large family ofphase II detoxification enzymes which play critical roles in theregulation of the conversion of toxic compounds to hydrophilicmetabolites [5, 6]. Glutathione S-transferase M1 (GSTM1) isone of the main subtypes of GSTs, and it has important roles inprotecting hosts against cancer [5]. GSTM1 gene is located onthe short arm of chromosome 1 (1p13.3), and there are severalpolymorphisms in the GSTM1 gene [7]. Among those poly-morphisms, a null variant in the GSTM1 gene is the mostcommon polymorphism and has been widely investigated asa risk biomarker for various cancers [8, 9]. The GSTM1 nullvariant can result in an absence of enzyme activity, and indi-viduals who carry the null variant are thought to be at increasedrisk of cancer [7]. There were many studies designed toevaluate the association of GSTM1 polymorphism with sus-ceptibility to colorectal cancer in Asians, but the results wereinconsistent [10–22]. These inconsistent results could be due tothe limited sample size and low power to detect the preciseeffect in a single study [10–22]. Thus, we performed a meta-analysis to quantitatively assess the association betweenGSTM1 polymorphism and colorectal cancer in Asians.

X. CaiDepartment of Urology, West China Hospital, Sichuan University,Chengdu 610041, Sichuan Province, People’s Republic of China

L. Yang :H. Chen : C. Wang (*)Department of Gastrointestinal Surgery, West China Hospital,Sichuan University, Chengdu 610041, Sichuan Province, Chinae-mail: wangcwest@hotmail.com

Tumor Biol. (2014) 35:949–953DOI 10.1007/s13277-013-1125-0

Methods

Literature search and inclusion criteria

We systematically searched the PubMed and Embase data-bases to identify the eligible studies. We used the followingkeywords: “polymorphism” or “Single Nucleotide Polymor-phism”; “GST”, “glutathione S-transferase”, “GSTM1”, or“glutathione S-transferase M1”; and “CRC” or “colorectalcancer”. There was no language restriction in the literaturesearch. The reference lists of the identified articles werealso examined to find other possible studies. The eligiblestudies had to meet the following inclusion criteria: (1) thestudies should assess the association between GSTM1polymorphism and colorectal cancer, (2) the studies shouldhave a case–control design, (3) the studies should providesufficient data for inferring odds ratio (OR) and corresponding95 % confidence intervals (95 %CI), and (4) the participantswere Asians. Reviews, case reports, or duplicate studies wereall excluded.

Data extraction

The data from the eligible studies that were selected instrict accordance with the inclusion criteria were inde-pendently extracted by two investigators. The follow-ing data were extracted from each study: first author'sname, year of publication, the country, the source ofcontrols, and the distributions of the respective geno-types of GSTM1 polymorphism in the case and controlgroups.

Statistical analysis

The association between GSTM1 polymorphism and colorec-tal cancer in Asians was estimated by calculating the pooledOR with its 95 % CI. Heterogeneity across studies was esti-mated using the I2 statistics to quantify the proportion of thetotal variation due to heterogeneity [23], and an I2<50 %suggested a lack of obvious heterogeneity. The meta-analysiswas carried out using random-effects [24] or fixed-effects [25]models based on the pooled effect estimates in the presence(I2>50 %) or absence (I2≤50 %) of obvious heterogeneity.The random-effect model was used when there was obviousheterogeneity. We further performed a cumulative meta-analysis to provide a framework for updating a genetic effectfrom all the studies and to measure how much the geneticeffect changes as evidence accumulates, and find the trend inestimated risk effect [26]. Potential publication bias was esti-mated by constructing funnel plots, and an asymmetric funnelplot indicated a relationship between effect and study size,which suggested the possibility of either publication bias or asystematic difference between smaller and larger studies. Sta-tistical analysis was performed with the RevMan 5.0 program(Cochrane Collaboration) and the STATA package version11.0 program (Stata Corporation, College Station, TX, USA).

Results

Characteristics of the included studies

After performing a careful search using the search strategy,70 potentially relevant publications were identified. Based

Fig. 1 Meta-analysis of the association between GSTM1 polymorphism and colorectal cancer in Asians

950 Tumor Biol. (2014) 35:949–953

on the inclusion criteria, 17 eligible studies with 5,907cases and 9,726 controls were included into the meta-analysis [10–22, 27–30]. Fourteen studies were publishedin English [10–22, 30], while the other three studieswere published in Chinese [27–29]. Those 17 case–con-trol studies were published from 1996 to 2011 [10–22,27–30]. The controls were mostly selected from non-cancer patients or healthy individuals [10–22, 27–30].Most studies were hospital-based studies. The controlswere mainly matched by age and gender to the cases in those17 studies.

Meta-analysis

The meta-analysis of those included studies suggests thatGSTM1 null genotype was significantly associated with co-lorectal cancer risk in Asians (OR=1.14, 95 %CI=1.013–1.29, P=0.03) (Fig. 1). The cumulativemeta-analyses showeda trend of an obvious association between the GSTM1 nullgenotype and the risk of colorectal cancer in Asians as infor-mation accumulated by year (Fig. 2).

The publication bias was detected based on the shape of thefunnel plot in the meta-analysis. As shown in Fig. 3, there was

Guo JY 1996

Katoh T 1996

Lee E 1998

Saadat I 2001

Seow A 2002

Zhu Y 2002

Chen K 2006

Fan CH 2006

Probst-Hensch NM 2006

Yoshida K 2007

Piao JM 2009

Nisa H 2010

Yang G 2010

Yeh CC 2010

Aghajany-Nasab M 2011

Koh WP 2011

Wang J 2011

ID

Study

1.65 (0.44, 6.17)

1.55 (0.95, 2.53)

1.13 (0.65, 1.94)

1.25 (0.78, 2.00)

1.22 (0.90, 1.65)

1.25 (0.96, 1.62)

1.20 (0.97, 1.48)

1.18 (0.99, 1.40)

1.13 (0.96, 1.31)

1.12 (0.97, 1.29)

1.08 (0.97, 1.19)

1.05 (0.95, 1.16)

1.04 (0.96, 1.13)

1.03 (0.96, 1.11)

1.13 (0.99, 1.29)

1.13 (1.00, 1.28)

1.14 (1.01, 1.29)

OR (95% CI)

1.65 (0.44, 6.17)

1.55 (0.95, 2.53)

1.13 (0.65, 1.94)

1.25 (0.78, 2.00)

1.22 (0.90, 1.65)

1.25 (0.96, 1.62)

1.20 (0.97, 1.48)

1.18 (0.99, 1.40)

1.13 (0.96, 1.31)

1.12 (0.97, 1.29)

1.08 (0.97, 1.19)

1.05 (0.95, 1.16)

1.04 (0.96, 1.13)

1.03 (0.96, 1.11)

1.13 (0.99, 1.29)

1.13 (1.00, 1.28)

1.14 (1.01, 1.29)

OR (95% CI)

1.5 .8 1 1.5 2 3

Fig. 2 Cumulative meta-analysisof the association betweenGSTM1 polymorphism andcolorectal cancer in Asians

Fig. 3 No obvious asymmetrywas observed in the shape of thefunnel plot

Tumor Biol. (2014) 35:949–953 951

no obvious asymmetry in the shape of the funnel plot, whichindicated that there was no obvious evidence of publicationbias in the present meta-analysis (Fig. 3).

Discussion

GSTM1 is one of the main subtypes of GSTs, and it hasimportant roles in protecting hosts against cancer [5]. TheGSTM1 gene null variant is the most common polymorphismand has been widely investigated as a risk biomarker forvarious cancers [8, 9]. The GSTM1 null variant can result inan absence of enzyme activity, and individuals who carry thenull variant are thought to be at increased risk of cancer [7].Previous studies have suggested that the GSTM1 null variantis associated with risks of lung cancer, prostate cancer, bladdercancer, and hepatocellular carcinoma [31–34].

There are a large number studies on the relationship be-tween GSTM1 polymorphism and colorectal cancer [35].Previous meta-analysis of all eligible studies suggested thatthe GSTM1 null allele carriers exhibited increased colorectalcancer risk in Caucasian populations (pooled OR=1.15, 95%CI 1.06–1.25, random effects), but no significant associa-tion was detected for Asians (pooled OR=1.03, 95 %CI 0.90–1.16, fixed effects) [35]. After the previous meta-analysis,many studies have been performed to further assess therelationship between GSTM1 polymorphism and colorectalcancer in Asians [8, 9, 18–22, 30], but the association betweenGSTM1 polymorphism and colorectal cancer in Asians wasstill inconclusive due to the inconsistent results from thepublished studies.

In the present meta-analysis, we analyzed 17 eligible stud-ies with 5,907 cases and 9,726 controls to quantitatively assessthe association between GSTM1 polymorphism and colorec-tal cancer in Asians. The meta-analysis of those includedstudies suggests that the GSTM1 null genotype was signifi-cantly associated with colorectal cancer risk in Asians (OR=1.14, 95 %CI=1.013–1.29, P=0.03) (Fig. 1). The cumulativemeta-analyses showed a trend of an obvious association be-tween the GSTM1 null genotype and risk of colorectal cancerin Asians as information accumulated by year (Fig. 2). Thus,the meta-analysis supports that there is an obvious associationbetween the GSTM1 null genotype and risk of colorectalcancer in Asians.

Similar to the other meta-analyses, there were several lim-itations in this meta-analysis. Firstly, we did not pool theadjusted estimation which was more precise to assess theassociation. Further studies can calculate the pooled OR,adjusting for other confounding factors. Secondly, most ofthose included studies in the meta-analysis did not analyzethe effects of the GSTM1 polymorphism on colon cancer andrectal cancer separately, and we did not perform the subgroupanalysis by the types of colorectal cancer, such as colon cancerand rectal cancer. Finally, gene–gene and gene–environment

interactions were not analyzed in the meta-analysis due to thelack of relevant studies. More case–control studies are neededto further analyze the possible gene–gene and gene–environ-ment interactions in the association.

In summary, despite the abovementioned limitations, thepresent study provides evidence that there is an obviousassociation between the GSTM1 null genotype and risk ofcolorectal cancer in Asians. More case–control studies areneeded to further analyze the possible gene–gene and gene–environment interactions in the association.

Conflicts of interests None

References

1. CunninghamD, AtkinW, LenzHJ, Lynch HT,Minsky B, NordlingerB, et al. Colorectal cancer. Lancet. 2010;375:1030–47.

2. Markowitz SD, Bertagnolli MM. Molecular origins of cancer: mo-lecular basis of colorectal cancer. N Engl J Med. 2009;361:2449–60.

3. Fearon ER. Molecular genetics of colorectal cancer. Annu RevPathol. 2011;6:479–507.

4. Peters U, Jiao S, Schumacher FR, Hutter CM, Aragaki AK, BaronJA, et al. Identification of genetic susceptibility loci for colorectaltumors in a genome-wide meta-analysis. Gastroenterology. 2013;144:799–807 e724.

5. Strange RC, Spiteri MA, Ramachandran S, Fryer AA. Glutathione-S-transferase family of enzymes. Mutat Res. 2001;482:21–6.

6. Oakley A. Glutathione transferases: a structural perspective. DrugMetab Rev. 2011;43:138–51.

7. Hayes JD, Strange RC. Glutathione S-transferase polymorphismsand their biological consequences. Pharmacology. 2000;61:154–66.

8. Zhang ZJ, Hao K, Shi R, Zhao G, Jiang GX, Song Y, et al. Glutathi-one S-transferase M1 (GSTM1) and glutathione S-transferase T1(GSTT1) null polymorphisms, smoking, and their interaction in oralcancer: a huge review and meta-analysis. Am J Epidemiol. 2011;173:847–57.

9. Taioli E, Flores-Obando RE, Agalliu I, Blanchet P, Bunker CH,Ferrell RE, et al. Multi-institutional prostate cancer study of geneticsusceptibility in populations of African descent. Carcinogenesis.2011;32:1361–5.

10. Guo JY,Wan DS, Zeng RP, ZhangQ. The polymorphism of GSTM1,mutagen sensitivity in colon cancer and healthy control. Mutat Res.1996;372:17–22.

11. Katoh T, Nagata N, Kuroda Y, Itoh H, Kawahara A, Kuroki N, et al.Glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) geneticpolymorphism and susceptibility to gastric and colorectal adenocar-cinoma. Carcinogenesis. 1996;17:1855–9.

12. Lee E, Huang Y, Zhao B, Seow-Choen F, Balakrishnan A, Chan SH.Genetic polymorphism of conjugating enzymes and cancer risk:GSTM1, GSTT1, NAT1 and NAT2. J Toxicol Sci. 1998;23 Suppl2:140–2.

13. Saadat I, Saadat M. Glutathione S-transferase M1 and T1 null geno-types and the risk of gastric and colorectal cancers. Cancer Lett.2001;169:21–6.

14. Seow A, Yuan JM, Sun CL, Van Den Berg D, Lee HP, Yu MC.Dietary isothiocyanates, glutathione S-transferase polymorphismsand colorectal cancer risk in the Singapore Chinese health study.Carcinogenesis. 2002;23:2055–61.

952 Tumor Biol. (2014) 35:949–953

15. Probst-Hensch NM, Sun CL, Van Den Berg D, Ceschi M, Koh WP,YuMC. The effect of the cyclin D1 (CCND1) A870G polymorphismon colorectal cancer risk is modified by glutathione-S-transferasepolymorphisms and isothiocyanate intake in the Singapore Chinesehealth study. Carcinogenesis. 2006;27:2475–82.

16. Yoshida K, Osawa K, Kasahara M, Miyaishi A, Nakanishi K,Hayamizu S, et al. Association of CYP1A1, CYP1A2, GSTM1 andNAT2 gene polymorphisms with colorectal cancer and smoking.Asian Pac J Cancer Prev. 2007;8:438–44.

17. Piao JM, Shin MH, Kweon SS, Kim HN, Choi JS, Bae WK, et al.Glutathione-S-transferase (GSTM1, GSTT1) and the risk of gastro-intestinal cancer in a Korean population. World J Gastroenterol.2009;15:5716–21.

18. Nisa H, Kono S, Yin G, Toyomura K, Nagano J, Mibu R, et al.Cigarette smoking, genetic polymorphisms and colorectal cancerrisk: the Fukuoka colorectal cancer study. BMC Cancer. 2010;10:274.

19. Yang G, Gao YT, Shu XO, Cai Q, Li GL, Li HL, et al. Isothiocyanateexposure, glutathione S-transferase polymorphisms, and colorectalcancer risk. Am J Clin Nutr. 2010;91:704–11.

20. Yeh CC, Lai CY, Hsieh LL, Tang R, Wu FY, Sung FC. Proteincarbonyl levels, glutathione S-transferase polymorphisms and riskof colorectal cancer. Carcinogenesis. 2010;31:228–33.

21. Koh WP, Nelson HH, Yuan JM, Van den Berg D, Jin A, Wang R,et al. Glutathione S-transferase (GST) gene polymorphisms, cigarettesmoking and colorectal cancer risk among Chinese in Singapore.Carcinogenesis. 2011;32:1507–11.

22. Wang J, Jiang J, Zhao Y, Gajalakshmi V, Kuriki K, Suzuki S, et al.Genetic polymorphisms of glutathione S-transferase genes and sus-ceptibility to colorectal cancer: a case–control study in an Indianpopulation. Cancer Epidemiol. 2011;35:66–72.

23. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring incon-sistency in meta-analyses. BMJ. 2003;327:557–60.

24. DerSimonian R, Laird N.Meta-analysis in clinical trials. Control ClinTrials. 1986;7:177–88.

25. Mantel N, Haenszel W. Statistical aspects of the analysis of data fromretrospective studies of disease. J Natl Cancer Inst. 1959;22:719–48.

26. Zintzaras E, Lau J. Synthesis of genetic association studies forpertinent gene-disease associations requires appropriate methodolog-ical and statistical approaches. J Clin Epidemiol. 2008;61:634–45.

27. Zhu Y, Deng C, Zhang Y, Zhou X, He X. The relationship betweenGSTM1, GSTT1 gene polymorphisms and susceptibility to sporadiccolorectal adenocarcinoma. Zhonghua Nei Ke Za Zhi. 2002;41:538–40.

28. ChenK, JiangQT,MaXY,YaoKY,LengSG,YuWP, et al. Associationsbetween genetic polymorphisms of glutathione S-transferaseM1 and T1,smoking and susceptibility to colorectal cancer: a case–control study.Zhonghua Zhong Liu Za Zhi. 2004;26:645–8.

29. Fan CH, JinMJ, Zhang Y, Song L, Xu H, Jiang QT, et al. Associationbetween genetic polymorphisms of metabolic enzymes and suscep-tibility of colorectal cancer. Zhonghua Yu Fang Yi Xue Za Zhi.2006;40:13–7.

30. Aghajany-Nasab M, Panjehpour M, Samiee SM, Rahimi F,Movahedian A. Glutathione S-transferase mu gene variants andcolorectal cancer development – use of sequence-specific probesfor an Iranian population. Asian Pac J Cancer Prev. 2011;12:1511–5.

31. Wang B, Huang G, Wang D, Li A, Xu Z, Dong R, et al. Nullgenotypes of GSTM1 and GSTT1 contribute to hepatocellular carci-noma risk: evidence from an updated meta-analysis. J Hepatol.2010;53:508–18.

32. Moore LE, Baris DR, Figueroa JD, Garcia-Closas M, Karagas MR,Schwenn MR, et al. GSTM1 null and NAT2 slow acetylation geno-types, smoking intensity and bladder cancer risk: results from theNew England bladder cancer study and NAT2 meta-analysis.Carcinogenesis. 2011;32:182–9.

33. GongM, DongW, Shi Z, Xu Y, NiW, An R. Genetic polymorphismsof GSTM1, GSTT1, and GSTP1 with prostate cancer risk: a meta-analysis of 57 studies. PLoS One. 2012;7:e50587.

34. Zhang Y, Liu C. The interaction between smoking and GSTM1variant on lung cancer in the Chinese population. Tumour Biol.2013;34:395–401.

35. Economopoulos KP, Sergentanis TN. GSTM1, GSTT1, GSTp1,GSTA1 and colorectal cancer risk: a comprehensive meta-analysis.Eur J Cancer. 2010;46:1617–31.

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