Oncotarget

Meta-Analysis:

Association between the Glutathione-S-transferase T1 null genotype and esophageal cancer susceptibility: a meta-analysis involving 11,163 subjects

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Oncotarget. 2018; 9:15111-15121. https://doi.org/10.18632/oncotarget.24534

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Feng He _, Changyu Liu, Ruijie Zhang, Zhipeng Hao, Yangkai Li, Ni Zhang and Liang Zheng

Abstract

Feng He1, Changyu Liu1, Ruijie Zhang1, Zhipeng Hao1, Yangkai Li1, Ni Zhang1 and Liang Zheng2

1Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China

2Department of Thoracic Surgery, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China

Correspondence to:

Ni Zhang, email: zhangnidoc@gmail.com

Liang Zheng, email: zhengliang1019@163.com

Keywords: Glutathione-S-transferase T1; esophageal cancer; gene polymorphism; meta-analysis

Received: June 20, 2017     Accepted: September 21, 2017     Epub: February 20, 2018     Published: March 13, 2018

ABSTRACT

Background: Glutathione-S-Transferase T1 (GSTT1) null genotype has been shown to be associated with the risk of esophageal cancer. However, the results remain inconsistent. Thus a comprehensive meta-analysis was conducted to assess the strength of association between GSTT1 null genotype and the risk of esophageal cancer.

Materials and Methods: A literature search of PubMed, Embase, China National Knowledge Infrastructure (CNKI) and Wanfang databases up to March 31, 2017 was conducted and 30 eligible articles with 4482 cases and 6681 controls were finally recruited. The strength of correlation between GSTT1 polymorphism and the susceptibility of esophageal cancer was assessed by the crude odds ratios (ORs) with 95% confidence intervals (CIs). Subgroup analyses and sensitivity analyses were performed to further identify the association.

Results: GSTT1 null genotype significantly increased the risk of esophageal cancer (OR = 1.20; 95% CI 1.04–1.40; P < 0.05). In a subgroup analysis by ethnicity, GSTT1 null genotype was correlated with a significantly increased risk of esophageal cancer among Asians (OR = 1.33; 95% CI 1.12–1.58; P < 0.05), instead of Caucasians or Africans (OR = 0.91; 95% CI 0.65–1.26; P > 0.05 for Caucasians and OR = 1.32; 95% CI 0.98–1.77; P > 0.05 for Africans). In the analysis by histological type, GSTT1 null genotype was correlated with a significantly increased risk of esophageal squamous cell carcinoma (OR = 1.34; 95% CI 1.12–1.61; P < 0.05), particularly among Asians (OR = 1.54; 95% CI 1.30–1.82; P < 0.05), but not among Caucasians or Africans (OR = 0.87; 95% CI 0.48–1.57; P > 0.05 for Caucasians and OR = 1.32; 95% CI 0.98–1.77; P > 0.05 for Africans). In addition, there is no significant correlation between GSTT1 null genotype and the risk of esophageal adenocarcinoma (OR = 0.98; 95% CI 0.71–1.35; P > 0.05).

Conclusions: Our findings demonstrate that GSTT1 null genotype significantly increases esophageal cancer risk, particularly in Asians.


INTRODUCTION

Esophageal cancer is the sixth leading cause of cancer-related mortality and the eighth most common cancer worldwide [1]. An estimated 455,800 new esophageal cancer cases and 400,200 deaths occurred in 2012 worldwide [2]. The two major types are esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EADC). Smoking and drinking are well-known environmental risk factors for ESCC, whereas obesity and chronic gastroesophageal refluxing are main EADC risk factors. However, only a subset of individuals exposed to those environmental risk factors develop EC, suggesting a role of host susceptibility factors. Some studies have suggested that genetic polymorphisms might explain individual differences in susceptibility to esophageal cancer [3, 4].

Glutathione-S-transferases (GSTs) are important phase II biotransformation enzymes that catalyzing the nucleophilic addition of glutathione to several hazardous xenobiotics, including phase I electrophilic and carcinogenic metabolites [5]. However, these enzymes can also activate certain chemicals that target cellular proteins and DNA to elicit detrimental carcinogenic effects through genotoxic and non-genotoxic mechanisms. One of important enzymes in GSTs family is GSTT1. GSTT1 is genetically polymorphic, and deletion polymorphism of the GSTT1 loci (null genotype) results in the loss of functional activity. Several studies have found that GSTT1 null genotype is strongly associated with susceptibility to a number of cancers, such as colorectal, renal and oral cancers et al. [68]. Previous studies have been published to estimate the association between GSTT1 null genotype and the risk of esophageal cancer, but the results are inconsistent [911].

To date, several meta-analysis studies have reported the association between null GSTT1 genotype and the risk of esophageal cancer. However, the results of these studies remain outdated and incomprehensive [1214]. In the last 4 years, many case-control studies were published to estimate this association. Thus, to obtain a conclusive result about this association, we performed current meta-analysis that includes all recent publications to review and summarize the association between the GSTT1 polymorphism and the risk of esophageal cancer.

RESULTS

Characteristics

In total, 100 articles were retrieved. Figure 1 summarized the selecting process. Finally, a total of 30 studies with 4482 cases and 6681 controls met the inclusion criteria [911, 1541]. Among them, 18 were from Asians, 10 were from Caucasians, and 2 were from Africans. There were 21 studies focused on the risk of ESCC with 3272 cases and 5535 controls, and 8 studies focused on the risk of EADC with 646 cases and 1908 controls. Characteristics of included studies and the distribution of GSTT1 polymorphism are summarized in Table 1 and Table 2, respectively.

Flow chart shows studies included procedure for meta-analysis.

Figure 1: Flow chart shows studies included procedure for meta-analysis.

Table 1: Characteristics of the individual studies included in the meta-analysis

Study

Year

Country

Ethnicity

Sample size

Genotype method

Makhdoomi MA

2014

India

Asian

492/492

multiplex PCR

Sharma A

2013

India

Asian

315/436

multiplex PCR

Dura P

2013

Netherlands

Caucasian

432/591

PCR

Talukdar FR

2013

India

Asian

112/130

PCR

Zhang L

2013

China

Asian

138/170

PCR

Djansugurova LB

2013

Kazakhstan

Caucasian

107/96

PCR

Gao P

2012

China

Asian

40/80

PCR

Matejcic M

2011

South Africa

African

528/876

PCR

Malik MA

2010

India

Asian

135/195

multiplex PCR

Li D

2010

South Africa

African

238/280

PCR

Moaven O

2010

Iran

Asian

148/136

PCR

Liu R

2010

China

Asian

97/97

multiplex PCR

Ji R

2010

China

Asian

189/216

multiplex PCR

Zendehdel K

2009

Sweden

Caucasian

172/470

multiplex PCR

Zhang WL

2009

China

Asian

88/72

PCR

Deng J

2008

China

Asian

87/162

PCR

Rossini A

2007

Brazil

Caucasian

125/252

multiplex PCR

Wideroff L

2007

USA

Caucasian

67/208

PCR

Casson AG

2006

Canada

Caucasian

56/95

multiplex PCR

Jain M

2006

India

Asian

100/137

multiplex PCR

Yin LH

2005

China

Asian

106/106

PCR

Roth MJ

2004

China

Asian

131/454

PCR

Abbas A

2004

French

Caucasian

70/115

multiplex PCR

Wang LD

2003

China

Asian

62/38

multiplex PCR

Casson AG

2003

Canada

Caucasian

45/45

multiplex PCR

Ribeiro Pinto LF

2003

Brazil

Caucasian

32/67

PCR

Gao CM

2002

China

Asian

141/223

multiplex PCR

Tan W

2000

China

Asian

150/150

multiplex PCR

van Lieshout EM

1999

Netherlands

Caucasian

34/247

PCR

Lin DX

1998

China

Asian

45/45

multiplex PCR

Table 2: Distribution of GSTT1 null genotype among cases and controls

Study

Year

Control

EC

ESCC

EADC

Present

Null

Present

Null

Present

Null

Present

Null

Makhdoomi MA

2014

367

125

306

186

306

186

/

/

Sharma A

2013

373

63

233

82

233

82

/

/

Dura P

2013

463

128

335

97

87

18

248

79

Talukdar FR

2013

92

38

66

46

66

46

/

/

Zhang L

2013

90

80

62

76

62

76

/

/

Djansugurova LB

2013

35

61

19

88

19

88

/

/

Gao P

2012

55

25

18

22

18

22

/

/

Matejcic M

2011

648

228

375

153

375

153

/

/

Malik MA

2010

146

49

110

25

/

/

/

/

Li D

2010

178

102

125

113

125

113

/

/

Moaven O

2010

105

31

112

36

112

36

/

/

Liu R

2010

57

40

34

63

34

63

/

/

Ji R

2010

122

94

91

98

91

98

/

/

Zendehdel K

2009

394

76

150

22

70

7

80

15

Zhang LW

2009

39

33

31

57

31

57

/

/

Deng J

2008

75

87

36

51

/

/

/

/

Rossini A

2007

192

60

110

15

110

15

/

/

Wideroff L

2007

173

35

59

8

/

/

59

8

Casson AG

2006

80

15

42

14

/

/

42

14

Jain M

2006

100

37

72

28

56

20

6

3

Yin LH

2005

55

51

60

46

/

/

/

/

Roth MJ

2004

211

243

54

77

54

77

/

/

Abbas A

2004

85

30

56

14

31

13

25

1

Wang LD

2003

18

20

28

34

25

34

/

/

Casson AG

2003

33

12

37

8

/

/

37

8

Rebeiro

2003

52

15

26

6

/

/

/

/

Gao CM

2002

104

119

67

74

/

/

/

/

Tan W

2000

91

59

90

60

90

60

/

/

van Lieshout EM

1999

198

49

28

6

11

2

17

4

Lin DX

1998

22

23

26

19

/

/

/

/

Abbreviations: EC: esophageal cancer; ESCC: esophageal squamous cell carcinoma; EADC: esophageal adenocarcinoma.

Quantitative synthesis

Table 3 showed the main result of the association between GSTT1 null genotype and the risk of esophageal cancer. Overall, there was a significant correlation of GSTT1 null genotype with esophageal cancer risk (OR = 1.20; 95% CI 1.04–1.40; P < 0.05; Table 3 and Figure 2). In a subgroup analysis by ethnicity, GSTT1 null genotype was correlated with a significantly increased risk of esophageal cancer among Asians (OR = 1.33; 95% CI 1.12–1.58; P < 0.05; Table 3 and Figure 2), but not among Caucasians and Africans (OR = 0.91; 95% CI 0.65–1.26; P > 0.05 for Caucasians and OR = 1.32; 95% CI 0.98–1.77; P > 0.05 for Africans; Table 3 and Figure 2).

Table 3: Meta-analysis of the GSTT1 null genotype and esophageal cancer risk

Number of Study

OR (95%CI)

P

P (Q-test)

I-squared

Total

30

1.20 (1.04–1.40)

0.014

0.000

60.2

Ethnicity

 Asians

18

1.33 (1.12–1.58)

0.001

0.003

54.9

 Caucasians

10

0.91 (0.65–1.26)

0.569

0.01

58.3

 Africans

2

1.32 (0.98–1.77)

0.070

0.157

50.0

ESCC

21

1.34 (1.12–1.61)

0.001

0.000

62.6

Ethnicity

 Asians

13

1.54 (1.30–1.82)

0.000

0.097

35.7

 Caucasians

6

0.87 (0.48–1.57)

0.640

0.002

73.5

 Africans

2

1.32 (0.98–1.77)

0.070

0.157

50.0

EADC

8

0.98 (0.71–1.35)

0.911

0.240

23.7

Forest plot of the association of GSTT1 null genotype with esophageal cancer risk.

Figure 2: Forest plot of the association of GSTT1 null genotype with esophageal cancer risk.

In the analysis by histological type, GSTT1 null genotype were correlated with a significantly increased risk of ESCC (OR = 1.34; 95% CI 1.12–1.61; P < 0.05; Table 3 and Figure 3). Moreover, in a subgroup analysis by ethnicity, GSTT1 null genotype was correlated with a significantly increased risk of ESCC among Asians (OR = 1.54; 95% CI 1.30–1.82; P < 0.05; Table 3 and Figure 3), but not among Caucasians and Africans (OR = 0.87; 95% CI 0.48–1.57; P > 0.05 for Caucasians and OR = 1.32; 95% CI 0.98–1.77; P > 0.05 for Africans; Table 3 and Figure 3). In addition, there is no significant correlation of GSTT1 null genotype with the risk of EADC (OR = 0.98; 95% CI 0.71–1.35; P > 0.05; Table 3 and Figure 4).

Forest plot of the association of GSTT1 null genotype with esophageal squamous cell carcinoma risk.

Figure 3: Forest plot of the association of GSTT1 null genotype with esophageal squamous cell carcinoma risk.

Forest plot of the association of GSTT1 null genotype with esophageal adenocarcinoma risk.

Figure 4: Forest plot of the association of GSTT1 null genotype with esophageal adenocarcinoma risk.

Test for publication bias, sensitivity analyses, and heterogeneity

Publication bias was assessed by both the Begg’s funnel plot and the Egger’s test. The shape of the Begg’s funnel plot did not reveal any evidence of obvious asymmetry (Figure 5). Egger’s test further suggested no evidence of publication bias (P = 0.210). Thus, there was no obvious publication bias in this meta-analysis.

Begg&#x0027;s funnel plot analysis of GSTT1 polymorphism with esophageal cancer risk.

Figure 5: Begg's funnel plot analysis of GSTT1 polymorphism with esophageal cancer risk.

The sensitivity analysis was conducted to test the influence of an individual data on the pooled ORs and CIs by eliding a study in turn. Our findings suggested that the present meta-analysis results were relatively robust and stable (Figure 6).

One-way sensitivity analysis of GSTT1 polymorphism with esophageal cancer risk.

Figure 6: One-way sensitivity analysis of GSTT1 polymorphism with esophageal cancer risk.

As showed in Figure 2 and Figure 3, heterogeneity was significant in overall and in some subgroups. Thus, we measured the sources of heterogeneity by subgroup analysis. The results showed that Caucasians may lead to the major source of heterogeneity.

DISCUSSION

Many studies suggest genetic variants play important roles in individual susceptibility to esophageal cancer [3, 42]. In decades, epidemiological studies have been performed to assess the association of GSTT1 null genotype with the risk of esophageal cancer. However, the results were inconsistent [34, 36]. Previous meta-analyses also investigated the association [1214], the findings should be interpreted with very cautions. In Weng et al. study, 11 studies included in the meta-analysis were in Chinese Han population. Although the results showed a significant association between GSTT1 null genotype and esophageal cancer risk, the single Chinese Han population limited the power of the statistical analysis [12]. Also In Yi et al. study, 15 studies included in the meta-analysis were in Asian population. Although the results showed a significant association between GSTT1 null genotype and esophageal cancer risk, the single Asian population limited the power of the statistical analysis [13]. In Cai et al. study, a total of 24 studies were used. Adjusted ORs with corresponding 95% CIs were reported in 9 studies. In the overall analysis there was no significant association between GSTT1 null genotype and esophageal cancer risk. However, meta-analysis of adjusted ORs showed a significant association between GSTT1 null genotype and esophageal cancer risk [14]. Because of the lack of available data, subgroup analysis by histological type was not performed in these studies [1214]. Thus we conducted a comprehensive meta-analysis, to investigate not only the strength of association between GSTT1 null genotype and the risk of esophageal cancer, but also the association of GSTT1 null genotype with the risk of different histological types.

This meta-analysis, including 30 case-control studies with 4482 cases and 6681 controls, identified the association between GSTT1 null genotype and esophageal cancer risk. GSTT1 null genotype significantly increased overall esophageal cancer risk. In a subgroup analysis by ethnicity, GSTT1 null genotype was correlated with a significantly increased risk of esophageal cancer among Asians. In the analysis by histological type, GSTT1 null genotype was correlated with a significantly increased risk of ESCC, particularly in Asians. However, there was no significant correlation of GSTT1 null genotype with the risk of EADC. To date, this is the first meta-analysis concerning the association of GSTT1 null genotype with the risk of different histological types.

GSTT1, encodes an enzyme that plays a crucial role in the detoxification of a variety of endogenous or exogenous carcinogens. It is located on 22q11.23 with 8146 base pairs, 5 exons and 4 introns in all [5]. GSTT1 is genetically polymorphic, and GSTT1 null genotype results in the loss of functional activity [12]. Our results demonstrated that GSTT1 null genotype significantly increased overall esophageal cancer risk.

Since the results from meta-analysis can be affected by histological types, a subgroup analysis was carried out regarding different histological type for the GSTT1 null genotype. GSTT1 null genotype was correlated with a significantly increased risk of ESCC among Asians, but not among Caucasians and Africans. However, there was no significant correlation of GSTT1 null genotype with the risk of EADC. All results should be interpreted with caution. Only two African studies were recruited in the current meta-analysis, which may restrict statistical power to detect a real assessment in Africans. More large scale studies are needed to verify the results. Subgroup analyses were also performed regarding ethnicity for the GSTT1 null genotype. GSTT1 null genotype was correlated with a significantly increased risk of esophageal cancer among Asians, but not among Caucasians and Africans. The results were more robust on histological type of ESCC. This meta-analysis confirmed the mutual effect of GSTT1 null genotype in different populations to the risk of esophageal cancer. Possible explanations include: (1) significance of these enzymes may vary with the ethnicity genetic backgrounds, environmental exposures and histological types. The regional difference in the frequency of esophageal cancer is probably due to genetic polymorphism and variable exposure to environmental factors; (2) GSTs metabolize a variety of overlapping substrates and individuals lacking GSTT1 can also metabolize the carcinogens by other alternative GST enzymes. Furthermore, there was only one study concerning the association between GSTT1 null genotype and EADC on Asians. Thus, we failed to evaluate the potential role of GSTT1 null genotype in EADC risk in Asians due to the lack of available data to date. More case-control studies on the GSTT1 null genotype are encouraged, especially in Asians, for a better understanding the role of GSTT1 null genotype in the EADC development.

Some limitations must be acknowledged in the current meta-analysis. First, significant heterogeneity was observed between publications for GSTT1 null genotype. Potential sources of heterogeneity include the study design, publication year, ethnicity, country, histological type, sample size, and so on. When subgroup analyses were carried out according to ethnicity and histological type, this heterogeneity was reduced or removed in some subgroups, implying different effects on histological types and ethnic populations. These findings should be interpreted with very cautions. Second, our findings were based on unadjusted ORs and CIs, whereas a more precisely investigation could be performed if the sufficient individual data were available. Third, only two African studies were recruited in the current meta-analysis, the results in African population should be interpreted with caution. More large scale studies are needed to verify the results in Africans. Finally, due to lack of uniform individual-level data, further stratified analysis to measure any interactions between gene–gene variation and gene-metabolic traits was not performed.

In conclusion, our meta-analysis findings demonstrated that GSTT1 null genotype significantly increased esophageal cancer risk, particularly in Asians. In addition, GSTT1 null genotype was correlated with a significantly increased risk of ESCC, particularly among Asians. However, more studies are warranted to confirm or refute these correlations, particularly with respect to gene-gene and gene-environment interactions.

MATERIALS AND METHODS

Study selection

Pubmed, Embase, China National Knowledge Infrastructure (CNKI) and Wanfang databases (the search was updated in March 31, 2017) were searched using the following terms: ‘glutathione S-transferase T1’ or ‘GSTT1’, ‘polymorphism’ or ‘variant’, and ‘esophageal’ or ‘esophagus’, and ‘cancer’ or ‘carcinoma’ or ‘tumor’ or ‘malignancy’. The literature search was limited to English or Chinese articles. Additional publications were identified by a manual search based on references of retrieved studied or reviews.

Inclusion and exclusion criteria

The selection criteria were: (1) in a case-control study design, (2) studies that evaluated the relationship between the GSTT1 null genotype polymorphism and esophageal cancer, (3) usable data on genotype frequency. Thus, reports without usable data, reviews, comments and duplicated publications were excluded.

Data extraction

The data were collected by two independent reviewers. The extracted information contained: first author, year of publication, country of origin, ethnicity, number of cases and controls, genotyping method and characteristics of cases and controls. When come to conflicting assessment, disagreements were settled through a discussion among all authors.

Statistical analysis

The strength of correlation between GSTT1 null genotype and the susceptibility of esophageal cancer was assessed by the crude odds ratios (ORs) with 95% confidence intervals (CIs). A P < 0.05 (two-tailed) was considered as statistical significance. A Chi-square-based I2 test was used to detect heterogeneity [43] and an I2 < 25% indicates low heterogeneity, 25% ≤ I2 ≤ 50% indicates moderate heterogeneity, and I2 > 50% indicates large heterogeneity [44]. When I2 > 50% or P < 0.10 (two-sided), the random-effects model (the DerSimonian-Laird method) was utilized to pool the data [45], otherwise the fixed-effects model (the Mantel-Haenszel method) was used [46]. Subgourp analyses were conducted according to different ethnicity to identify the specific effects of heterogeneity. Publication bias was assessed by Begg’s funnel plot and Egger’s test [47]. Sensitivity analyses were conducted by one-way method. All statistical analyses were performed using STATA version 12.0 software (Stata Corporation, College Station, TX, USA).

Abbreviations

Glutathione-S-Transferase T1, GSTT1; China National Knowledge Infrastructure, CNKI; odds ratios, ORs; confidence intervals, CIs; esophageal squamous cell carcinoma, ESCC; esophageal adenocarcinoma, EADC.

Author contributions

FH, NZ and LZ designed the study. All authors were involved in article search, extraction, analysis and interpretation of data. FH drafted the manuscript, which was critically revised by NZ and LZ. All authors read and approved the final manuscript.

ACKNOWLEDGMENTS

We thank Dr. Haiyong Gu for his invaluable help. This study is supported in part by Changzhou High-Level Medical Talents Training Project (No: 2016CZBJ043) and The Applied Basic Research Programs of ChangZhou (No: CJ20159030).

CONFLICTS OF INTEREST

The authors report no conflicts of interest.

FUNDING

Changzhou High-Level Medical Talents Training Project (No: 2016CZBJ043). The Applied Basic Research Programs of ChangZhou (No: CJ20159030).

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