RESEARCH ARTICLE

Tumor necrosis factor-α 238 G/A polymorphism and gastriccancer risk: a meta-analysis

Jian-yong Yu & Li Li &HengMa &Kai Liu &Xurui Cheng &

Yan-liang Li & Xi-lin Song

Received: 26 May 2013 /Accepted: 24 June 2013 /Published online: 31 July 2013# International Society of Oncology and BioMarkers (ISOBM) 2013

Abstract Though many studies were performed to assess theassociation between tumor necrosis factor-α (TNF-α) 238G/Apolymorphism and gastric cancer risk, there were no conclu-sive findings. A meta-analysis of previous published stud-ies was performed to get a comprehensive assessment ofthe association between TNF-α 238 G/A polymorphismsand gastric cancer. The pooled odds ratios (ORs) and 95 %confidence intervals (95 % CIs) were calculated to assess theassociation. Fifteen studies with a total of 7,795 participantswere finally included into this meta-analysis. Overall, there wasan obvious association between TNF-α 238 G/A polymorphismand increased risk of gastric cancer (Avs. G: OR=1.32, 95%CI1.02–1.72, P=0.036; GA vs. GG: OR=1.32, 95 % CI 1.01–1.72, P=0.042; and AA/GAvs. GG: OR=1.34, 95 % CI 1.02–1.76, P=0.036). Subgroup analysis by ethnicity showed thestatistically significant association between TNF-α 238 G/Apolymorphism and gastric cancer was limited to Asian popula-tions (Avs. G: OR=1.59, 95 % CI 1.29–1.97, P<0.001; GAvs.GG: OR=1.63, 95 % CI 1.29–2.04, P<0.001; and AA/GA vs.GG: OR=1.64, 95 %CI 1.31–2.05, P<0.001), and there wasno obvious association in Caucasians. In conclusion, TNF-α238 G/A polymorphism is significantly associated with in-creased risk of gastric cancer, especially in Asians.

Keywords TNF-α 238 G/A a . Gastric cancer .

Polymorphism .Meta-analysis

Introduction

Gastric cancer is one of the most common cancers and causesserious damage to human health in the world [1]. Previousstudies have suggested that gastric cancer is a multifactorialdisease, and both environmental and genetic factors playimportant roles in the development of gastric cancer [2, 3].Tobacco smoking and Helicobacter pylori infection havebeen identified as major risk factors of gastric cancer [2, 3].H. pylori infection can cause chronic inflammation in thestomach, which may further result in the development ofgastric cancer [4, 5]. Tumor necrosis factor-α (TNF-α) isan inflammatory cytokine which may play important roles onthe immune response and the progression of gastric cancer[6–8]. Genetic variants of inflammation-related cytokinesare a potential risk factor because H. pylori infection caninduce chronic inflammation in gastric mucosa which is acritical step in gastric carcinogenesis. Therefore, geneticpolymorphisms in the TNF-α gene have been supposed ascandidate risk factors of gastric cancer [7]. Currently, thereare several common single-nucleotide polymorphisms iden-tified in the TNF-α gene which can regulate TNF-α expres-sion, TNF-α 308G/A and 238 G/A [7, 9]. There are a largenumber of studies on the association between TNF-α308G/A and gastric cancer; TNF-α 308G/A has been suc-cessfully identified as one risk factor of gastric cancer [10,11]. Though many studies were also performed to assess theassociation between TNF-α 238 G/A polymorphism andgastric cancer risk, there were no conclusive findings. Ameta-analysis of previous published studies was performed

Jian-yong Yu and Li Li contributed equally to the study.

J.<y. Yu :H. Ma :K. Liu :X. Cheng :Y.<l. Li :X.<l. Song (*)Department of Gastrointestinal Surgery, Shandong Cancer Hospital,Jinan 250117, Chinae-mail: xilinwendeng@hotmail.com

L. LiDepartment of Trauma Surgery, Wendeng Osteopathic Hospital,Wendeng, Shandong Province, China

Tumor Biol. (2013) 34:3859–3863DOI 10.1007/s13277-013-0972-z

NOTE: Weights are from random effects analysis

Overall (I-squared = 59.8%, p = 0.002)

Crusius JB 2008

Wu MS 2004

Bai JP 2010

Zambon CF 2005

Jang WH 2001

Study

Zeng QD 2007

Hou L 2007

ID

Xing P 2006

Kamangar F 2006

Lee SG 2004

Yi D 2011

Wu MS 2003

Lu W 2005

Yang JJ 2009

Garcia-Gonzqlez 2007

1.32 (1.02, 1.72)

0.68 (0.41, 1.13)

1.03 (0.36, 2.96)

2.85 (1.29, 6.31)

1.27 (0.75, 2.14)

0.26 (0.06, 1.17)

2.13 (1.28, 3.57)

1.23 (0.70, 2.16)

OR (95% CI)

2.13 (1.28, 3.57)

2.26 (0.68, 7.50)

0.88 (0.51, 1.53)

2.39 (1.06, 5.37)

1.31 (0.51, 3.36)

1.54 (0.88, 2.71)

1.57 (0.74, 3.32)

0.80 (0.57, 1.12)

100.00

8.48

4.11

5.80

8.30

2.43

%

8.38

7.90

Weight

8.38

3.45

8.03

5.66

4.78

7.90

6.14

10.27

1.32 (1.02, 1.72)

0.68 (0.41, 1.13)

1.03 (0.36, 2.96)

2.85 (1.29, 6.31)

1.27 (0.75, 2.14)

0.26 (0.06, 1.17)

2.13 (1.28, 3.57)

1.23 (0.70, 2.16)

OR (95% CI)

2.13 (1.28, 3.57)

2.26 (0.68, 7.50)

0.88 (0.51, 1.53)

2.39 (1.06, 5.37)

1.31 (0.51, 3.36)

1.54 (0.88, 2.71)

1.57 (0.74, 3.32)

0.80 (0.57, 1.12)

100.00

8.48

4.11

5.80

8.30

2.43

%

8.38

7.90

Weight

8.38

3.45

8.03

5.66

4.78

7.90

6.14

10.27

1.057 1 17.5

NOTE: Weights are from random effects analysis

Overall (I-squared = 53.9%, p = 0.007)

Zeng QD 2007

Wu MS 2003

Jang WH 2001

Bai JP 2010

Xing P 2006

Zambon CF 2005

Lee SG 2004

Study

ID

Yi D 2011

Lu W 2005

Kamangar F 2006

Crusius JB 2008

Wu MS 2004

Hou L 2007

Yang JJ 2009

Garcia-Gonzqlez 2007

1.32 (1.01, 1.72)

2.44 (1.40, 4.26)

1.05 (0.26, 4.26)

0.29 (0.06, 1.37)

2.21 (0.94, 5.19)

2.44 (1.40, 4.26)

0.88 (0.47, 1.65)

0.88 (0.50, 1.54)

OR (95% CI)

2.45 (1.08, 5.57)

1.46 (0.82, 2.63)

2.30 (0.69, 7.71)

0.65 (0.38, 1.11)

1.03 (0.21, 5.16)

1.24 (0.70, 2.20)

1.61 (0.74, 3.48)

0.99 (0.68, 1.45)

100.00

8.67

2.90

2.46

5.76

8.67

7.92

8.62

%

Weight

6.02

8.36

3.62

8.83

2.30

8.51

6.44

10.91

1.32 (1.01, 1.72)

2.44 (1.40, 4.26)

1.05 (0.26, 4.26)

0.29 (0.06, 1.37)

2.21 (0.94, 5.19)

2.44 (1.40, 4.26)

0.88 (0.47, 1.65)

0.88 (0.50, 1.54)

OR (95% CI)

2.45 (1.08, 5.57)

1.46 (0.82, 2.63)

2.30 (0.69, 7.71)

0.65 (0.38, 1.11)

1.03 (0.21, 5.16)

1.24 (0.70, 2.20)

1.61 (0.74, 3.48)

0.99 (0.68, 1.45)

100.00

8.67

2.90

2.46

5.76

8.67

7.92

8.62

%

Weight

6.02

8.36

3.62

8.83

2.30

8.51

6.44

10.91

1.0619 1 16.2

NOTE: Weights are from random effects analysis

Overall (I-squared = 58.0%, p = 0.003)

ID

Zambon CF 2005

Yang JJ 2009

Yi D 2011

Garcia-Gonzqlez 2007

Crusius JB 2008

Study

Lu W 2005

Kamangar F 2006

Wu MS 2004

Wu MS 2003

Lee SG 2004

Hou L 2007

Bai JP 2010

Xing P 2006

Zeng QD 2007

Jang WH 2001

1.34 (1.02, 1.76)

OR (95% CI)

1.07 (0.60, 1.91)

1.61 (0.74, 3.48)

2.45 (1.08, 5.57)

0.89 (0.62, 1.28)

0.66 (0.39, 1.12)

1.52 (0.85, 2.71)

2.30 (0.69, 7.71)

1.03 (0.29, 3.61)

1.23 (0.41, 3.71)

0.88 (0.50, 1.54)

1.24 (0.70, 2.20)

2.60 (1.13, 5.98)

2.44 (1.40, 4.26)

2.44 (1.40, 4.26)

0.27 (0.06, 1.24)

100.00

Weight

8.12

6.29

5.90

10.40

8.61

%

8.09

3.63

3.44

4.11

8.28

8.17

5.81

8.32

8.32

2.52

1.34 (1.02, 1.76)

OR (95% CI)

1.07 (0.60, 1.91)

1.61 (0.74, 3.48)

2.45 (1.08, 5.57)

0.89 (0.62, 1.28)

0.66 (0.39, 1.12)

1.52 (0.85, 2.71)

2.30 (0.69, 7.71)

1.03 (0.29, 3.61)

1.23 (0.41, 3.71)

0.88 (0.50, 1.54)

1.24 (0.70, 2.20)

2.60 (1.13, 5.98)

2.44 (1.40, 4.26)

2.44 (1.40, 4.26)

0.27 (0.06, 1.24)

100.00

Weight

8.12

6.29

5.90

10.40

8.61

%

8.09

3.63

3.44

4.11

8.28

8.17

5.81

8.32

8.32

2.52

1.0573 1 17.5

a

b

c

Fig. 1 Forest plot describing theassociation between TNF-α238G/A polymorphism andgastric cancer risk (each study isshown by the point estimate ofthe OR and 95 % CI and the sizeof the square is proportional tothe weight of each study)

3860 Tumor Biol. (2013) 34:3859–3863

to get a comprehensive assessment of the association be-tween TNF-α 238 G/A polymorphism and gastric cancer.

Methods

Literature search and inclusion criteria

A literature search was performed in the PubMed andWanfangdatabases to identify those studies assessing the associationbetween TNF-α 238 G/A polymorphism and gastric cancerrisk. There were no language restrictions and the last searchtime was 18 March 2013. We used the keywords and subjectterms: (“gastric carcinoma”, “gastric cancer”, or “stomach can-cer”) and (“tumor necrosis factor”, or “TNF”, or “TNF-α”, or“238 G/A”) and (“polymorphism” or “variant” or “genotype”or “mutation”). All eligible studies were retrieved and theirbibliographies were checked for other relevant publications.

The following inclusion criteria were used in the meta-analysis: (1) case–control studies comparing gastric cancercases with healthy or noncancer controls; (2) studies evalu-ating the association between TNF-α 238 G/A polymor-phism and gastric cancer risk; (3) sufficient genotype dataof TNF-α 238 G/A polymorphism were reported. Case-onlystudies, case reports, reviews, or studies without useable datawere all excluded.

Data extraction

The following data were extracted: first author, year of publi-cation, country, ethnicity, study design, diagnostic criteria,source of cases and controls, number of cases and controls,genotyping method, and frequencies of TNF-α 238 G/A geno-types in both cases and controls. Two investigators performedthe data extraction independently and the conflicting data weresettled by discussion among all investigators.

Statistical analysis

The strength of the associations between TNF-α 238 G/Apolymorphism and gastric cancer risk was estimated usingodds ratios (ORs) and their 95 % confidence interval (95 %CIs). The following contrasts for the associations betweenTNF-α 238 G/A polymorphism and gastric cancer risk wereevaluated: the allele model (Avs. G), the heterozygote model(GAvs. GG), and the dominant model (AA/GAvs. GG). TheI2 statistic to quantify the proportion of the total variation dueto heterogeneity were calculated and an I2 value of more than50 % was interpreted as significant heterogeneity amongstudies [12]. When the effects were assumed to be homoge-nous, the fixed-effects model was used (Mantel–Haenszelmethod) [13]. If obvious heterogeneity was present, therandom-effects model was used (DerSimonian–Laird meth-od) [14]. Subgroup analysis based on ethnicity was alsoperformed. Potential publication bias was assessed by visualinspection of the funnel plot, in which the standard error of

Table 1 Meta-analysis of theassociation between TNF-α238G/A polymorphism andgastric cancer risk

OR odds ratio, 95 % CI 95 %confidence interval

Groups Studies (subjects) OR (95 % CI) P value I2 value (%)

Total studies

A vs. G 15 (7,795) 1.32 (1.02–1.72) 0.036 59.8

GA vs. GG 15 (7,795) 1.32 (1.01–1.72) 0.042 53.9

AA/GA vs. GG 15 (7,795) 1.34 (1.02–1.76) 0.036 58.0

Caucasians

A vs. G 5 (3,970) 0.93 (0.74–1.15) 0.488 39.9

GA vs. GG 5 (3,970) 0.95 (0.75–1.21) 0.696 19.0

AA/GA vs. GG 5 (3,970) 0.94 (0.74–1.19) 0.593 21.3

Asians

A vs. G 10 (3,825) 1.59 (1.29–1.97) <0.001 45.1

GA vs. GG 10 (3,825) 1.63 (1.29–2.04) <0.001 42.9

AA/GA vs. GG 10 (3,825) 1.64 (1.31–2.05) <0.001 47.1

0.2

.4.6

.8

-2 -1 0 1 2logor

Funnel plot with pseudo 95% confidence limits

Fig. 2 Funnel plot for the detection of the publication bias in themeta-analysis

Tumor Biol. (2013) 34:3859–3863 3861

logOR of each study was plotted against its logOR, and anasymmetric plot suggested possible publication bias. All anal-yses were conducted using STATA (Version 11.0, StataCorp,College Station, TX, USA). All P values were two-sided inthe meta-analysis.

Results

Study characteristics

Fifteen studies with a total of 7,795 participants were finallyincluded into this meta-analysis [15–29]. Among those 15studies, 10 studies were from Asian populations [15–19, 22,25, 27–29] while five studies were from Caucasians [20, 21,23, 24, 26]. The sample size of cases ranged from 52 to 404,while the sample size of the controls ranged from 92 to 1123in the controls [15–29].

Meta-analysis

Overall, there was an obvious association between TNF-α238 G/A polymorphism and increased risk of gastric cancer(A vs. G: OR=1.32, 95 % CI 1.02–1.72, P=0.036; GA vs.GG: OR=1.32, 95 % CI 1.01–1.72, P=0.042; AA/GA vs.GG: OR=1.34, 95 % CI 1.02–1.76, P=0.036; Fig. 1,Table 1). Subgroup analysis by ethnicity showed the statis-tically significant association between TNF-α 238 G/A poly-morphism and gastric cancer was limited to Asian popula-tions (A vs. G: OR=1.59, 95 % CI 1.29–1.97, P<0.001; GAvs. GG: OR=1.63, 95 % CI 1.29–2.04, P<0.001; AA/GAvs.GG: OR=1.64, 95 % CI 1.31–2.05, P<0.001), and there wasno obvious association in Caucasians (Table 1).

Publication bias was investigated by Begg’s funnel plotand the funnel plots showed there was low possibility ofasymmetry (Fig. 2). Therefore, there was no obvious risk ofpublication bias in the meta-analysis.

Discussion

Gastric cancer is a multifactorial disease, and both environ-mental and genetic factors play important roles in the devel-opment of gastric cancer [2, 3]. H. pylori infection has beenidentified as the major risk factor of gastric cancer [2, 3]. H.pylori infection can cause chronic inflammation in the stom-ach, which may further result in the development of gastriccancer [4, 5]. Genetic variants of inflammation-related cyto-kines are a potential risk factor because H. pylori infectioncan induce chronic inflammation in gastric mucosa which isa critical step in gastric carcinogenesis.

TNF-α is an inflammatory cytokine which may playimportant roles on the immune response and the progression

of many cancers including gastric cancer [6–8]. Therefore,genetic polymorphisms in the TNF-α gene have been sup-posed as candidate risk factors of cancer [7]. Currently, thereare several common single nucleotide polymorphisms identi-fied in the TNF-α gene which can regulate the TNF-α expres-sion, and TNF-α 308G/A and 238 G/A [7, 9]. There are alarge number of studies on the association between TNF-α308G/A polymorphism and gastric cancer, and TNF-α308G/A has been successfully identified as one risk factor ofgastric cancer [10, 11]. In addition, TNF-α 308G/A polymor-phism has also been identified as risk factors of other cancers,such as cervical cancer and breast cancer [30, 31]. Thosepositive associations above suggest that TNF-α plays impor-tant roles in the carcinogenesis of common cancers.

Though many studies were also performed to assess theassociation between TNF-α 238 G/A polymorphism and gas-tric cancer risk, there were no conclusive findings. Therefore,we performed a meta-analysis of previous published studies toget a comprehensive assessment of the association betweenTNF-α 238 G/A polymorphism and gastric cancer. Finally, 15studies with a total of 7,795 participants were finally includedinto this meta-analysis. Overall, there was an obvious associ-ation between TNF-α 238 G/A polymorphism and increasedrisk of gastric cancer (Avs. G: OR=1.32, 95 % CI 1.02–1.72,P=0.036; GA vs. GG: OR=1.32, 95 % CI 1.01–1.72,P=0.042; AA/GA vs. GG: OR=1.34, 95 % CI 1.02–1.76,P=0.036; Table 1). Subgroup analysis by ethnicity showed thestatistically significant association between TNF-α 238 G/Apolymorphism and gastric cancer was limited to Asian popu-lations and there was no obvious association in Caucasians(Table 1). In conclusion, TNF-α 238 G/A polymorphism issignificantly associated with increased risk of gastric cancer,especially in Asians.

Conflicts of interest None

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