Clin Exp Med DOI 10.1007/s10238-015-0363-4
ORIGINAL ARTICLE
The tumor necrosis factor-a-238 polymorphism and digestive system cancer risk: a meta-analysis Ming Hui1 • Xiaojuan Yan2 • Ying Jiang3,4
Received: 11 March 2015 / Accepted: 26 May 2015 Ó Springer-Verlag Italia 2015
Abstract Many studies have reported the association between tumor necrosis factor-a (TNF-a)-238 polymorphism and digestive system cancer susceptibility, but the results were inconclusive. We performed a meta-analysis to derive a more precise estimation of the relationship between TNF-a-238 G/A polymorphism and digestive system cancer risk. Pooled analysis for the TNF-a-238 G/A polymorphism contained 26 studies with a total of 4849 cases and 8567 controls. The meta-analysis observed a significant association between TNF-a-238 G/A polymorphism and digestive system cancer risk in the overall population (GA vs GG: OR 1.19, 95 % CI 1.00–1.40, Pheterpgeneity = 0.016; A vs G: OR 1.19, 95 % CI 1.03–1.39, Pheterpgeneity = 0.015; dominant model: OR 1.20, 95 % CI 1.02–1.41, Pheterpgeneity = 0.012). In the analysis of the ethnic subgroups, however, similar results were observed only in the Asian population, but not in the Caucasian population. Therefore, this meta-analysis suggests that TNF-a-238 G/A polymorphism is associated with a significantly increased risk of digestive system
& Ying Jiang [email protected] 1
Department of Gastroenterology, The Second Affiliated Hospital of Xinjiang Medical University, Urumchi 830011, China
2
Department of Emergency, Urumchi First People’s Hospital, Urumchi 830000, China
3
Department of Infectious Diseases, The Second Affiliated Hospital of Xinjiang Medical University, Urumchi 830011, China
4
Department of Infectious Diseases, The Second Affiliated Hospital of Xinjiang Medical University, No. 38, Lane 2, Nanhu East Road, Urumchi 830000, China
cancer. Further large and well-designed studies are needed to confirm these findings. Keywords Tumor necrosis factor-a Digestive system cancer Polymorphism Meta-analysis
Introduction Digestive system cancer, including esophageal, gastric, hepatocellular, colorectal and gallbladder cancer, which has a higher cancer-related mortality compared to any other system in the body [1], has become a major public health issue worldwide. Various etiological factors of carcinogenesis include hereditary mutations and susceptibility polymorphisms, inflammation due to infectious agents, environmental and dietary factors. Hereditary and genetic abnormalities usually influence the risk of digestive carcinomas slightly or moderately [2–4]. Epidemiological studies have revealed that chronic inflammation predisposes individuals to cancer [5, 6]. Moreover, inflammation has been linked to the pathogenesis of tumors in up to 15 % of human cancers [7]. Cytokines are important inflammatory mediators, which act as part of the regulatory network to directly or indirectly activate downstream signaling pathways in the development of malignancies [8, 9]. There has been evidence that human predisposition to cancer could be influenced by single-nucleotide polymorphisms (SNPs) located in genes encoding cytokines and their receptors, mostly in promoter regions [10]. TNF-a gene is located on chromosome 6p21.231 in the polymorphic region of MHC III, and its promoter polymorphisms have been intensively studied as a potential determinant of disease susceptibility [11]. There is also an
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Clin Exp Med Fig. 1 Flow diagram of studies identification
increasing evidence that TNF-a may promote the development and spread of cancer [12]. There are several polymorphisms in the TNF-a gene which change the transcription of TNF-a and regulate the TNF-a production, and one of them is TNF-a-238 G/A polymorphism (rs361525) [13]. So far, TNF-a promoter polymorphism has been related to numerous cancers, such as cervical cancer [14], renal cell carcinoma [15], bladder cancer [16], breast carcinoma [17] and non-small cell lung carcinoma [18]. Recent evidence has suggested that TNF-a-238 G/A gene polymorphism may be associated with increased digestive cancer risk [19–21]; however, individually published results are inconclusive [22, 23]. Therefore, we attempt to perform a meta-analysis of all eligible case– control studies to provide insights into these associations, which may promote our understanding of the exact role of the TNF-a-238 G/A gene polymorphism in the development of carcinogenesis in the digestive organs.
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Materials and methods Search strategy We extracted eligible case–control studies by searching databases and manual search of references of relative reviews and articles. To identify all the studies that examined the association of tumor necrosis factor-a-238 polymorphism and cancer risk, we conducted a computerized literature search of Embase, PubMed and China National Knowledge Infrastructure (CNKI). The combination of the following key words were used as search terms: ‘‘tumor necrosis factor-a-238’’ or ‘‘TNF-a 238’’; ‘‘Cancer,’’ ‘‘carcinoma’’ or ‘‘tumor’’; ‘‘polymorphism’’ or ‘‘variation.’’ There was no limitation of research, and the last research was carried out on Sep 25, 2014. To explore potentially additional studies, we also examined the references of articles and reviews.
Clin Exp Med Table 1 Characteristics of studies included in this meta-analysis Author
Year
Country
Ethnicity
Cancer type
Genotyping methods
Sample size (case/control)
Case GG
Control GA
AA
GG
PHWE
GA
AA
Jang-a
2001
Korea
Asian
Gastric
PCR-RFLP
52/92
46
4
2
85
7
0
0.704
Jang-b
2001
Korea
Asian
Colorectal
PCR-RFLP
27/92
24
3
0
85
7
0
0.704
Heneghan
2003
China
Asian
Liver
PCR-RFLP
98/172
96
2
0
168
4
0
0.877
Wang
2003
Japan
Asian
Liver
Sequencing
125/204
111
13
1
178
24
2
0.255
Wu
2003
China
Asian
Gastric
Sequencing
220/230
176
31
13
185
29
16
\0.001
Lee
2004
Korea
Asian
Gastric
Sequencing
341/261
297
43
1
218
42
1
0.493
Lu Niro
2005 2005
China Italy
Asian Caucasian
Gastric Liver
DHPLC Sequencing
250/300 30/96
214 26
36 4
0 0
274 88
24 8
2 0
0.081 0.670
Zambon
2005
Italy
Caucasian
Gastric
Taqman
129/644
95
31
3
496
138
10
0.910
Kamangar
2006
Finland
Caucasian
Gastric
Taqman
112/208
86
23
3
154
52
2
0.292
Xing
2006
China
Asian
Gastric
Gene chip
130/142
84
46
0
116
26
0
0.230
GarciaGonzalez
2007
Spain
Caucasian
Gastric
Taqman
404/404
309
84
11
320
77
7
0.350
Hou
2007
Spain
Caucasian
Gastric
Taqman
305/427
186
98
21
304
109
15
0.187
Huang
2007
China
Asian
Liver
PCR-RFLP
100/150
88
12
0
143
7
0
0.770
Jeng
2007
China
Asian
Liver
Sequencing
108/108
102
6
0
106
2
0
0.923
Kummee
2007
Thailand
Asian
Liver
PCR-RFLP
50/250
44
5
1
236
14
0
0.649
Crusius
2008
Netherlands
Caucasian
Gastric
Sequencing
235/1123
218
16
1
1004
114
5
0.367
Garrity-Park Madani
2008 2008
USA Iran
Caucasian Caucasian
Colorectal Colorectal
Sequencing PCR-RFLP
114/114 51/46
109 51
5 0
0 0
107 45
6 1
1 0
0.017 0.941
Wang
2008
China
Asian
Colorectal
Taqman
343/670
320
22
1
620
50
0
0.316
Jeng
2009
Korea
Asian
Liver
Sequencing
200/200
194
6
0
198
2
0
0.943
Jung
2009
Korea
Asian
Liver
Pyrosequencing
227/365
193
34
0
336
28
1
0.610
Yang
2009
Korea
Asian
Gastric
SNaPshot
83/331
73
10
0
305
26
0
0.457
Wang
2010
China
Asian
Liver
Sequencing
230/513
209
20
1
455
57
1
0.571
Whiteman
2010
Australia
Caucasian
Esophageal
Gene chip
759/1299
674
81
4
1165
125
9
0.007
Chen
2011
China
Asian
Liver
Sequencing
126/126
120
6
0
115
11
0
0.608
PCR-RFLP polymerase chain reaction–restriction fragment length polymorphism, HWE Hardy–Weinberg equilibrium
Selection criteria Studies were selected according to the following inclusion criteria: (1) case–control studies which evaluated the association between TNF-a-238 polymorphism and digestive system cancer; (2) genotype and allele data available; and (3) the control population did not contain malignant tumor patients. Studies were excluded if one of the following existed: (1) no control population; (2) duplicate of previous publication; and (3) data unavailable for calculating genotype or allele frequencies.
Fig. 2 Frequencies of the TNF-a-238 A allele among control subjects stratified by ethnicity
Data extraction All the available data were extracted from each study by two investigators independently according to the inclusion criteria listed above. For each study, we recorded the first
author, year of publication, country of origin, ethnicity, cancer type, the method of genotyping, the number of cases and controls and genotype distributions in cases and controls.
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Clin Exp Med Table 2 Quantitative analyses of the TNF-a-238 polymorphism on digestive system cancer risk Variables
Na
GA versus GG OR (95 % CI)
Total
A versus G 2
AA/GA versus GG (dominant) 2
P (Z)
P (Q)
I (%)
OR (95 % CI)
P (Z)
P (Q)
I (%)
OR (95 % CI)
P (Z)
P (Q)
I2 (%)
26
1.19(1.00–1.40)
0.046
0.016
41.2
1.19 (1.03–1.39)
0.022
0.015
41.5
1.20 (1.02–1.41)
0.030
0.012
42.5
9 17
1.10(0.92–1.31) 1.31(1.01–1.70)
0.301 0.045
0.309 0.010
15 50
1.12 (0.94–1.35) 1.30 (1.03–1.64)
0.211 0.030
0.155 0.015
32.8 47.7
1.11 (0.92–1.35) 1.32 (1.02–1.70)
0.272 0.034
0.196 0.011
27.9 49.6
Ethnicities Caucasian Asian Cancer type Gastric
11
1.19 (0.94–1.50)
0.152
0.013
55.4
1.20 (0.98–1.46)
0.072
0.016
54.3
1.21 (0.98–1.51)
0.101
0.011
56.2
Liver
10
1.37 (0.91–2.06)
0.134
0.053
46.2
1.39 (0.94–2.05)
0.097
0.055
45.8
1.39 (0.93–2.09)
0.112
0.051
46.6
Colorectal
4
0.88 (0.56–1.38)
0.574
0.793
0
0.90 (0.59–1.38)
0.639
0.703
0
0.89 (0.57–1.38)
0.599
0.765
0
Esophageal
1
1.12 (0.83–1.50)
0.452
–
1.07 (0.81–1.40)
0.630
–
–
1.10 (0.82–1.46)
0.531
–
–
Yes
23
1.21 (0.99–1.48)
0.059
0.006
47.6
1.24 (1.04–1.48)
0.014
0.013
44.1
1.24 (1.02–1.51)
0.028
0.007
47.3
No
3
1.11 (0.86–1.43)
0.439
0.884
0
1.02 (0.82–1.27)
0.882
0.629
0
1.06 (0.83–1.34)
0.645
0.763
0
HWE
P(Z) Z test used to determine the significance of the overall OR; P(Q) Cochran’ s Chi-square Q statistic test used to assess the heterogeneity in subgroups
Statistical analysis Hardy–Weinberg equilibrium was examined by Chi-square goodness-of-fit test (P [ 0.05) using gene frequencies of the healthy individuals. The heterogeneity of the studies was assessed using the Cochran’s Q test (considered significant for P \ 0.10) and was quantified by the I2 statistic. Both fixed-effects (the Mantel–Haenszel method, which weights the studies by the inverse of the variance of estimates) and random-effects (the Der Simonian and Laird method, which weights the studies by the inverse of the sum of the individual sampling variance and the between studies variance) models were used to combine the data. Relative influence of each study on the pooled estimate was assessed by omitting one study at a time for sensitivity analysis. Publication bias was evaluated by visual inspection of symmetry of Begg’s funnel plot and assessment of Egger’s test (P \ 0.05 was regarded as representative of statistical significance). Statistical analyses were done in STATA software, version 12.0 (STATA Corp., College Station, TX, USA), and all tests were two-sided.
Results Characteristics of the studies There were 239 papers relevant to the search words. The flowchart of selection of studies and reasons for exclusion is presented in Fig. 1. Of those, 37 records excluded after duplicates removed and 202 articles were judged
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potentially relevant. Following abstracts screened for relevance, 40 full-text articles comprehensively assessed against inclusion criteria. Finally, 25 articles were included in the final meta-analysis. There were 26 studies with 4849 cases and 8567 controls for the TNF-a-238 polymorphism. There were 9 studies conducted in Caucasians and 17 studies in Asians. Study characteristics are summarized in Table 1. The genotype distributions in the controls of all studies were consistent with HWE except for three studies [24–26]. Quantitative synthesis There was a variation in the A allele frequency of the TNFa-238 G/A polymorphism among the controls across different ethnicities, ranging from 0.005 to 0.162. For Caucasian controls, the A allele frequency was 0.081, which was slightly higher than that in Asian controls (0.047, P = 0.05; Fig. 2). Overall, there was a significant difference in the TNF-a-238 G/A genotype distribution between the digestive system cancer patients and the controls (GA vs GG: OR 1.19, 95 % CI 1.00–1.40, Pheterpgeneity = 0.016; A vs G: OR 1.19, 95 % CI 1.03–1.39, Pheterpgeneity = 0.015; dominant model: OR 1.20, 95 % CI 1.02–1.41, Pheterpgeneity = 0.012) (Table 2, Fig. 3). In the analysis of the ethnic subgroups, similar results were observed in the Asian population (GA vs GG: OR 1.31, 95 % CI 1.01–1.70, Pheterpgeneity = 0.010; A vs G: OR 1.30, 95 % CI 1.03–1.64, Pheterpgeneity = 0.015; dominant model: OR 1.32, 95 % CI 1.02–-1.70, Pheterpgeneity = 0.011), but not in the Caucasian population (Table 2; Fig. 4). When stratified
Clin Exp Med
Fig. 3 Odds ratios (OR) and 95 % confidence interval (CI) of individual studies and pooled data for the association of the TNF-a-238 G/A polymorphism and digestive system cancer risk in dominant model
by cancer type, however, no significant association was observed among the single cancer type (Table 2). Furthermore, when the three studies deviation from HWE were excluded, we found that there was significant association between the TNF-a-238 polymorphism and the risk of digestive system cancers in the allele model and dominant comparisons (A vs G: OR 1.24, 95 % CI 1.04–1.48, Pheterpgeneity = 0.013; dominant model: OR 1.24, 95 % CI 1.02–1.51, Pheterpgeneity = 0.007) (Table 2).
Publication bias Begg’s funnel plot and Egger’s test were performed to assess publication bias among the literature. There was no evidence of publication bias for TNF-a-238 in GA versus GG (Begg’s test P = 0.597; Egger’s test P = 0.707), in A versus G (Begg’s test P = 0.659; Egger’s test P = 0.671) and in AA/GA versus GG (Begg’s test P = 0.692; Egger’s test P = 0.663) (Fig. 6).
Sensitivity analysis
Discussion Sensitivity analyses were performed to assess the influence of individual dataset on the pooled ORs by sequentially removing each eligible study. Any single study was omitted, while the overall statistical significance does not change, indicating that our results are statistically robust (Fig. 5).
Tumor necrosis factor-a (TNF-a) is the most important proinflammatory cytokine involved in the growth, differentiation, cellular function and survival of many cells. It is produced by diverse kinds of cells, such as macrophages, neutrophils, fibroblasts, keratinocytes, NK cells, T and B
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Clin Exp Med
Fig. 4 Forest plot of the odds ratio (OR) and 95 % confidence intervals (CIs) of studies on the association between digestive system cancer and the TNF-a-238 G/A polymorphism stratified by ethnicity in dominant model
cells, and tumor cells [27]. As inflammation has been assumed as a key factor involving in the pathogenesis of cancer, TNF-a, the most crucial inflammatory cytokine, has been implicated in both the development and progression through pathways of ‘‘the nuclear factor-kappa B (NF-kB) and the activator protein 1 (AP-1) transcription factor complexes activation’’ in experimental and human cancer studies [22, 28]. Because A allele of TNF-a at 238 in the promoter region was found to down-regulate gene expression [29, 30], studies on the relationship between this variant and cancers have been extensively investigated during recent decades [19–26, 31–33]. To our knowledge, the current meta-analysis is the largest one to investigate the association between TNF-a-238 G/A polymorphism and digestive system cancer risk. Pooled analysis for the TNF-a-238 G/A polymorphism contained 26 studies with a total of 4849 cases and 8567
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controls. The meta-analysis observed a significant association between TNF-a-238 G/A polymorphism and digestive system cancer risk in the overall population (GA vs GG: OR 1.19, 95 % CI 1.00–1.40, Pheterpgeneity = 0.016; A vs G: OR 1.19, 95 % CI 1.03–1.39, Pheterpgeneity = 0.015; dominant model: OR 1.20, 95 % CI 1.02–1.41, Pheterpgeneity = 0.012). In the analysis of the ethnic subgroups, however, similar results were observed only in the Asian population, but not in the Caucasian population. Recently, Yu et al. [34] conducted a comprehensive metaanalysis about TNF-a-238 G/A polymorphism and gastric cancer susceptibility and found that the statistically significant association between TNF-a-238 G/A polymorphism and gastric cancer was limited to Asian populations, consistent with the results of this meta-analysis. Heterogeneity is a potential problem when interpreting the results of meta-analyses. In this meta-analysis,
Clin Exp Med Fig. 5 Sensitivity analysis: examining the influence of individual studies to pooled odds ratios (OR) for TNF-a-238 G/A polymorphism in dominant model
Fig. 6 Begg’s funnel plot for publication bias test. Each point represents a separate study for the indicated association for dominant model of TNF-a-238 G/A polymorphism
heterogeneity was found in the overall and subgroup analyses; thus, the random-effects model was used. Sensitivity analyses were also conducted by sequentially removing each eligible study. With this exclusion, the estimated pooled OR did not change significantly, strengthening our confidence in our results. Furthermore, this study suggests that the population selection and the study that was not in HWE were not sources of heterogeneity. Alternatively, lifestyle, environment and other unknown factors may be sources of heterogeneity. The current study has some inevitable limitations that should be acknowledged. First, only published studies were
included in this meta-analysis, which may have biased our results. Second, there was significant heterogeneity among included studies. Even though we used the random-effect model to calculate pooled ORs, the precision of outcome would be affected. Third, our results were based on an unadjusted estimate, and a more precise analysis would have been conducted if more detailed individual data were available. In summary, this meta-analysis demonstrates that the TNF-a-238 G/A polymorphism is associated with a significantly increased risk of digestive system cancer. Additionally, this increased risk of digestive cancer was only detected in Asians; there was no significant association in Caucasians. However, future well-designed large studies particularly stratified by gene–gene and gene–environment interactions might be necessary to clarify the possible role of the TNF-a-238 G/A polymorphism in the susceptibility to digestive system cancer. Conflict of interest
None.
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ORIGINAL ARTICLE
The tumor necrosis factor-a-238 polymorphism and digestive system cancer risk: a meta-analysis Ming Hui1 • Xiaojuan Yan2 • Ying Jiang3,4
Received: 11 March 2015 / Accepted: 26 May 2015 Ó Springer-Verlag Italia 2015
Abstract Many studies have reported the association between tumor necrosis factor-a (TNF-a)-238 polymorphism and digestive system cancer susceptibility, but the results were inconclusive. We performed a meta-analysis to derive a more precise estimation of the relationship between TNF-a-238 G/A polymorphism and digestive system cancer risk. Pooled analysis for the TNF-a-238 G/A polymorphism contained 26 studies with a total of 4849 cases and 8567 controls. The meta-analysis observed a significant association between TNF-a-238 G/A polymorphism and digestive system cancer risk in the overall population (GA vs GG: OR 1.19, 95 % CI 1.00–1.40, Pheterpgeneity = 0.016; A vs G: OR 1.19, 95 % CI 1.03–1.39, Pheterpgeneity = 0.015; dominant model: OR 1.20, 95 % CI 1.02–1.41, Pheterpgeneity = 0.012). In the analysis of the ethnic subgroups, however, similar results were observed only in the Asian population, but not in the Caucasian population. Therefore, this meta-analysis suggests that TNF-a-238 G/A polymorphism is associated with a significantly increased risk of digestive system
& Ying Jiang [email protected] 1
Department of Gastroenterology, The Second Affiliated Hospital of Xinjiang Medical University, Urumchi 830011, China
2
Department of Emergency, Urumchi First People’s Hospital, Urumchi 830000, China
3
Department of Infectious Diseases, The Second Affiliated Hospital of Xinjiang Medical University, Urumchi 830011, China
4
Department of Infectious Diseases, The Second Affiliated Hospital of Xinjiang Medical University, No. 38, Lane 2, Nanhu East Road, Urumchi 830000, China
cancer. Further large and well-designed studies are needed to confirm these findings. Keywords Tumor necrosis factor-a Digestive system cancer Polymorphism Meta-analysis
Introduction Digestive system cancer, including esophageal, gastric, hepatocellular, colorectal and gallbladder cancer, which has a higher cancer-related mortality compared to any other system in the body [1], has become a major public health issue worldwide. Various etiological factors of carcinogenesis include hereditary mutations and susceptibility polymorphisms, inflammation due to infectious agents, environmental and dietary factors. Hereditary and genetic abnormalities usually influence the risk of digestive carcinomas slightly or moderately [2–4]. Epidemiological studies have revealed that chronic inflammation predisposes individuals to cancer [5, 6]. Moreover, inflammation has been linked to the pathogenesis of tumors in up to 15 % of human cancers [7]. Cytokines are important inflammatory mediators, which act as part of the regulatory network to directly or indirectly activate downstream signaling pathways in the development of malignancies [8, 9]. There has been evidence that human predisposition to cancer could be influenced by single-nucleotide polymorphisms (SNPs) located in genes encoding cytokines and their receptors, mostly in promoter regions [10]. TNF-a gene is located on chromosome 6p21.231 in the polymorphic region of MHC III, and its promoter polymorphisms have been intensively studied as a potential determinant of disease susceptibility [11]. There is also an
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Clin Exp Med Fig. 1 Flow diagram of studies identification
increasing evidence that TNF-a may promote the development and spread of cancer [12]. There are several polymorphisms in the TNF-a gene which change the transcription of TNF-a and regulate the TNF-a production, and one of them is TNF-a-238 G/A polymorphism (rs361525) [13]. So far, TNF-a promoter polymorphism has been related to numerous cancers, such as cervical cancer [14], renal cell carcinoma [15], bladder cancer [16], breast carcinoma [17] and non-small cell lung carcinoma [18]. Recent evidence has suggested that TNF-a-238 G/A gene polymorphism may be associated with increased digestive cancer risk [19–21]; however, individually published results are inconclusive [22, 23]. Therefore, we attempt to perform a meta-analysis of all eligible case– control studies to provide insights into these associations, which may promote our understanding of the exact role of the TNF-a-238 G/A gene polymorphism in the development of carcinogenesis in the digestive organs.
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Materials and methods Search strategy We extracted eligible case–control studies by searching databases and manual search of references of relative reviews and articles. To identify all the studies that examined the association of tumor necrosis factor-a-238 polymorphism and cancer risk, we conducted a computerized literature search of Embase, PubMed and China National Knowledge Infrastructure (CNKI). The combination of the following key words were used as search terms: ‘‘tumor necrosis factor-a-238’’ or ‘‘TNF-a 238’’; ‘‘Cancer,’’ ‘‘carcinoma’’ or ‘‘tumor’’; ‘‘polymorphism’’ or ‘‘variation.’’ There was no limitation of research, and the last research was carried out on Sep 25, 2014. To explore potentially additional studies, we also examined the references of articles and reviews.
Clin Exp Med Table 1 Characteristics of studies included in this meta-analysis Author
Year
Country
Ethnicity
Cancer type
Genotyping methods
Sample size (case/control)
Case GG
Control GA
AA
GG
PHWE
GA
AA
Jang-a
2001
Korea
Asian
Gastric
PCR-RFLP
52/92
46
4
2
85
7
0
0.704
Jang-b
2001
Korea
Asian
Colorectal
PCR-RFLP
27/92
24
3
0
85
7
0
0.704
Heneghan
2003
China
Asian
Liver
PCR-RFLP
98/172
96
2
0
168
4
0
0.877
Wang
2003
Japan
Asian
Liver
Sequencing
125/204
111
13
1
178
24
2
0.255
Wu
2003
China
Asian
Gastric
Sequencing
220/230
176
31
13
185
29
16
\0.001
Lee
2004
Korea
Asian
Gastric
Sequencing
341/261
297
43
1
218
42
1
0.493
Lu Niro
2005 2005
China Italy
Asian Caucasian
Gastric Liver
DHPLC Sequencing
250/300 30/96
214 26
36 4
0 0
274 88
24 8
2 0
0.081 0.670
Zambon
2005
Italy
Caucasian
Gastric
Taqman
129/644
95
31
3
496
138
10
0.910
Kamangar
2006
Finland
Caucasian
Gastric
Taqman
112/208
86
23
3
154
52
2
0.292
2006
China
Asian
Gastric
Gene chip
130/142
84
46
0
116
26
0
0.230
GarciaGonzalez
2007
Spain
Caucasian
Gastric
Taqman
404/404
309
84
11
320
77
7
0.350
Hou
2007
Spain
Caucasian
Gastric
Taqman
305/427
186
98
21
304
109
15
0.187
Huang
2007
China
Asian
Liver
PCR-RFLP
100/150
88
12
0
143
7
0
0.770
Jeng
2007
China
Asian
Liver
Sequencing
108/108
102
6
0
106
2
0
0.923
Kummee
2007
Thailand
Asian
Liver
PCR-RFLP
50/250
44
5
1
236
14
0
0.649
Crusius
2008
Netherlands
Caucasian
Gastric
Sequencing
235/1123
218
16
1
1004
114
5
0.367
Garrity-Park Madani
2008 2008
USA Iran
Caucasian Caucasian
Colorectal Colorectal
Sequencing PCR-RFLP
114/114 51/46
109 51
5 0
0 0
107 45
6 1
1 0
0.017 0.941
Wang
2008
China
Asian
Colorectal
Taqman
343/670
320
22
1
620
50
0
0.316
Jeng
2009
Korea
Asian
Liver
Sequencing
200/200
194
6
0
198
2
0
0.943
Jung
2009
Korea
Asian
Liver
Pyrosequencing
227/365
193
34
0
336
28
1
0.610
Yang
2009
Korea
Asian
Gastric
SNaPshot
83/331
73
10
0
305
26
0
0.457
Wang
2010
China
Asian
Liver
Sequencing
230/513
209
20
1
455
57
1
0.571
Whiteman
2010
Australia
Caucasian
Esophageal
Gene chip
759/1299
674
81
4
1165
125
9
0.007
Chen
2011
China
Asian
Liver
Sequencing
126/126
120
6
0
115
11
0
0.608
PCR-RFLP polymerase chain reaction–restriction fragment length polymorphism, HWE Hardy–Weinberg equilibrium
Selection criteria Studies were selected according to the following inclusion criteria: (1) case–control studies which evaluated the association between TNF-a-238 polymorphism and digestive system cancer; (2) genotype and allele data available; and (3) the control population did not contain malignant tumor patients. Studies were excluded if one of the following existed: (1) no control population; (2) duplicate of previous publication; and (3) data unavailable for calculating genotype or allele frequencies.
Fig. 2 Frequencies of the TNF-a-238 A allele among control subjects stratified by ethnicity
Data extraction All the available data were extracted from each study by two investigators independently according to the inclusion criteria listed above. For each study, we recorded the first
author, year of publication, country of origin, ethnicity, cancer type, the method of genotyping, the number of cases and controls and genotype distributions in cases and controls.
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Clin Exp Med Table 2 Quantitative analyses of the TNF-a-238 polymorphism on digestive system cancer risk Variables
Na
GA versus GG OR (95 % CI)
Total
A versus G 2
AA/GA versus GG (dominant) 2
P (Z)
P (Q)
I (%)
OR (95 % CI)
P (Z)
P (Q)
I (%)
OR (95 % CI)
P (Z)
P (Q)
I2 (%)
26
1.19(1.00–1.40)
0.046
0.016
41.2
1.19 (1.03–1.39)
0.022
0.015
41.5
1.20 (1.02–1.41)
0.030
0.012
42.5
9 17
1.10(0.92–1.31) 1.31(1.01–1.70)
0.301 0.045
0.309 0.010
15 50
1.12 (0.94–1.35) 1.30 (1.03–1.64)
0.211 0.030
0.155 0.015
32.8 47.7
1.11 (0.92–1.35) 1.32 (1.02–1.70)
0.272 0.034
0.196 0.011
27.9 49.6
Ethnicities Caucasian Asian Cancer type Gastric
11
1.19 (0.94–1.50)
0.152
0.013
55.4
1.20 (0.98–1.46)
0.072
0.016
54.3
1.21 (0.98–1.51)
0.101
0.011
56.2
Liver
10
1.37 (0.91–2.06)
0.134
0.053
46.2
1.39 (0.94–2.05)
0.097
0.055
45.8
1.39 (0.93–2.09)
0.112
0.051
46.6
Colorectal
4
0.88 (0.56–1.38)
0.574
0.793
0
0.90 (0.59–1.38)
0.639
0.703
0
0.89 (0.57–1.38)
0.599
0.765
0
Esophageal
1
1.12 (0.83–1.50)
0.452
–
1.07 (0.81–1.40)
0.630
–
–
1.10 (0.82–1.46)
0.531
–
–
Yes
23
1.21 (0.99–1.48)
0.059
0.006
47.6
1.24 (1.04–1.48)
0.014
0.013
44.1
1.24 (1.02–1.51)
0.028
0.007
47.3
No
3
1.11 (0.86–1.43)
0.439
0.884
0
1.02 (0.82–1.27)
0.882
0.629
0
1.06 (0.83–1.34)
0.645
0.763
0
HWE
P(Z) Z test used to determine the significance of the overall OR; P(Q) Cochran’ s Chi-square Q statistic test used to assess the heterogeneity in subgroups
Statistical analysis Hardy–Weinberg equilibrium was examined by Chi-square goodness-of-fit test (P [ 0.05) using gene frequencies of the healthy individuals. The heterogeneity of the studies was assessed using the Cochran’s Q test (considered significant for P \ 0.10) and was quantified by the I2 statistic. Both fixed-effects (the Mantel–Haenszel method, which weights the studies by the inverse of the variance of estimates) and random-effects (the Der Simonian and Laird method, which weights the studies by the inverse of the sum of the individual sampling variance and the between studies variance) models were used to combine the data. Relative influence of each study on the pooled estimate was assessed by omitting one study at a time for sensitivity analysis. Publication bias was evaluated by visual inspection of symmetry of Begg’s funnel plot and assessment of Egger’s test (P \ 0.05 was regarded as representative of statistical significance). Statistical analyses were done in STATA software, version 12.0 (STATA Corp., College Station, TX, USA), and all tests were two-sided.
Results Characteristics of the studies There were 239 papers relevant to the search words. The flowchart of selection of studies and reasons for exclusion is presented in Fig. 1. Of those, 37 records excluded after duplicates removed and 202 articles were judged
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potentially relevant. Following abstracts screened for relevance, 40 full-text articles comprehensively assessed against inclusion criteria. Finally, 25 articles were included in the final meta-analysis. There were 26 studies with 4849 cases and 8567 controls for the TNF-a-238 polymorphism. There were 9 studies conducted in Caucasians and 17 studies in Asians. Study characteristics are summarized in Table 1. The genotype distributions in the controls of all studies were consistent with HWE except for three studies [24–26]. Quantitative synthesis There was a variation in the A allele frequency of the TNFa-238 G/A polymorphism among the controls across different ethnicities, ranging from 0.005 to 0.162. For Caucasian controls, the A allele frequency was 0.081, which was slightly higher than that in Asian controls (0.047, P = 0.05; Fig. 2). Overall, there was a significant difference in the TNF-a-238 G/A genotype distribution between the digestive system cancer patients and the controls (GA vs GG: OR 1.19, 95 % CI 1.00–1.40, Pheterpgeneity = 0.016; A vs G: OR 1.19, 95 % CI 1.03–1.39, Pheterpgeneity = 0.015; dominant model: OR 1.20, 95 % CI 1.02–1.41, Pheterpgeneity = 0.012) (Table 2, Fig. 3). In the analysis of the ethnic subgroups, similar results were observed in the Asian population (GA vs GG: OR 1.31, 95 % CI 1.01–1.70, Pheterpgeneity = 0.010; A vs G: OR 1.30, 95 % CI 1.03–1.64, Pheterpgeneity = 0.015; dominant model: OR 1.32, 95 % CI 1.02–-1.70, Pheterpgeneity = 0.011), but not in the Caucasian population (Table 2; Fig. 4). When stratified
Clin Exp Med
Fig. 3 Odds ratios (OR) and 95 % confidence interval (CI) of individual studies and pooled data for the association of the TNF-a-238 G/A polymorphism and digestive system cancer risk in dominant model
by cancer type, however, no significant association was observed among the single cancer type (Table 2). Furthermore, when the three studies deviation from HWE were excluded, we found that there was significant association between the TNF-a-238 polymorphism and the risk of digestive system cancers in the allele model and dominant comparisons (A vs G: OR 1.24, 95 % CI 1.04–1.48, Pheterpgeneity = 0.013; dominant model: OR 1.24, 95 % CI 1.02–1.51, Pheterpgeneity = 0.007) (Table 2).
Publication bias Begg’s funnel plot and Egger’s test were performed to assess publication bias among the literature. There was no evidence of publication bias for TNF-a-238 in GA versus GG (Begg’s test P = 0.597; Egger’s test P = 0.707), in A versus G (Begg’s test P = 0.659; Egger’s test P = 0.671) and in AA/GA versus GG (Begg’s test P = 0.692; Egger’s test P = 0.663) (Fig. 6).
Sensitivity analysis
Discussion Sensitivity analyses were performed to assess the influence of individual dataset on the pooled ORs by sequentially removing each eligible study. Any single study was omitted, while the overall statistical significance does not change, indicating that our results are statistically robust (Fig. 5).
Tumor necrosis factor-a (TNF-a) is the most important proinflammatory cytokine involved in the growth, differentiation, cellular function and survival of many cells. It is produced by diverse kinds of cells, such as macrophages, neutrophils, fibroblasts, keratinocytes, NK cells, T and B
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Clin Exp Med
Fig. 4 Forest plot of the odds ratio (OR) and 95 % confidence intervals (CIs) of studies on the association between digestive system cancer and the TNF-a-238 G/A polymorphism stratified by ethnicity in dominant model
cells, and tumor cells [27]. As inflammation has been assumed as a key factor involving in the pathogenesis of cancer, TNF-a, the most crucial inflammatory cytokine, has been implicated in both the development and progression through pathways of ‘‘the nuclear factor-kappa B (NF-kB) and the activator protein 1 (AP-1) transcription factor complexes activation’’ in experimental and human cancer studies [22, 28]. Because A allele of TNF-a at 238 in the promoter region was found to down-regulate gene expression [29, 30], studies on the relationship between this variant and cancers have been extensively investigated during recent decades [19–26, 31–33]. To our knowledge, the current meta-analysis is the largest one to investigate the association between TNF-a-238 G/A polymorphism and digestive system cancer risk. Pooled analysis for the TNF-a-238 G/A polymorphism contained 26 studies with a total of 4849 cases and 8567
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controls. The meta-analysis observed a significant association between TNF-a-238 G/A polymorphism and digestive system cancer risk in the overall population (GA vs GG: OR 1.19, 95 % CI 1.00–1.40, Pheterpgeneity = 0.016; A vs G: OR 1.19, 95 % CI 1.03–1.39, Pheterpgeneity = 0.015; dominant model: OR 1.20, 95 % CI 1.02–1.41, Pheterpgeneity = 0.012). In the analysis of the ethnic subgroups, however, similar results were observed only in the Asian population, but not in the Caucasian population. Recently, Yu et al. [34] conducted a comprehensive metaanalysis about TNF-a-238 G/A polymorphism and gastric cancer susceptibility and found that the statistically significant association between TNF-a-238 G/A polymorphism and gastric cancer was limited to Asian populations, consistent with the results of this meta-analysis. Heterogeneity is a potential problem when interpreting the results of meta-analyses. In this meta-analysis,
Clin Exp Med Fig. 5 Sensitivity analysis: examining the influence of individual studies to pooled odds ratios (OR) for TNF-a-238 G/A polymorphism in dominant model
Fig. 6 Begg’s funnel plot for publication bias test. Each point represents a separate study for the indicated association for dominant model of TNF-a-238 G/A polymorphism
heterogeneity was found in the overall and subgroup analyses; thus, the random-effects model was used. Sensitivity analyses were also conducted by sequentially removing each eligible study. With this exclusion, the estimated pooled OR did not change significantly, strengthening our confidence in our results. Furthermore, this study suggests that the population selection and the study that was not in HWE were not sources of heterogeneity. Alternatively, lifestyle, environment and other unknown factors may be sources of heterogeneity. The current study has some inevitable limitations that should be acknowledged. First, only published studies were
included in this meta-analysis, which may have biased our results. Second, there was significant heterogeneity among included studies. Even though we used the random-effect model to calculate pooled ORs, the precision of outcome would be affected. Third, our results were based on an unadjusted estimate, and a more precise analysis would have been conducted if more detailed individual data were available. In summary, this meta-analysis demonstrates that the TNF-a-238 G/A polymorphism is associated with a significantly increased risk of digestive system cancer. Additionally, this increased risk of digestive cancer was only detected in Asians; there was no significant association in Caucasians. However, future well-designed large studies particularly stratified by gene–gene and gene–environment interactions might be necessary to clarify the possible role of the TNF-a-238 G/A polymorphism in the susceptibility to digestive system cancer. Conflict of interest
None.
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