Tumor Biol. (2014) 35:9693–9699 DOI 10.1007/s13277-014-2265-6
RESEARCH ARTICLE
Association between TNF-α gene 308G>A polymorphism and lung cancer risk: a meta-analysis Haojun Xie & Hongmei Yao & Yating Huo & Ning Li & Yuanxiong Cheng
Received: 21 May 2014 / Accepted: 19 June 2014 / Published online: 27 June 2014 # International Society of Oncology and BioMarkers (ISOBM) 2014
Abstract Many studies have investigated the association between tumor necrosis factor alpha (TNF-α) gene 308G/A polymorphism and lung cancer risk, but the results were inconsistent. We thus comprehensively searched the PubMed, EMBASE, and BIOSIS Previews databases and extracted data from all eligible articles to estimate the association between TNF-α gene 308G/A polymorphism and lung cancer risk. The pooled odds ratio (OR) with 95 % confidence intervals (CIs) were calculated. Twelve case–control studies in 11 articles involving 2,436 cases and 2,573 controls were included in the meta-analysis to assess the association between TNF-α gene 308G>A polymorphism and susceptibility to lung cancer. Overall, TNF-α gene 308G>A polymorphism was significantly associated with an increased risk of lung cancer for A vs. G (OR=1.13, 95 % CI 1.00~1.27, P=0.04). Subgroup analysis by ethnicity showed that there was a significant association between TNF-α gene 308G>A polymorphism and increased risk of lung cancer in Asians, but not in Caucasians. In subgroup analysis by tumor type, there were significant associations between TNF-α gene 308G>A polymorphism and increased risk of lung cancer in small cell lung cancer (SCLC) for AA+AG vs. GG, in non-small cell lung Haojun Xie and Hongmei Yao equally contributed to the study and should be considered as first authors. H. Xie : Y. Huo : Y. Cheng (*) Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou, Guangdong, China e-mail: [email protected] H. Yao Department of Respiratory Medicine, Guizhou Provincial People’s Hospital, Guiyang, China N. Li Department of Respiratory and Critical Care Medicine, Shantou Central Hospital, Guangdong, China
cancer (NSCLC) for A vs. G, AA vs. GG, and AA+AG vs. GG. No association between the genotypes and different stages of lung cancer was detected. The meta-analysis suggests that TNF-α gene 308G>A polymorphism is associated with an increased risk of lung cancer, particularly among Asians, both for SCLC and NSCLC, considering tumor type. Keywords TNF-α . Lung cancer . Polymorphism . Meta-analysis
Introduction Lung cancer is one of the most prevalent cancers worldwide [1, 2] and the leading cause of cancer-related mortality [1, 3]. The well-known risk factor for lung cancer is an excessive exposure to tobacco smoke, and the risk of lung cancer development is 20–40 times higher in lifelong smokers compared to non-smokers [4]. However, only a minority of heavy smokers will ultimately develop into cancer during their lifetime. Nonsmoking relatives of lung cancer cases were also at higher risk when compared with non-smoking relatives of controls [5]. In addition, the familial aggregation of lung cancer has been described in numerous studies [5–7]. All stated above implies that genetic factors may play a pivotal role in the pathogenesis of lung cancer. Inflammation has been implicated in the evolution of cancer [8]. Studies show that there are differences between lung cancers and controls in circulating cytokine expression [9–11]. Tumor necrosis factor alpha (TNF-α) is an important inducer of the inflammatory response [12]. In addition to inducing the death of cancer cells, TNF-α can activate cancer cell survival and proliferation pathways and can promote angiogenesis and tumor cell migration and invasion [13]. Several polymorphisms in the TNF-α gene promoter have been reported, including single nucleotide
9694
Tumor Biol. (2014) 35:9693–9699
Fig. 1 Flow diagram for inclusion of studies in meta-analysis. The initial search identified 427 articles, of which 12 studies in 11 articles were included in the final analysis
polymorphisms at loci −238, –308, and –857. It has been observed that TNF-α −308G>A polymorphism may influence the risk of breast cancer, gastric cancer, and hepatocellular cancer [14–16]. To date, many epidemiologic studies have been conducted to clarify the role of TNF-α −308G>A polymorphism in the development of lung cancer [17–27] but yielded controversial results, which is possibly due to the small sample size. Furthermore, two meta-analyses that incorporated data in several case–control studies have shown no significant association between this polymorphism and the risk of lung cancer [28, 29]. Therefore, we present herein the results of a comprehensively updated meta-analysis of all relevant published data to
investigate the association between TNF-α −308G/A polymorphisms and lung cancer risk.
Materials and methods Publication search Two investigators (H.X. and Y.H.) independently carried out a systematic search of the PubMed, EMBASE, and BIOSIS Previews databases for articles published until 1 April 2014 to identify potentially relevant articles. The
Table 1 Characteristics of the case-control studies included in meta-analysis First author
Year
Country
Ethnicity
Cases Controls Gender/male Age (years) Genotyping (n) (n) Median/range method
HWE (P value/ control group)
Colakogullari [17] Flego [18] Flego [19] Helmig [20]
2008 2009 2013 2010
Turkey Croatia Croatia Germany
Caucasian Caucasian Caucasian Caucasian
44 230 201 326
59 230 230 177
40 144 NA NA
62 67 59.37±11.11 34–84
SSP-PCR PCR-RFLP PCR-RFLP Rapid capillary PCR
0.054 0.584 0.584 0.854
Huang [21] Kaabachi [22] Kim [23] Seifart [24]
2005 2013 2013 2005
China Tunisia Korea Germany
Asian African Asian Caucasian
65 133 616 107
65 174 611 242
53 121 483 104
PCR-RFLP PCR-RFLP SNP-IT™ assays PCR-RFLP
0.501 0.298 0.989 0.373
Shih [25]
2005 China
Asian
202
205
146
65±11 56.7±9.6 65.3±10.2 NSCLC 65.4 SCLC 63.3 64.6±8.1
PCR-RFLP
0.842
Stankovic [26] Van Dyke [27]a Van Dyke [27]b
2009 Serbia 2009 USA 2009 USA
Caucasian 70 African-Americans 94 Caucasian 354
99 102 375
57 0 0
58.7±7.5 58±9 61±9
PCR-RFLP GoldenGate GoldenGate
0.905 0.339 0.606
HWE Hardy–Weinberg equilibrium, NA not available, PCR polymerase chain reaction, RFLP restricted fragment length polymorphisms, SSP sequencespecific primer, SCLC small cell lung cancer, NSCLC non-small cell lung cancer a
African-Americans
b
Caucasian
Tumor Biol. (2014) 35:9693–9699
9695
Fig. 2 Odds ratios (ORs) for associations between TNF-α gene 308G>A polymorphism and lung cancer risk in overall studies. The sizes of the squares indicate the relative weight of each study. Bars 95 % confidence interval (CI)
search terms utilized in our study were as follows: TNF-α AND polymorphism AND lung cancer. No publication language restrictions were imposed. All the searched studies were retrieved, and we also checked their references for other relevant publications.
Inclusion and exclusion criteria The inclusion criteria of our study were as follows: (1) human studies evaluating associations between TNF-α 308G/A polymorphisms and lung cancer risk; (2) there were at least two comparison groups, for example, lung cancer vs. control groups; and (3) genotype distributions in comparison groups should be available for estimating an odds ratio (OR) with 95 % confidence interval (CI). Studies would be discarded if they met one of the following criteria: (1) not relevant to TNF-α 308G/A polymorphisms or lung cancer, (2) the design is based on family or sibling pairs, and (3) reviews or abstracts do not have useful information. If the same patient population was reported in several publications, we included the most complete study in our meta-analysis. If original genotype frequency data were not reported, we would send an email to the corresponding author for additional data. Studies were excluded from our meta-analysis if their authors did not provide us related data. Table 2 Genotype distribution considering tumor stage in TNF-α gene 308G>A polymorphism First author
Year
Tumor stage I+II (n) (GG/GA/AA) III+IV (n) (GG/GA/AA)
Flego [18] 2009 35/8/2 Kaabachi [22] 2013 5/4/1 Shih [25] 2005 41/10/0
134/44/7 70/45/8 146/5/0
Data extraction In the data collection process, two investigators (H.X. and H.Y.) independently examined full manuscripts of eligible studies and relevant data were extracted into predesigned data collection form. We verified accuracy of data by comparing collection forms from each investigator. Any disagreement was resolved by discussion, or the third author (Y.C.) would evaluate these articles. The following information was collected from each eligible study: first author’s name, year of publication, original country, ethnicity, sample size, genotyping method, age, and genotype numbers in cases and controls. Publication bias Publication bias of studies was assessed using funnel plot, and P0.10 for the Q test indicates a lack of heterogeneity among the studies, and then, the pooled OR estimate of each study was calculated by the fixed effects model. Otherwise, the random effects model was used. Statistical analyses were performed using the RevMan5.2 software (Nordic Cochrane Center, Copenhagen, Denmark) and the Stata 12.0 software (Stata Corporation, College
12
Overall
7
Caucasian
3
3
ADa
SQa
107/460
231/609
265/609
1,290/1,622
444/702
1,071/1,142
878/882
2,436/2,573
Case/ Control
1.39 [0.87, 2.21] (0.17)
1.02 [0.80, 1.29] (0.9) 1.24 [1.07, 1.43] (0.005) 1.22 [0.89, 1.67] (0.22) 1.17 [0.84, 1.61] (0.36)
1.70 [1.36, 2.14] (T polymorphism and cancer risk: a meta-analysis of 28 case-control studies. PLoS One. 2013;8: e56722. 33. Pennica D, Nedwin GE, Hayflick JS, Seeburg PH, Derynck R, Palladino MA, et al. Human tumour necrosis factor: precursor structure, expression and homology to lymphotoxin. Nature. 1984;312: 724–9. 34. Tracey KJ, Wei H, Manogue KR, Fong Y, Hesse DG, Nguyen HT, et al. Cachectin/tumor necrosis factor induces cachexia, anemia, and inflammation. J Exp Med. 1988;167:1211–27. 35. Wu Y, Antony S, Meitzler JL, Doroshow JH. Molecular mechanisms underlying chronic inflammation-associated cancers. Cancer Lett. 2014;345:164–73. 36. Kroeger KM, Carville KS, Abraham LJ. The -308 tumor necrosis factor-alpha promoter polymorphism effects transcription. Mol Immunol. 1997;34:391–9.
RESEARCH ARTICLE
Association between TNF-α gene 308G>A polymorphism and lung cancer risk: a meta-analysis Haojun Xie & Hongmei Yao & Yating Huo & Ning Li & Yuanxiong Cheng
Received: 21 May 2014 / Accepted: 19 June 2014 / Published online: 27 June 2014 # International Society of Oncology and BioMarkers (ISOBM) 2014
Abstract Many studies have investigated the association between tumor necrosis factor alpha (TNF-α) gene 308G/A polymorphism and lung cancer risk, but the results were inconsistent. We thus comprehensively searched the PubMed, EMBASE, and BIOSIS Previews databases and extracted data from all eligible articles to estimate the association between TNF-α gene 308G/A polymorphism and lung cancer risk. The pooled odds ratio (OR) with 95 % confidence intervals (CIs) were calculated. Twelve case–control studies in 11 articles involving 2,436 cases and 2,573 controls were included in the meta-analysis to assess the association between TNF-α gene 308G>A polymorphism and susceptibility to lung cancer. Overall, TNF-α gene 308G>A polymorphism was significantly associated with an increased risk of lung cancer for A vs. G (OR=1.13, 95 % CI 1.00~1.27, P=0.04). Subgroup analysis by ethnicity showed that there was a significant association between TNF-α gene 308G>A polymorphism and increased risk of lung cancer in Asians, but not in Caucasians. In subgroup analysis by tumor type, there were significant associations between TNF-α gene 308G>A polymorphism and increased risk of lung cancer in small cell lung cancer (SCLC) for AA+AG vs. GG, in non-small cell lung Haojun Xie and Hongmei Yao equally contributed to the study and should be considered as first authors. H. Xie : Y. Huo : Y. Cheng (*) Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou, Guangdong, China e-mail: [email protected] H. Yao Department of Respiratory Medicine, Guizhou Provincial People’s Hospital, Guiyang, China N. Li Department of Respiratory and Critical Care Medicine, Shantou Central Hospital, Guangdong, China
cancer (NSCLC) for A vs. G, AA vs. GG, and AA+AG vs. GG. No association between the genotypes and different stages of lung cancer was detected. The meta-analysis suggests that TNF-α gene 308G>A polymorphism is associated with an increased risk of lung cancer, particularly among Asians, both for SCLC and NSCLC, considering tumor type. Keywords TNF-α . Lung cancer . Polymorphism . Meta-analysis
Introduction Lung cancer is one of the most prevalent cancers worldwide [1, 2] and the leading cause of cancer-related mortality [1, 3]. The well-known risk factor for lung cancer is an excessive exposure to tobacco smoke, and the risk of lung cancer development is 20–40 times higher in lifelong smokers compared to non-smokers [4]. However, only a minority of heavy smokers will ultimately develop into cancer during their lifetime. Nonsmoking relatives of lung cancer cases were also at higher risk when compared with non-smoking relatives of controls [5]. In addition, the familial aggregation of lung cancer has been described in numerous studies [5–7]. All stated above implies that genetic factors may play a pivotal role in the pathogenesis of lung cancer. Inflammation has been implicated in the evolution of cancer [8]. Studies show that there are differences between lung cancers and controls in circulating cytokine expression [9–11]. Tumor necrosis factor alpha (TNF-α) is an important inducer of the inflammatory response [12]. In addition to inducing the death of cancer cells, TNF-α can activate cancer cell survival and proliferation pathways and can promote angiogenesis and tumor cell migration and invasion [13]. Several polymorphisms in the TNF-α gene promoter have been reported, including single nucleotide
9694
Tumor Biol. (2014) 35:9693–9699
Fig. 1 Flow diagram for inclusion of studies in meta-analysis. The initial search identified 427 articles, of which 12 studies in 11 articles were included in the final analysis
polymorphisms at loci −238, –308, and –857. It has been observed that TNF-α −308G>A polymorphism may influence the risk of breast cancer, gastric cancer, and hepatocellular cancer [14–16]. To date, many epidemiologic studies have been conducted to clarify the role of TNF-α −308G>A polymorphism in the development of lung cancer [17–27] but yielded controversial results, which is possibly due to the small sample size. Furthermore, two meta-analyses that incorporated data in several case–control studies have shown no significant association between this polymorphism and the risk of lung cancer [28, 29]. Therefore, we present herein the results of a comprehensively updated meta-analysis of all relevant published data to
investigate the association between TNF-α −308G/A polymorphisms and lung cancer risk.
Materials and methods Publication search Two investigators (H.X. and Y.H.) independently carried out a systematic search of the PubMed, EMBASE, and BIOSIS Previews databases for articles published until 1 April 2014 to identify potentially relevant articles. The
Table 1 Characteristics of the case-control studies included in meta-analysis First author
Year
Country
Ethnicity
Cases Controls Gender/male Age (years) Genotyping (n) (n) Median/range method
HWE (P value/ control group)
Colakogullari [17] Flego [18] Flego [19] Helmig [20]
2008 2009 2013 2010
Turkey Croatia Croatia Germany
Caucasian Caucasian Caucasian Caucasian
44 230 201 326
59 230 230 177
40 144 NA NA
62 67 59.37±11.11 34–84
SSP-PCR PCR-RFLP PCR-RFLP Rapid capillary PCR
0.054 0.584 0.584 0.854
Huang [21] Kaabachi [22] Kim [23] Seifart [24]
2005 2013 2013 2005
China Tunisia Korea Germany
Asian African Asian Caucasian
65 133 616 107
65 174 611 242
53 121 483 104
PCR-RFLP PCR-RFLP SNP-IT™ assays PCR-RFLP
0.501 0.298 0.989 0.373
Shih [25]
2005 China
Asian
202
205
146
65±11 56.7±9.6 65.3±10.2 NSCLC 65.4 SCLC 63.3 64.6±8.1
PCR-RFLP
0.842
Stankovic [26] Van Dyke [27]a Van Dyke [27]b
2009 Serbia 2009 USA 2009 USA
Caucasian 70 African-Americans 94 Caucasian 354
99 102 375
57 0 0
58.7±7.5 58±9 61±9
PCR-RFLP GoldenGate GoldenGate
0.905 0.339 0.606
HWE Hardy–Weinberg equilibrium, NA not available, PCR polymerase chain reaction, RFLP restricted fragment length polymorphisms, SSP sequencespecific primer, SCLC small cell lung cancer, NSCLC non-small cell lung cancer a
African-Americans
b
Caucasian
Tumor Biol. (2014) 35:9693–9699
9695
Fig. 2 Odds ratios (ORs) for associations between TNF-α gene 308G>A polymorphism and lung cancer risk in overall studies. The sizes of the squares indicate the relative weight of each study. Bars 95 % confidence interval (CI)
search terms utilized in our study were as follows: TNF-α AND polymorphism AND lung cancer. No publication language restrictions were imposed. All the searched studies were retrieved, and we also checked their references for other relevant publications.
Inclusion and exclusion criteria The inclusion criteria of our study were as follows: (1) human studies evaluating associations between TNF-α 308G/A polymorphisms and lung cancer risk; (2) there were at least two comparison groups, for example, lung cancer vs. control groups; and (3) genotype distributions in comparison groups should be available for estimating an odds ratio (OR) with 95 % confidence interval (CI). Studies would be discarded if they met one of the following criteria: (1) not relevant to TNF-α 308G/A polymorphisms or lung cancer, (2) the design is based on family or sibling pairs, and (3) reviews or abstracts do not have useful information. If the same patient population was reported in several publications, we included the most complete study in our meta-analysis. If original genotype frequency data were not reported, we would send an email to the corresponding author for additional data. Studies were excluded from our meta-analysis if their authors did not provide us related data. Table 2 Genotype distribution considering tumor stage in TNF-α gene 308G>A polymorphism First author
Year
Tumor stage I+II (n) (GG/GA/AA) III+IV (n) (GG/GA/AA)
Flego [18] 2009 35/8/2 Kaabachi [22] 2013 5/4/1 Shih [25] 2005 41/10/0
134/44/7 70/45/8 146/5/0
Data extraction In the data collection process, two investigators (H.X. and H.Y.) independently examined full manuscripts of eligible studies and relevant data were extracted into predesigned data collection form. We verified accuracy of data by comparing collection forms from each investigator. Any disagreement was resolved by discussion, or the third author (Y.C.) would evaluate these articles. The following information was collected from each eligible study: first author’s name, year of publication, original country, ethnicity, sample size, genotyping method, age, and genotype numbers in cases and controls. Publication bias Publication bias of studies was assessed using funnel plot, and P0.10 for the Q test indicates a lack of heterogeneity among the studies, and then, the pooled OR estimate of each study was calculated by the fixed effects model. Otherwise, the random effects model was used. Statistical analyses were performed using the RevMan5.2 software (Nordic Cochrane Center, Copenhagen, Denmark) and the Stata 12.0 software (Stata Corporation, College
12
Overall
7
Caucasian
3
3
ADa
SQa
107/460
231/609
265/609
1,290/1,622
444/702
1,071/1,142
878/882
2,436/2,573
Case/ Control
1.39 [0.87, 2.21] (0.17)
1.02 [0.80, 1.29] (0.9) 1.24 [1.07, 1.43] (0.005) 1.22 [0.89, 1.67] (0.22) 1.17 [0.84, 1.61] (0.36)
1.70 [1.36, 2.14] (T polymorphism and cancer risk: a meta-analysis of 28 case-control studies. PLoS One. 2013;8: e56722. 33. Pennica D, Nedwin GE, Hayflick JS, Seeburg PH, Derynck R, Palladino MA, et al. Human tumour necrosis factor: precursor structure, expression and homology to lymphotoxin. Nature. 1984;312: 724–9. 34. Tracey KJ, Wei H, Manogue KR, Fong Y, Hesse DG, Nguyen HT, et al. Cachectin/tumor necrosis factor induces cachexia, anemia, and inflammation. J Exp Med. 1988;167:1211–27. 35. Wu Y, Antony S, Meitzler JL, Doroshow JH. Molecular mechanisms underlying chronic inflammation-associated cancers. Cancer Lett. 2014;345:164–73. 36. Kroeger KM, Carville KS, Abraham LJ. The -308 tumor necrosis factor-alpha promoter polymorphism effects transcription. Mol Immunol. 1997;34:391–9.
