hepatocellular carcinoma ( hcc ) is the fifth most common cancer in men and the seventh in women ( 1 ) , accounting for 70% - 85% of primary liver cancers ( 2 ) . hepatitis b virus ( hbv ) and hepatitis c virus ( hcv ) infections are the main causes of hcc ; however , only a fraction of patients with these infections will develop hcc during their lifetimes . the prevalence of hcc is correlated with the incidence of hbv and hcv in regions with a high risk of these infections , such as asia and africa , where hbv and hcv are the primary cause of hcc . tumor necrosis factor- ( tnf- ) , which is associated with hcc susceptibility , is a multi - functional cytokine that helps to regulate different pathways involved in inflammation , immunity , apoptosis , anti - apoptosis , and tumorigenesis ( 3 ) . tnf- was first believed to be an anti - tumor cytokine , but emerging evidence does not confirm this role . new research has identified tnf- in a majority of cancers associated with inflammation , acting as a tumor - promoting factor . indeed , it plays two different roles associated with cancer : it can be an endogenous tumor - promoter , or it can act as a cancer - killer ( 4 ) along with activated macrophages , which are the major source of tnf- , monocytes , lymphoid cells , and mast cells . tnf- can also be produced by various tumor cells , including breast cancer , b - lymphoma , and colon carcinoma . considerable research has confirmed the role of tnf- in the promotion and progression of human cancers . it can cause activation of activator protein 1 ( ap-1 ) and nuclear factor - kappa b ( nf-b ) transcription factors through different pathways ( 5 ) . in some studies , tnf- expression was elevated in hcc patients ( 6 , 7 ) ; however , in other studies , a lower level of tnf- was reported in hcc patients compared to healthy controls ( 8 , 9 ) . the critical role of tnf- in hbv reactivation was also recently discussed by author ( 10 ) . many studies have been performed on the association between the frequency of susceptible tnf- promoter alleles and hcc development . the most - studied polymorphism of tnf- promoter positions in hcc development risk are -308 g / a , -238 g / a , -857 c / t , and -863 c / a . wilson et al . ( 11 ) identified a biallelic polymorphism in the tnf- promoter at position -308 ( tnf--308 ) , which was introduced as g to a transition polymorphism . the a allele in tnf--308 results in a higher constitutive and inducible level of tnf expression compared to the g allele ( 13 ) . all of these studies indicate the importance of tnf--308 polymorphisms in the risk of hcc development . a systematic literature search for all published articles related to hcc and tnf--308 polymorphisms was conducted using the databases of pubmed , scopus , and google scholar . the last search update was on july 12 , 2015 , using the keywords  tumor necrosis factor-  or  tumor necrosis factor - alpha  or tnf-  ,  polymorphism  or  genotype  or  snp  , and  hepatocellular carcinoma  or  hcc  or  liver cancer  . the inclusion criteria were : 1 ) the study design must be case - control . 3 ) the study must include at least two groups , including a case group and a control group . 4 ) the frequency of alleles and genotypes for both groups , case and control , must be given or calculated . review articles , systematic reviews , and meta - analyses were excluded , but their references were checked for possible eligible studies based on the above criteria . all of the extracted data , including year of publication , country , study period , genotyping method , number of cases and controls , and frequency of genotypes and alleles , were categorized , then entered into our database . statistical analyses were carried out using comprehensive meta - analysis ( cma ) software , version 2 . odds ratios ( ors ) and 95% confidence intervals ( cis ) were used to measure the association between tnf--308 polymorphisms and the risk of hcc development . heterogeneity among the studies was examined with the cochran q test and i statistics . when significant heterogeneity was observed ( pheterogeneity < 0.1 and i > 50% ) , the random effect model was used . however , in homogeneous conditions ( pheterogeneity > 0.1 and i < 50% ) , the fixed - effect model was employed . publication bias was investigated visually with funnel plots . for calculation of overall effect size in the absence of one study , a sensitivity analysis was conducted . in this meta - analysis , both the allelic and the genotype genetics models , including per - allele ( a vs. g ) , co - dominant ( aa vs. gg ) , dominant ( aa + ag vs. gg ) , and recessive models ( aa vs. ag + gg ) , were analyzed in order to evaluate the associations between the tnf--308 g / a allele and hcc development risk . a systematic literature search for all published articles related to hcc and tnf--308 polymorphisms was conducted using the databases of pubmed , scopus , and google scholar . the last search update was on july 12 , 2015 , using the keywords  tumor necrosis factor-  or  tumor necrosis factor - alpha  or tnf-  ,  polymorphism  or  genotype  or  snp  , and  hepatocellular carcinoma  or  hcc  or  liver cancer  . the inclusion criteria were : 1 ) the study design must be case - control . 3 ) the study must include at least two groups , including a case group and a control group . 4 ) the frequency of alleles and genotypes for both groups , case and control , must be given or calculated . review articles , systematic reviews , and meta - analyses were excluded , but their references were checked for possible eligible studies based on the above criteria . all of the extracted data , including year of publication , country , study period , genotyping method , number of cases and controls , and frequency of genotypes and alleles , were categorized , then entered into our database . statistical analyses were carried out using comprehensive meta - analysis ( cma ) software , version 2 . odds ratios ( ors ) and 95% confidence intervals ( cis ) were used to measure the association between tnf--308 polymorphisms and the risk of hcc development . heterogeneity among the studies was examined with the cochran q test and i statistics . when significant heterogeneity was observed ( pheterogeneity < 0.1 and i > 50% ) , the random effect model was used . however , in homogeneous conditions ( pheterogeneity > 0.1 and i < 50% ) , the fixed - effect model was employed . publication bias was investigated visually with funnel plots . for calculation of overall effect size in the absence of one study , a sensitivity analysis was conducted . in this meta - analysis , both the allelic and the genotype genetics models , including per - allele ( a vs. g ) , co - dominant ( aa vs. gg ) , dominant ( aa + ag vs. gg ) , and recessive models ( aa vs. ag + gg ) , were analyzed in order to evaluate the associations between the tnf--308 g / a allele and hcc development risk . only articles in the english language were chosen for primary screening . after omitting 53 duplicate studies , 234 articles were considered for skimming of titles and abstracts , and 52 articles were subsequently selected for careful scanning of the context . more than half of these ( 29 studies ) were excluded because they contained insufficient or non - relevant data for this analysis . finally , 23 eligible studies were entered into our meta - analysis ( figure 1 ) . in three of these studies , the ga and aa genotypes were reported in overall form instead of separately , so they could be included only in the dominant - model analysis . figure 2 indicates the association of the allelic model ( a vs. g ) and the risk of hcc . overall , the a allele was identified more frequently in hcc patients than in controls ( 13.4% vs. 8.4% , respectively ) . ( 14 ) were the only authors to report a statistically significant difference from the overall result . in analyzing the allelic model , because of high heterogeneity ( pheterogeneity < 0.001 , i = 85% ) figure 2 shows that mutant allele a in tnf--308 was related to increased hcc risk ( p = 0.001 , or [ 95% ci ] = 1.77 [ 1.26 - 2.50 ] ) . for the co - dominant model ( aa vs. gg ) , considering the significant heterogeneity among the studies ( pheterogeneity = 0.003 , i = 55% ) , a random - effect model was employed . the analysis of the co - dominant model ( p < 0.020 , or [ 95% ci ] = 2.14 [ 1.13 - 4.06 ] ) , shown in figure 3 , identified a possible association with hcc risk , but this result may be influenced by removing one study . due its significant heterogeneity ( pheterogeneity = 0.006 , i = 52% ) , a random model was used for the recessive model ( figure 4 ) , showing a statistically significant association with the hcc risk ( p < 0.047 , or [ 95% ci ] = 1.83 [ 1.01 - 3.33 ] ) . however , similar to the co - dominant model , its results were not trustworthy . after analyzing the results of selected articles for the dominant model , it was noted that there was a significant association between this model in tnf--308 and the risk of hcc development ( p < 0.001 , or [ 95% ci ] = 1.80 [ 1.29 - 2.51 ] ) . 0.001 , i = 81% ) among the selected studies , the random model was used instead of the fixed model in the dominant model . table 2 also summarizes the most important results for all four of the analyzed models . after checking the effect of omitting any given study with a sensitivity analysis , the results of the allelic and dominant models were concluded to be completely reliable , while the other two models were considered unreliable because of alterations of the overall results in the sensitivity analysis . figure 6 shows the sensitivity analysis results for the analyzed models . to evaluate for any evidence of publication bias among the included studies , funnel plots for all four of the models only articles in the english language were chosen for primary screening . after omitting 53 duplicate studies , 234 articles were considered for skimming of titles and abstracts , and 52 articles were subsequently selected for careful scanning of the context . more than half of these ( 29 studies ) were excluded because they contained insufficient or non - relevant data for this analysis . finally , 23 eligible studies were entered into our meta - analysis ( figure 1 ) . in three of these studies , the ga and aa genotypes were reported in overall form instead of separately , so they could be included only in the dominant - model analysis . figure 2 indicates the association of the allelic model ( a vs. g ) and the risk of hcc . overall , the a allele was identified more frequently in hcc patients than in controls ( 13.4% vs. 8.4% , respectively ) . ( 14 ) were the only authors to report a statistically significant difference from the overall result . in analyzing the allelic model , because of high heterogeneity ( pheterogeneity < 0.001 , i = 85% ) , a random effect model was used . figure 2 shows that mutant allele a in tnf--308 was related to increased hcc risk ( p = 0.001 , or [ 95% ci ] = 1.77 [ 1.26 - 2.50 ] ) . for the co - dominant model ( aa vs. gg ) , considering the significant heterogeneity among the studies ( pheterogeneity = 0.003 , i = 55% ) , a random - effect model was employed . the analysis of the co - dominant model ( p < 0.020 , or [ 95% ci ] = 2.14 [ 1.13 - 4.06 ] ) , shown in figure 3 , identified a possible association with hcc risk , but this result may be influenced by removing one study . due its significant heterogeneity ( pheterogeneity = 0.006 , i = 52% ) , a random model was used for the recessive model ( figure 4 ) , showing a statistically significant association with the hcc risk ( p < 0.047 , or [ 95% ci ] = 1.83 [ 1.01 - 3.33 ] ) . however , similar to the co - dominant model , its results were not trustworthy . after analyzing the results of selected articles for the dominant model , it was noted that there was a significant association between this model in tnf--308 and the risk of hcc development ( p < 0.001 , or [ 95% ci ] = 1.80 [ 1.29 - 2.51 ] ) . = 81% ) among the selected studies , the random model was used instead of the fixed model in the dominant model . table 2 also summarizes the most important results for all four of the analyzed models . after checking the effect of omitting any given study with a sensitivity analysis , the results of the allelic and dominant models were concluded to be completely reliable , while the other two models were considered unreliable because of alterations of the overall results in the sensitivity analysis . to evaluate for any evidence of publication bias among the included studies , funnel plots for all four of the models were performed ( figure 7 ) . there are several risk factors for hcc development , including cirrhosis , hbv , hcv , toxins , drinking - water contamination , and alcohol ( 37 ) . hcc most often develops as an outcome of hbv or hcv infections , which can be affected by various factors ( 38 , 39 ) . various cytokines and cells are deeply involved in several types of diseases , such as hcc and viral hepatitis . having a plan of their activity and functions may lead to the emergence of new therapeutic options and also better management of hbv infection ( 40 , 41 ) . for example , recently , tavakolpour ( 41 ) used the function of cytokines and cells to introduce a new therapeutic approach for chronic hbv . finding the association between tnf- polymorphisms may also lead to the emergence of some options to better management of hcc . tnf- polymorphisms can regulate the expression of this cytokine , and different meta - analyses have shown an association between tnf--308 g / a and the risk of hcc ( 44 - 47 ) . however , the results for tnf-238 g / a in this context have been controversial ( 44 - 46 , 48 ) . furthermore , there is limited evidence of an association between hcc and tnf-863 c / a , and no association between tnf-857 c / t or tnf-1031 t / c and the risk of hcc ( 19 ) . table 3 summarizes the results of recent meta - analyses that sought to identify links between hcc risk and different positions of tnf- promoter . the present meta - analysis investigated associations between tnf--308 g / a and the risk of hcc in an allelic model and all genotype models . the results for the allelic model , reflecting 20 studies , indicated a significant association with hcc risk . in addition to the a vs. g model , the aa vs. gg model was associated with hcc . however , hu et al . ( 46 ) and cheng et al . ( 48 ) did not report a relationship between this model and hcc risk . thus , the present meta - analysis introduced an association between a co - dominant genotype model with hcc for the first time . however , a sensitivity analysis showed that these results should be considered unreliable . thus , further studies are necessary to determine whether there is any significant association in this regard . in a recessive model , the p value was very close to 0.05 , indicating statistical significance , but this was not trustworthy , as the sensitivity analysis found no association on the recessive model between hcc risk and tnf--308 . similar to our analysis , all of the published meta - analyses found no relationship on the recessive model . for the dominant model , similar to all of the previously published meta - analyses , a significant association with hcc was found in the present study , confirming the previous results . in all of the models , thus , a random model was used for the analyses . in the allelic and dominant models , which were considered significantly associated with hcc in previous analyses , an association with hcc differentiation of this result with previous studies was associated with the co - dominant model , which was not calculated in most of the other meta - analyses . among all of the published results , talaat s study was considerably different from the others , reporting the g allele as a risk factor for hcc . two other studies investigated egyptian populations , but all of them introduced the a allele as a risk factor for hcc . in other hcv cases that developed hcc , the results were not as different as they were in this study . a sensitivity analysis , which removes one study and repeats the analysis , may reveal that the overall results depend on a certain study or not . after the sensitivity analysis in the present study , the reliability of the final results , which showed associations between the allelic and the dominant models with hcc , was confirmed . despite an association of the co - dominant and recessive models with hcc , based on the sensitivity analysis results , this association was not trustworthy . first , only english - language studies were included , although there are studies published in other languages , especially chinese . another limitation is the high heterogeneity of the data , which can cause deviations from factual results . environmental factors and primary diseases that cause hcc should also be considered , but this was impractical with the low number of included studies . in this analysis , it was assumed that all of the enrolled studies contained accurate data ; however , this may not be true . on the other hand , there were also some advantages in this analysis that previous studies lacked . for example , this meta - analysis included 23 studies , which is the highest number among similar meta - analyses . the last update of the literature search was on july 12 , 2015 , which is considerably more recent than the last meta - analysis . to obtain more valid and reliable results ,
contexthepatocellular carcinoma ( hcc ) is a common disorder throughout the world that can develop due to various factors , including genetics . 
 tumor necrosis factor- ( tnf- ) is the most frequently studied cytokine related to the risk of developing hcc , and an association between the 308 position of the tnf- promoter ( tnf--308 ) and hcc risk has been confirmed in various reports.evidence acquisitionthe pubmed , scopus , and google scholar databases were searched through july 12 , 2015 , for studies on associations between tnf--308 and the risk of hcc . to determine this association , odds ratios ( ors ) and 95% confidence intervals ( 95% cis ) 
 were calculated.resultsa total of 23 case - control studies were investigated , involving 3,389 cases and 4,235 controls . 
 the overall conclusion was that the a allele was more frequent in case groups compared to control groups ( 13.4% vs. 8.4% ) . 
 thus , the a allele was significantly associated with increased hcc risk ( or = 1.77 ; 95% ci = [ 1.26 - 2.50 ] ; p value < 0.002 ) . 
 in addition to the allelic model , the dominant model ( aa + ag vs. gg ) was significantly associated with hcc risk ( or = 1.80 ; ci = [ 1.29 - 2.51 ] ; p value < 0.001 ) . in the sensitivity analysis for co - 
 dominant ( aa vs. gg ) and recessive models ( aa vs. ag + gg ) , no trustworthy associations with the risk of hcc development were observed.conclusionsthis meta - analysis indicated that the tnf--308 g / a polymorphism is significantly associated with increased susceptibility to hcc 
 . however , to confirm this finding , more studies are needed on tnf--308 g / a polymorphisms associated with hcc .