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 cancer is a major public health problem worldwide ; it is the primary and secondary causes of death in economically developed and developing countries , respectively .
the global concern on cancer continues to intensify as a result of the aging and expanding world population and the increasing adoption of cancer - causing habits .
the mechanism of carcinogenesis remains largely unknown although genetic susceptibility is a known possible explanation for the interindividual variation in cancer risk .
nuclear factor-b ( nf-b ) was initially identified in 1986 as a transcription factor which binds to a 10  bp dna element in kappa immunoglobulin light - chain enhancer in b cells .
the nf-b family consists of p50 ( nf-b1 ) , p52 ( nf-b2 ) , p65 ( rela ) , c - rel ( rel ) , and relb .
the major form of nf-b is a heterodimer of the p50 and p65/rela subunits which are encoded by the nfkb1 and nfkb2 genes , respectively .
the human nfkb1 gene is mapped to chromosome 4q24 and encodes a 50  kda dna - binding protein ( p50 ) that can act as a master regulator of inflammation and cancer development [ 57 ] . a common insertion / deletion polymorphism ( 94ins / del attg , rs28362491 ) in the promoter region of the nfkb1 gene elicits a regulatory effect on the nfkb1 gene .
a previous meta - analysis concluded that the deletion allele serves as a risk or protective allele for cancer susceptibility in caucasian or asian populations , respectively ; however , it revealed no association between the polymorphism and cancer risk .
an increasing number of studies have assessed the association between the nfkb1 promoter 94ins / del attg polymorphism and cancer risk [ 1012 ] . however , these studies obtained conflicting results .
therefore , we collected all available data to perform an updated meta - analysis that generates a precise estimation to comprehensively and objectively investigate the association between the nfkb1 promoter 94ins / del attg polymorphism and cancer risk .
a comprehensive literature search for relevant articles published ( last search updated in september 15 , 2013 ) in pubmed ( http://www.ncbi.nlm.nih.gov/pubmed/ ) was performed with the following key words : (  genetic polymorphism ,  
polymorphism ,   snp ,   single nucleotide polymorphism ,   gene mutation ,  or
 genetic variant  ) , (  neoplasm ,   cancer ,   tumor ,   carcinoma ,  or  carcinogenesis  ) , and (  nfkb1 ,   nf-b1 ,   nuclear factor kappa b1 ,   nf kappa b1 ,  or
the reviews and references of eligible studies were hand - searched for additional relevant publications .
the most recent or complete study was selected when more than one publications contain overlapping data .
case - control studies that evaluated the association of the nfkb1 promoter 94ins / del attg polymorphism with cancer risk and described in detail the genotype distributions of the polymorphism in cases and controls were included in this meta - analysis .
studies that were not for cancer research , were only case population , and were duplication of previous publication were excluded in this meta - analysis .
information was carefully extracted from eligible studies independently by two investigators ( xiao yang and pengchao li ) according to the inclusion criteria listed above , and the result was reviewed by a third investigator ( jun tao ) .
the following data were collected from each study : surname of first author , year of publication , ethnicity , genotyping method , source of controls , frequencies of the genotypes in cases and controls , cancer type , and hardy - weinberg equilibrium ( hwe ) of genotype distribution among controls .
 studies that investigated more than one type of cancer were regarded as individual datasets only in subgroup analyses according to cancer type .
articles that reported different ethnic groups and countries or locations were considered different study samples for each category cited above .
the strength of association between the nfkb1 promoter 94ins / del attg polymorphism and cancer risk was estimated through pooled odds ratio ( or ) with its corresponding 95% ci .
pooled ors were calculated for insertion allele versus deletion allele , ins / ins versus del / del , ins / del versus del / del , ins / ins + ins / del versus del / del , and ins / ins versus ins / del + del / del .
subgroup stratification analyses by ethnicity and cancer type were conducted to identify the association of the 94ins / del attg polymorphism with cancer susceptibility .
the between - study heterogeneity of the studies included in this meta - analysis was evaluated using the q and i statistic tests , where i > 50% indicated heterogeneity .
the random - effects model was selected when i was significant ( > 50% ) ; otherwise , the fixed - effects model was selected .
the allele frequencies of the nfkb1 promoter 94ins / del attg polymorphism from the respective study were determined by allele counting .
in addition , a chi - square test was used to determine whether or not the observed frequencies of genotypes conform to hwe . pooled or in the current meta - analysis
in addition to the comparison among all subjects , we performed stratification analyses by cancer type ( if one cancer type contained only one studies , it was combined into the  other cancers  group ) and ethnicity .
begg 's funnel plot and egger 's test were adopted to evaluate the publication bias in our meta - analysis [ 14 , 15 ] .
all statistical analyses were performed by stata 10.0 software ( statacorp , college station , tx , usa ) .
a total of 21 case - control studies involving 6127 cases and 9239 controls were analysed .
the allele and genotype frequencies of the nfkb1 promoter 94ins / del attg polymorphism were extracted from all eligible studies . in total , this meta - analysis included 3 bladder cancer studies , 4 colorectal cancer studies , 2 ovarian cancer studies , 2 oral cancer studies , 2 prostate cancer studies , and 8 studies with the  other cancers .  of the 21 studies , 14 were conducted among asians and 7 were conducted among caucasians .
the results of hwe test for the genotype distribution in the control population are shown in table 1 .
six of the eligible studies were not in hwe [ 10 , 11 , 18 , 21 , 31 ] .
the pooled ors of the included case - control studies revealed a statistically significant association between the nfkb1 promoter 94ins / del attg polymorphism and cancer risk across the four genetic models ins / ins versus del / del , or = 1.47 , 95% , ci = 1.111.93 ; dominant model , or = 1.26 , 95%  ci = 1.031.53 ; recessive model , or = 1.26 , 95%  ci = 1.051.51 ; and ins allele versus del allele , or = 1.19 , 95% , ci = 1.051.35 ( table 2 , figure 2 ) .
stratified analyses also revealed a significant association between the polymorphism and ovarian , oral , and prostate cancers in the various models .
ethnic subgroup analyses revealed significant increases in cancer risk in the four models among asians but not among caucasians .
the results became prominent when the six studies that deviated from hwe were excluded ( see supplementary table 1 and supplementary figure 1 in supplementary material available online at http://dx.doi.org/10.1155/2014/612972 ) .
publication bias was evaluated by begg 's funnel plot and egger 's test , and the visual asymmetry was determined in the funnel plot analysis ( figure 3 ) .
the results of egger 's tests for all genetic models are shown in supplementary table 2 ( ins allele versus del allele , p = 0.004 ) .
nf-b serves important functions in pathogenetic regulation and influences cancer development and aggressiveness by enhancing tumour angiogenesis , antiapoptosis , and proliferation and by repressing immune response [ 7 , 33 , 34 ] .
several investigators reported the constitutive activation of nf-b in various malignancies [ 35 , 36 ] , including nonsmall cell lung carcinoma and colon , prostate , breast , bone , and brain cancers .
p50 overexpression is frequently observed in various tumour tissues ; hence , p50 is potentially involved in tumourigenesis .
a polymorphism in the promoter region of nfkb1 encoding the p50 subunit of nf-b modulates gene activity .
a meta - analysis of all eligible studies in 2010 suggested that the deletion allele serves as a protective or risk allele for cancer susceptibility among asians or caucasians , respectively .
after the reported study , numerous studies further assessed the relationship between the nfkb1 promoter 94ins / del attg polymorphism and cancer among asians and caucasians [ 10 , 12 , 32 ] .
however , the association remains inconclusive because of the inconsistent results from the published studies .
li et al .   found an association between del / del genotype and bladder cancer risk but none between the polymorphism and hepatocellular carcinoma susceptibility . in this study , we analysed 21 eligible case - control studies with 6127 cases and 9239 controls .
the results of this meta - analysis revealed a significant association between insertion allele careers and enhanced cancer risk .
the probable mechanism behind the observed association may be linked to the enhanced expression and activity of p50 ( nf-b1 ) .
the insertion allele is reportedly associated with the increased promoter activity and enhanced nfkb1 mrna expression [ 8 , 12 , 17 ] .
the major effect of p50 ( nf-b1 ) is mediated by its function as a component of the transcription factor nf-b , which is among the major signalling pathways involved in the cellular response to environmental stress .
p50 serves an important function in inhibiting cell apoptosis by modulating the expression levels of several survival genes , such as bcl-2 homologue a1 , pai-2 , and iap gene family .
certain antiapoptosis proteins , such as bcl - xl and fas - associated death domain - like il-1-converting enzyme inhibitor protein , are upregulated through the nf-b signalling pathway [ 4042 ] .
in addition , accumulated evidence illustrated that the p50 ( nf-b1 ) signalling pathways participate in cellular proliferation by increasing il-5 , promoting mapk phosphorylation [ 7 , 44 ] , and modulating cyclin d1 expression . therefore , the observed association between the 94ins / del attg polymorphism and cancer risk can be accounted for by the insertion allele that can inhibit apoptosis and promote cellular proliferation by upregulating the expression of p50 ( nfkb1 ) [ 8 , 12 , 17 ] , which was implicated in the abovementioned mechanism . in the stratified analyses ,
the increased cancer risk remained in subgroups of asians but not in those of caucasians .
the ethnic differences in the allele frequencies may be caused by natural selection or balance to other related genetic variants .
the increased cancer risk also remained in the subgroups of ovarian , oral , and prostate cancers .
this result suggested that the nfkb1 gene might function as a prominent factor in these cancers .
therefore , further investigations are warranted to validate ethnic difference and cancer specificity in the effect of this functional polymorphism on cancer susceptibility .
first , significant between - study heterogeneity was detected in some comparisons and may be distorting the meta - analysis .
however , the association between the insertion allele and cancer risk in the overall population and in the asian population became pronounced when the six studies that deviated from hwe were excluded .
third , the studies included in the analysis used different genotyping methods with different quality control issues that may have also influenced the results .
fourth , publication bias was observed in our study , which may affect the validity of conclusion . in the stratified analysis
, we found that the publication bias was significant among the asian groups and other cancer groups but not significant among the caucasian , bladder , and colorectal cancer groups .
the sample sizes of the included studies were diverse , and most of them were insufficiently large .
finally , only three controls were population based ; thus , they may not represent the general population .
therefore , the results of this study should be interpreted with caution . in conclusion ,
nuclear factor-b is associated with the pathogenesis of numerous malignancies , and the functional polymorphism 94ins / del attg ( rs28362491 ) in the human nfkb1 gene is associated with cancer risk . 
 previous studies on the association between the 94ins / del attg polymorphism and cancer risk reported conflicting results . to clarify this relationship 
 , we performed a meta - analysis of 21 case - control studies involving 6127 cases and 9238 controls . 
 we used pooled odds ratios ( ors ) with their 95% confidence intervals ( 95% cis ) to assess the association . 
 we found that the nfkb1 promoter 94ins / del attg polymorphism was significantly associated with cancer risk in four genetic models ( ins / ins versus del / del , or = 1.47 , 95% ci = 1.111.93 ; dominant model , or = 1.26 , 95% ci = 1.031.53 ; recessive model , or = 1.26 , 95% ci = 1.051.51 ; ins allele versus del allele , or = 1.19 , 95% ci = 1.051.35 ) . 
 stratified analyses revealed a significant association between the polymorphism and ovarian , oral , and prostate cancers . 
 similar results were determined in an asian population and not in a caucasian population . 
 thus , our results suggested that the polymorphism can contribute to cancer risk . 
 moreover , the polymorphism can exert race- and cancer - specific effects on cancer risk . 
 further large - scale and functional studies are necessary to elucidate this possible effect .