cancer is a major public health problem all over the world , and has become one of the primary causes of morbidity and mortality .
the epidemiology of cancer is influenced by the aging and growth of the world population and a rise in cancer - causing behaviors ; therefore , the global burden of cancer is rapidly increasing . the etiology of cancer is complex and is still obscure .
recent research suggests that single - nucleotide polymorphisms ( snps ) in genes play critical roles in cancer development and progression [ 36 ] . among these snps , icam-1 polymorphisms have been shown to be particularly important .
icam-1 , a single - chain 76110 kda glycoprotein , is a member of the immunoglobulin superfamily , which is involved in cell adhesion and signalling .
studies indicate that icam-1 plays an important role in tumorigenesis and tumor progression , specifically by facilitating tumor invasion and metastases .
many case - control studies have demonstrated that icam-1 polymorphisms ( rs5491 , rs3093030 , rs281432 , and rs1799969 ) are associated with susceptibility to many cancers , including colorectal cancer , breast cancer , diffuse astrocytoma , prostate cancer , cutaneous malignant melanoma , ovarian cancer , urothelial cell carcinoma , oral cancer , and acute promyelocytic leukanemia ( apl ) . in view of the relevance of icam-1 polymorphisms
( rs5491 , rs3093030 , rs281432 , and rs1799969 ) in susceptibility to cancer , many studies have been conducted [ 918 ] but the results were inconclusive and inconsistent . in 2014 ,
wang et al .   performed a meta - analysis of 14 studies and concluded that icam-1 rs5498 polymorphism was associated with cancer susceptibility . in the present study
, we aimed to clarify the relationship between other icam-1 polymorphisms ( rs5491 , rs3093030 , rs281432 , and rs1799969 ) and cancer susceptibility based on all eligible published case - control studies .
all eligible case - control studies on the relationship between polymorphisms of icam-1 ( rs5491 , rs3093030 , rs281432 , and rs1799969 ) and cancer susceptibility up to june 16 , 2015 were identified by a systematic literature search in pubmed , web of science , and google scholar .
 neoplasms  ) and (  polymorphism  or  variant  or  mutation  ) .
in addition , for each retrieved publication , a manual search for relevant references was also conducted to find additional case - control studies .
the inclusion criteria were : 1 ) evaluation of the icam-1 polymorphisms and cancer susceptibility , 2 ) case - control studies , and 3 ) presenting available information to assess the odds ratio ( or ) with 95% confidence interval ( ci ) .
major reasons for exclusion of studies were : 1 ) no control population , 2 ) abstracts and reviews , 3 ) no available genotype frequency , 4 ) duplication of the previous publication , and 5 ) non - human studies .
two investigators ( xiaolong zhang and junjie huang ) independently extracted data on icam-1 polymorphisms , first author , year of publication , ethnicity of the case - control studies , genotyping methods , source of controls , type of cancer , and genotype number in cancer cases and controls .
we evaluated the association between icam-1 polymorphisms and cancer susceptibility by or and 95% ci .
the significance of the pooled or was determined by the z - test and p<0.05 was considered statistically significant .
a total of 4 genetic models were selected : allele contrasts , additive genetic model , recessive genetic model , and dominant genetic model separately .
heterogeneity was detected by the -based q statistic test to assess the heterogeneity within the case - control studies .
when there was heterogeneity ( p<0.10 , i>50% ) , the random - effects model was used to calculate the pooled ors ; otherwise , the fixed - effects model was used .
stratification analyses of cancer type , genotyping method , and source of control were conducted .
sensitivity analyses were further performed to calculate the stability of the results by removing each case - control study from the enrolled pooled data to detect the influence of the respective data set on the pooled ors . to examine the potential publication bias ,
the stata 12.0 ( stata corporation , college station , tx ) was used to conduct all statistical analyses .
the study quality was assessed independently by xiaolong zhang and junjie huang by referring to the newcastle - ottawa scale ( nos ) , which examines the quality of non - randomized studies by the selection of participants , comparability of groups , and exposure assessment .
all eligible case - control studies on the relationship between polymorphisms of icam-1 ( rs5491 , rs3093030 , rs281432 , and rs1799969 ) and cancer susceptibility up to june 16 , 2015 were identified by a systematic literature search in pubmed , web of science , and google scholar .
 neoplasms  ) and (  polymorphism  or  variant  or  mutation  ) .
in addition , for each retrieved publication , a manual search for relevant references was also conducted to find additional case - control studies .
the inclusion criteria were : 1 ) evaluation of the icam-1 polymorphisms and cancer susceptibility , 2 ) case - control studies , and 3 ) presenting available information to assess the odds ratio ( or ) with 95% confidence interval ( ci ) .
major reasons for exclusion of studies were : 1 ) no control population , 2 ) abstracts and reviews , 3 ) no available genotype frequency , 4 ) duplication of the previous publication , and 5 ) non - human studies .
two investigators ( xiaolong zhang and junjie huang ) independently extracted data on icam-1 polymorphisms , first author , year of publication , ethnicity of the case - control studies , genotyping methods , source of controls , type of cancer , and genotype number in cancer cases and controls .
we evaluated the association between icam-1 polymorphisms and cancer susceptibility by or and 95% ci .
the significance of the pooled or was determined by the z - test and p<0.05 was considered statistically significant .
a total of 4 genetic models were selected : allele contrasts , additive genetic model , recessive genetic model , and dominant genetic model separately .
heterogeneity was detected by the -based q statistic test to assess the heterogeneity within the case - control studies .
when there was heterogeneity ( p<0.10 , i>50% ) , the random - effects model was used to calculate the pooled ors ; otherwise , the fixed - effects model was used .
stratification analyses of cancer type , genotyping method , and source of control were conducted .
sensitivity analyses were further performed to calculate the stability of the results by removing each case - control study from the enrolled pooled data to detect the influence of the respective data set on the pooled ors . to examine the potential publication bias ,
the stata 12.0 ( stata corporation , college station , tx ) was used to conduct all statistical analyses .
the study quality was assessed independently by xiaolong zhang and junjie huang by referring to the newcastle - ottawa scale ( nos ) , which examines the quality of non - randomized studies by the selection of participants , comparability of groups , and exposure assessment .
after a systematic literature search and selection based on the inclusion criteria , 140 publications were considered for eligibility . however , among these eligible articles , 115 are disqualified because they were not about polymorphisms , were not cancer studies , or they were reviews or letters . of the remaining 25 publications ,
7 were based on case - only design , 5 were not polymorphism studies , and 4 were not about susceptibility to cancer . as a result , 9 publications with 14 case - control studies including 4608 cancer cases and 4913 controls were included in the present meta - analysis .
eight studies were conducted in people of asian ethnicity , 6 studies were conducted in people of white ethnicity , and only 1 study was conducted in people of african ethnicity . in addition , there were 10 studies done by pcr , 4 performed by taqman , and only 1 conducted by pcr - rflp .
the control groups consisted of 10 population - based studies and 5 hospital - based studies .
of these included studies , 3 reported urothelial cell carcinoma and 3 reported oral cancer .
two studies were on breast cancer , 2 were on apl , and 2 were on ovarian cancer .
prostate cancer , cutaneous melanoma , and colorectal cancer were also mentioned in other studies .
the results of the meta - analysis for the association between icam-1 polymorphisms ( rs5491 , rs3093030 , rs281432 , and rs1799969 ) and susceptibility to cancer are presented in table 2 . according to the outcomes of heterogeneity analysis ,
obvious heterogeneity was identified in icam-1 rs3093030 polymorphism ( c vs. t : p=0.012 , i=52.6% ; cc vs. tt : p=0.003 , i=62.1% ; cc vs. tc+tt : p=0.003 , i=62.1% ) therefore , the random - effects model was used to estimate the pooled ors in these genetic models . according to the present analysis
, we discovered that icam-1 rs1799969 polymorphism was significantly associated with overall cancer susceptibility ( table 2c , c vs. t : or=1.662 , 95%ci = 1.2882.143 , p=0.141 , figure 2a ; ct vs. tt : or=1.860 , 95%ci=1.3982.474 , p=0.507 , figure 2b ; cc+ct vs. tt : or=1.812 , 95%ci=1.3732.391 , p=0.284 , figure 2c ) .
nevertheless , no relevance was identified between other icam-1 polymorphisms ( table 2a , rs5491 ; table 2b , rs3093030 ; table 2d , rs281432 ) and overall cancer susceptibility . in stratified analysis of the source of controls ,
an increased susceptibility of the population - based group in rs1799969 polymorphism was found in 3 genetic models ( table 2c , c vs. t : or=2.007 , 95%ci=1.4712.737 , p=0.778 ; ct vs. tt : or=2.110 , 95%ci=1.5022.962 , p=0.852 ; cc+ct vs. tt : or=2.151 , 95%ci=1.5393.006 , p=0.907 ) .
interestingly , we also identified an increased susceptibility for asians in rs3093030 polymorphism ( table 2b , cc vs. tc+tt : or=1.728 , 95%ci=1.2342.421 , p=0.787 , figure 3 ) in the stratification analysis by ethnicity .
egger s test and begg s funnel plot were performed to examine the publication bias risk and we found no publication bias ( figure 4a4d ) . additionally , the quality of the enrolled studies is shown in table 3 .
after a systematic literature search and selection based on the inclusion criteria , 140 publications were considered for eligibility . however , among these eligible articles , 115 are disqualified because they were not about polymorphisms , were not cancer studies , or they were reviews or letters . of the remaining 25 publications ,
7 were based on case - only design , 5 were not polymorphism studies , and 4 were not about susceptibility to cancer . as a result , 9 publications with 14 case - control studies including 4608 cancer cases and 4913 controls were included in the present meta - analysis .
eight studies were conducted in people of asian ethnicity , 6 studies were conducted in people of white ethnicity , and only 1 study was conducted in people of african ethnicity . in addition , there were 10 studies done by pcr , 4 performed by taqman , and only 1 conducted by pcr - rflp .
the control groups consisted of 10 population - based studies and 5 hospital - based studies .
of these included studies , 3 reported urothelial cell carcinoma and 3 reported oral cancer .
two studies were on breast cancer , 2 were on apl , and 2 were on ovarian cancer .
prostate cancer , cutaneous melanoma , and colorectal cancer were also mentioned in other studies .
the results of the meta - analysis for the association between icam-1 polymorphisms ( rs5491 , rs3093030 , rs281432 , and rs1799969 ) and susceptibility to cancer are presented in table 2 . according to the outcomes of heterogeneity analysis ,
obvious heterogeneity was identified in icam-1 rs3093030 polymorphism ( c vs. t : p=0.012 , i=52.6% ; cc vs. tt : p=0.003 , i=62.1% ; cc vs. tc+tt : p=0.003 , i=62.1% ) therefore , the random - effects model was used to estimate the pooled ors in these genetic models . according to the present analysis
, we discovered that icam-1 rs1799969 polymorphism was significantly associated with overall cancer susceptibility ( table 2c , c vs. t : or=1.662 , 95%ci = 1.2882.143 , p=0.141 , figure 2a ; ct vs. tt : or=1.860 , 95%ci=1.3982.474 , p=0.507 , figure 2b ; cc+ct vs. tt : or=1.812 , 95%ci=1.3732.391 , p=0.284 , figure 2c ) .
nevertheless , no relevance was identified between other icam-1 polymorphisms ( table 2a , rs5491 ; table 2b , rs3093030 ; table 2d , rs281432 ) and overall cancer susceptibility . in stratified analysis of the source of controls , an increased susceptibility of the population - based group in rs1799969 polymorphism
was found in 3 genetic models ( table 2c , c vs. t : or=2.007 , 95%ci=1.4712.737 , p=0.778 ; ct vs. tt : or=2.110 , 95%ci=1.5022.962 , p=0.852 ; cc+ct vs. tt : or=2.151 , 95%ci=1.5393.006 , p=0.907 ) .
interestingly , we also identified an increased susceptibility for asians in rs3093030 polymorphism ( table 2b , cc vs. tc+tt : or=1.728 , 95%ci=1.2342.421 , p=0.787 , figure 3 ) in the stratification analysis by ethnicity .
egger s test and begg s funnel plot were performed to examine the publication bias risk and we found no publication bias ( figure 4a4d ) . additionally , the quality of the enrolled studies is shown in table 3 .
icam-1 , a cell adhesion molecule with a key role in inflammation and immune surveillance , has been implicated in carcinogenesis by facilitating instability of the tumor environment . in 2014 ,
wang et al . conducted a meta - analysis and concluded that icam-1 rs5498 polymorphism was associated with cancer susceptibility .
however , the association between cancer susceptibility and other polymorphisms of icam-1 ( rs5491 , rs3093030 , rs281432 , and rs1799969 ) remained unclear .
recently , dore et al .   demonstrated that no significant association was detected between icam-1 rs1799969 polymorphism and apl in whites .
obtained the opposite results in breast cancer , colorectal cancer , and cutaneous malignant melanoma , respectively .
in addition , several publications ( case - control studies ) indicated that icam-1 polymorphisms ( rs5491 , rs3093030 , and rs281432 ) were also involved in tumorigenesis and tumor progression .
however , the conclusions were inconclusive because of the limited number of relevant published reports .
we aimed to comprehensively define the association between icam-1 polymorphisms ( rs5491 , rs3093030 , rs281432 , and rs1799969 ) and cancer susceptibility in a total of 9 publications , including 14 case - control studies with 4608 cases and 4913 controls .
moreover , in the stratified analysis , significant cancer susceptibility in population - based and asian groups was identified for rs1799969 and rs3093030 , respectively .
it was well - established that hospital - based studies may have selection bias ; the controls may only represent a poorly - defined reference population rather than the general population or the population of interest , especially when the genotypes examined are relevant to disease - related factors that the hospital - based controls may have been exposed to .
the selection of appropriate and representative controls is of great importance in reducing biases in polymorphism association studies .
therefore , we conducted subgroup analysis by source of control and found that the source of control did not influence our conclusions . although we conducted a comprehensive retrieval of all eligible studies , several limitations of this meta - analysis should be acknowledged .
firstly , the number of currently available case - control studies enrolled in our study was small and we could not achieve definitive results . secondly , lack of detailed data on individuals limited the precision of our analysis of adjusted estimates involving other factors such as age and sex .
thirdly , only 1 study discussed the genetic predisposition of every icam-1 polymorphism to each cancer , and we could not evaluate the effects of a single polymorphism of icam-1 on a specific cancer because eligible case - control studies were insufficient for pooled analysis . finally , the effect of icam-1 polymorphisms on cancer susceptibility might be affected by complex factors , such as histological types of cancer and matching criteria .
results of our meta - analysis show that icam-1 polymorphism rs1799969 is significantly associated with increased susceptibility to cancer .
future well - designed studies are warranted to further explore the relationship between icam-1 polymorphisms and cancer susceptibility .
 backgroundmany epidemiology studies have indicated that polymorphisms in icam-1 are associated with a variety of cancers , but published data are contradictory and inconclusive . 
 therefore , we conducted the current meta - analysis to elaborate the effects of icam-1 polymorphisms ( rs5491 , rs3093030 , rs281432 , and rs1799969 ) on cancer susceptibility.material/methodswe conducted a comprehensive literature search in pubmed , web of science , and google scholar . 
 odds ratios ( ors ) with 95% confidence intervals ( cis ) were estimated to assess the association between icam-1 polymorphisms and cancer susceptibility.resultswe enrolled 14 published case - control studies including 4608 cancer cases and 4913 controls . 
 we found an increased susceptibility of cancer in polymorphism rs1799969 ( c vs. t : or=1.662 , 95%ci=1.2882.143 , p=0141 ; ct vs. tt : or=1.860 , 95%ci=1.3982.474 , p=0.507 ; cc+ct vs. tt : or=1.812 , 95%ci=1.3732.391 , p=0.284 ) of icam-1 among the overall population . 
 however , no association between polymorphisms rs5491 , rs3093030 , or rs281432 of icam-1 and cancer susceptibility was identified . in the stratification analysis by ethnicity , we identified an increased susceptibility for asians in rs3093030 polymorphism ( cc vs. tc+tt : or=1.728 , 95% ci=1.2342.421 , p=0.787).conclusionsour results suggest that the icam-1 polymorphism rs1799969 is significantly associated with increased susceptibility to overall cancer . 
 further studies ( preferably prospective ) are warranted to validate these relationships . 
Background
Material and Methods
Literature search strategy
Selection criteria
Data extraction
Statistical analysis
Quality evaluation
Results
Study characteristics
Meta-analysis
Sensitivity analyses and publication bias
Discussion
Conclusions