Correlations Between IL-8-251A/T Polymorphisms And Susceptibilities To Esophageal Squamous Cell Carcinoma And Gastric Cardiac Adenocarcinoma

Objective: Esophageal cancer is one of the most common malignant tumors in the world. A very remarkable feature of the cancer is the highly centralized occurrence in the high risk regions, with the difference in incidence and mortality rates as large as 500 times exist between the high and low risk areas. The South Taihang mountain region of our country has been well recognized as the highest incidence area for esophageal cancer in the world. Recently it is know that this area not only bears high risk for esophageal cancer, but also for cardiac cancer. However, early diagnosis of the cancer is hard to achieve because patients in the early stage have no obvious symptoms, and majority of patients treated in tumor hospital are in the late stage, so the five year survival rates after operation were low. So determination of individuals with high risk and detection of esophageal cancer and gastric cardiac cancer at earlier stages probably gives the best chance to improve prognosis.The aim of this study is to investigate whether the -251A/T polymorphism of the IL-8 promoter was associated with susceptibility to esophageal squamous cell carcinoma (ESCC) and gastric cardiac adenocarcinoma (GCA) in south of Taihang mountain, a high incidence area of China.Methods: This population-based case-control study included 320 cases esophageal squamous carcinoma, 340 cases gastric cardiac adenocarcinoma and 404 cases healthy controls ,came from high incidence region of Taihang mountain. The total patients were diagnosed by histopathology, and detected the infection of H.pylori in GCA by RUT ,histopathology and 14C-urea breath test. In the same period, we collected the disease history, personal history, family history,and so on. Genomic DNA was extracted by tiangen kit. IL-8 polymorphisms were analyzed by polymerase chain reaction(PCR)-restriction fragment length polymorphis -m (RFLP). Random sampling of DNA sequencing analysis was used to confirm the results of IL-8 genotyping. Hardy-Weinberg analysis was performed by comparing the observed and expected genotype frequencies in study groups using Chi-square test. Comparison of the IL-8 genotype and allelotype distribution in the study groups was performed by means of two-sided contingency tables using Chi-square test. The odds ratio (OR) and 95% confidence interval (CI) were calculated using an unconditional logistic regression model and adjusted by age and gender accordingly.Results: 1 Demographic characteristics of ESCC,GCA patients and healthy controls:1.1 The frequency of positive family history of upper gastrointestinal cancer (UGIC) in ESCC (44.7%) and GCA (48.6%) patients was significantly higher than that in healthy controls (32.6%) (χ~2= 4.707 and17.785, P <0.05),so family history of UGIC significantly enhanced the risk of developing ESCC and GCA[the age, gender, smoking status, and infection of H.pylori (GCA) adjusted odds ratio(OR)=1.721, 95% confident interval(CI)= 1.251-2.367; OR=3.679, 95%CI = 2.178-6.216].1.2 The proportion of smokers in ESCC and GCA patients(51.3% and 47.1% respectively) were significantly different from that in healthy controls (38.9%)(χ2=10.383 and 4.467, P =0.001 and 0.035, respectively),[the adjusted odds ratio(OR)=1.684,95% confident interval(CI)=1.215-2.336; OR=1.211, 95%CI= 0.736-1.992],so smoking significantly enhanced the risk of developing ESCC,but not GCA.1.3 Infection of H.pylori in GCA patients(65.7%)was significantly more common than that in healthy controls(35.1%)(χ~2=4.896, P =0.001),so infection of H.pylori was a risk factor of developing GCA[the adjusted odds ratio(OR)=5.276,95%CI= 3.230-8.618].2 The distribution of the IL-8 polymorphisms among ESCC,GCA patients and healthy conctrols did not significantly deviate from those expected by Hardy-Weinberg equilibrium(P >0.05).The frequency of the IL-8-251 AA,AT,TT in healthy controls were 18.3%,49.5%,32.2%,in ESCC patients were 15.6%,23.1%,29.7% and in GCA patients were 24.7%, 49.7%,25.6%。The allelotype and genotype distribution of the IL-8-251A/T SNPs in the overall ESCC patients were not significantly different from that in healthy controls(P >0.05).However, the frequency of IL-8-251 A allelotype and AA genotype distribution in GCA patients(49.6% and 24.7%,respectively)was significantly higher than that in healthy controls(43.1% and 18.3%)(χ~2=6.26 and 6.299, P =0.012 and 0.043, respectively).Compared with individuals with the TT genotype, individuals with the AA genotype had significantly higher risk to develop GCA[the adjusted OR=2.014,95%CI=1.017-3.990].3 Stratification analysis by smoking status found that the IL-8-251A/T polymorphisms didn't increase the risk of developing ESCC and GCA in all subgroups.4 When stratified by family history of UGIC, a significant association of the IL-8-251 AA genotype with increased risk of ESCC and GCA were observed among individuals with positive family history, compared with the TT genotype[the adjusted OR=2.378 and 14.895,95%CI=1.075-5.258 and 2.889-76.516, respectively],while IL-8-251A/T polymorphisms didn't increase the risk of developing ESCC and GCA among the subjects without family history of UGIC [the adjusted OR=0.497 and 1.120,95%CI=0.243-1.018 and 0.452-2.779, respectively].5 When stratified by infection of H.pylori, the frequency of AA genotype in the group of positive H.pylori infection was significantly higher than that in negative group(P =0.017), AA genotype significantly increased susceptibility to GCA among individuals with H.pylori infection[the adjusted OR=3.520, 95%CI=1.249-9.918].Conclusions: 1 IL-8-251AA genotype significantly increased the risk of developing GCA, while IL-8-251 polymorphisms might not be independent factors to predict the risk of the development of ESCC in South Taihang mountain.2 Family history of upper gastrointestinal cancer(UGIC) significantly enhanced the risk of developing ESCC and GCA, stratification analysis showed that IL-8-251AA genotype significantly enhanced susceptibilities to ESCC and GCA among the individuals with UGIC history, IL-8-251 polymorphisms might not be independent factors to predict the risk of the development of ESCC, notwithstanding.3 H.pylori infection increased the risk of developing GCA, IL-8-251AA genotype significantly enhanced susceptibilities to GCA among the individuals with H.pylori infection .4 Smoking significantly enhanced the risk of developing ESCC, while there was no relationship between smoking and GCA, no evidence was found that IL-8-251 AA genotype enhanced susceptibilities to ESCC and GCA among smokers or non-smokers.