Cyp1a1 Gene Polymorphisms And Susceptibility To Developing Esophageal Cancer

Esophageal cancer(EC) is a common malignant tumor of the digestive tract and the sixth leading cause of cancer death,with a sharp variation in its geographic distribution.The difference between high and low areas can be 500 times.Most victims live in the "esophageal cancer belt",which stretches from Northern-Central China westward through Central Asia to Northern Iran.The occurrence of esophageal cancer is a complex processes of multi-factor, multi-step and multi-channel,and combined effects of environmental factors and genetic factors.Most of environmental carcinogens are pre-carcinogens.They have carcinogenicity after activated by phase-â… enzymes.Activated carcinogens could be detoxified by phase-â…¡enzymes,and the susceptibility to carcinoma may be related to the imbalance of the pre-carcinogen activation and inactivation.Cumulative data show,polymorphisms of the gene which control carcinogen metabolism becoming the basis of individual differences in susceptibility to tumor.The cytochrome P450 (CYP1A1) enzyme superfamily constitutes the majority of Phaseâ… enzymes.Gene polymorphisms of CYP1A1 could induce the difference of enzymes activation and sensitivity to carcinogens.It has been found that gene polymorphisms of CYP1A1, CYP2E1 and CYP2A6 were associated with susceptibility to EC.CYP1A1 gene codes aryl hydrocarbon hydroxyla(AHH) which catalyses oxidation of polycyclic aromatic hydrocarbon carcinogens was considered tumor susceptibility-related candidate genes, and CYP1A1 gene polymorphism.Smoking may have a joint role in the occurrence of EC.The research about association between CYP1A1 gene polymorphisms and susceptibility to EC,and the joint role with environmental factors(smoking and drinking),is helpful to discover the mechanism of EC.It can make an exact molecular diagnosis,screen on the groups with high risks,and provide theoretical foundation for taking effective interventions.ObjectiveThe purpose of this study is to explore the association between metabolizing enzymes CYP1A1 gene polymorphisms,Mspâ… (Tâ†'C) in 3' non-coding region and Ile/Val(Aâ†'G) in exon7,and esophageal cancer susceptibility,and the joint roles of environment-gene and gene-gene,which may provide theoretical foundation for discovering the mechanism of EC and taking effective interventions.MethodsData from 16 literatures(8 for Mspâ… ,14 for Ile/Val) about case-control studies on association of cytochromeP450 polymorphisms with esophageal cancer risk were analyzed by Meta-analysis.The synthesis quantitative analysis was performed with Revman4.0 software,and processed sub-group analysis according to pathological types(esophageal squamous cell carcinoma(ESCC) /esophageal adenocarcinoma (EAC)).A population-based case-control study conducted on 157 patients with EC and 157 healthy controls matched to cases by 1:1 ratio was carried out.Genome DNA was extracted by phenol chloroform extraction from blood.The genotypes of polymorphisms were detected by the polymerase chain reaction-restriction fragment length polymorphisms(PCR-RFLP).Then the products of CYP1A1Mspâ… and Ile/Val were electrophoresed on 2.0%agarose gels or 3.0%agarose gels.Disease history, behavior habits(smoking,drinking),individual data and family history of upper gastrointestinal tract were surveyed by interviewing all subjects.Chi square test was used to compare genotype distribution between EC case group and healthy control group,and analyze the joint roles between CYP1A1 gene polymorphisms and smoking or drinking in occurrence of EC.Haplotype analysis was applied with SNPHAP software.Results1 Meta analysis results1.1 CYP1A1 Mspâ… Variant heterozygous genotype(T/C),variant homozygous genotype(C/C) and combined variant genotype(T/C+C/C),showed no association with EC risk compared with wild genotype(T/T).Odds ratio(OR) and 95% confidence interval(95%C/) were 1.25(0.85～1.82),1.16(0.69～1.94) and 1.17 (0.82～1.66),respectively.Stratified analysis results showed that variant homozygous genotype(C/C) and combined variant genotype(T/C+C/C),compared with wild genotype(T/T),had no association with esophageal adenocarcinoma(EAC) risk,but the individual carrying variant heterozygous genotype(T/C) had an increased risk of developing EAC(OR:2.80,95%CI 1.06～7.40);however,because only one literature was included in the meta-analysis,it has limited practical significance.We did not observe the statistically significant association of CYP1A1 gene Mspâ… polymorphism with susceptibility to esophageal squamous cell carcinoma(ESCC),and pooled OR (95%C/) is 1.21(0.84～1.74),1.21(0.87～1.68)and 1.17(0.82～1.69),respectively. 1.2 CYP1A1 Ile/Val Variant heterozygous genotype(Ile/Val) and combined variant genotype(Ile/Val+ Val/Val),compared with wild genotype(Ile/Ile),had higher risk, OR(95%CI) were 1.16(1.11～1.59) and 1.39(1.07～1.80),respectively.But variant homozygous genotype(Val/Val) has no association with EC risk(OR:1.62,95%CI 0.87～3.00).Stratified analysis results shows,compared with wild genotype(Ile/Ile), individuals carrying variant heterozygous genotype(Ile/Val) and combined variant genotype(Ile/Val+Val/Val) suffered from the risk of ESCC increased 0.34 times (OR:1.34,95%CI 1.11～1.61) and 0.43 times(OR:1.43,95%CI 1.07～1.91),but variant homozygous genotye showed no higher ESCC risk(OR:1.60,95%CI 0.91 3.11).It was fail to discover CYP1A1 Ile/Val gene polymorphism and susceptibility to EAC associated statistically,and ORs(95%CI) were 0.93(0.26～1.74),1.60(0.08～ 32.2) and 1.20(0.62～2.30),respectively.2 Case-control study results2.1 Genotype distribution Genotypes distribution of the two polymorphisms in CYP1A1 gene was consistent with Hardy-Weinberg equilibrium(HWE) in the heathy control group(P＞0.05).Frequencies of three genotypes of Mspâ… (T/T,T/C and C/C) were 29.9%,62.4%,7.7%and 39.5%,49.0%,11.4%in the case group and the control group,and there is no significant difference(χ~2=5.784,P＞0.05).Proportions of T and C alleles were 61.1%,38.9%and 64.0%,36.0%,and there was also no significant difference(χ~2=0.551,P＞0.05).Frequencies of three genotypes of Ile/Val polymorphism(Ile/Ile,Ile/Val and Val/Val) were 46.5%,45.9%,7.6%and 60.5%, 31.9%,7.6%in the case group and the control group,and there was significant difference(χ~2=6.848,P＜0.05).Proportions of A and G alleles are 69.8%,30.2%and 64.0%,36.0%,and there is significant difference(χ~2=0.551,P＞0.05). 2.2 Gene polymorphisms and esophageal cancer risk:The risk of EC in individuals carrying CYP1A1 Mspâ… variant heterozygous genotype(T/C) was higher than individuals carrying wild genotype(OR:1.68,95%CI 1.04～2.72).The risk of EC in individuals carrying CYP1A1 Ile/Val variant heterozygous genotype(Ile/Val) was higher than individuals carrying wild genotype(OR:1.87,95%CI 1.17～3.01).The risk of the individual carrying mutative genotype was higher than the individual carrying wild genotype(OR:1.76,95%CI 1.12～2.76).2.3 haplotype analysis results:Haplotype analysis was performed with SNPHAP software.There were four haplotypes,TA,TG,CA and CG.The result showed, compared with wild referent haplotype TA,CG haplotype which carries two variant locus is risk factor of EC(OR:1.43,95%CI 1.00～2.04),and the frequency of case group was higher than that of control group(P＜0.05).TG and CA haplotypes with only one mutative locus had no association with EC risk,and the ORs(95%CI) are 0.88(0.45～1.73) and 0.74(0.48～1.16).2.4 Combined genotype analysis of CYP1A1 polymorphisms:Compared with the individual carrying a wild genotype,the susceptibility to EC of individuals both carrying a mutation(TC/AG) increased 2 times(OR:2.07,95%CI 1.14～3.78),but other combined genotypes has no association with EC risk(P＞0.05).2.5 Gene-environment interaction:Compared with non-smokers carrying Mspâ… wild genotype(T/T),the EC risk of the smoker carrying variant heterozygous genotype (T/C) increased 1.13 times(OR:2.13,95%CI 1.01～4.48).Compared with non-smoker carrying Ile/Val wild genotype(Ile/Ile),we failed to discover the interaction of smoking and variant genotypes in EC developing.We also failed to find the interaction of smoking and variant genotypes in EC developing.ConclusionsMeta analysis revealed that CYP1A1 Mspâ… site may not be associated with esophageal cancer risk.Carrying heterozygous CYP1A1 mutant genotype(Ile/Val) and mutant genotypes(Ile/Val+Val/Val) may be the risk factors of ESCC,but the relationship between gene polymorphisms and EAC susceptibility needs further research.The case-control study shows,carrying CYP1A1 Mspâ… mutative genotype and CYP1A1 Ile/Val mutative genotype(Ile/Val or Ile/Val+ Val/Val) are risk factors of EC.Carrying haplotype CG is risk factor of EC,and combined genotype TC/AG is risk genotype of EC.Smoking and carrying CYP1A1 Msp/mutative genotype(T/C) have a cooperative role in EC developing,but smoking and CYP1A1 Ile/Val may not have a cooperative role.Drinking and carrying CYP1A1 susceptible genotypes may not exist in a cooperative role.