【作者】 宋雅辉；

【导师】 尹立红；

【作者基本信息】 东南大学 ， 劳动卫生与环境卫生学， 2004， 硕士

【摘要】 目的:食管癌是淮安地区发病率最高的恶性肿瘤,它的发病是遗传易感性与环境因素共同作用的结果。为此,我们对淮安人群食管癌易感基因与环境危险因素在食管癌发生中的交互作用进行了研究。方法:本研究采用1:1配对病例-对照的研究方法,对淮安106例诊断明确的原发性食管癌病人,以及作为对照的106例非肿瘤、非消化系统疾病者进行了包括吸烟、饮酒、饮食、饮水类型等方面的流行病学调查;并采集病例和对照的外周血5ml,提取DNA,应用PCR-RFLP方法对Ⅰ相代谢酶基因CYP1A1、CYP2E1和Ⅱ相代谢酶基因GSTM1、 GSTT1以及修复酶基因XRCC1、XPD进行了基因型在两组人群中的分布及其与食管癌易感性关系的研究。应用多因素条件Logistic回归分析方法,对环境危险因素进行筛选,并对环境因素人群归因危险度做了分析。应用多因素Logistic回归分析,对在食管癌发生中代谢酶基因与修复酶基因的交互作用以及环境-环境、基因-环境的交互作用进行了分析。结果:研究结果显示,XRCC1 Arg399Gln的多态性改变与食管癌易感性相关,携带突变纯合子Gln/Gln的个体患食管癌的易感性显著高于对照人群。对代谢酶基因与修复酶基因交互作用的分析发现,CYP2E1的突变基因型与GSTT1基因的缺失型同时存在的个体,其患食管癌的危险性下降,这类人对食管癌的易感性低于正常人。同时,存在XRCC1 194位与399位的突变基因型的个体对食管癌的发生易感性也有所降低,提示不能低估基因间的交互作用对基因功能的影响。经多因素条件Logistic回归分析,吸烟深度、喜食烫食或冷食、常食用腌腊制品、饮水类型以及消化道肿瘤家族史是本次调查淮安食管癌的环境危险因素;对环境因素人群归因危险度的分析结果显示,依次控制上述五项危险因素,可使食管癌的发病分别降低23.56%、18.07%、29.58%、29.29%和25.13%;若同时控制这五项食管癌的危险因素,则可使食管癌的发病减少72.79%;在食管癌发生中环境因素-环境因素的交互作用分析显示,消化道肿瘤家族史与食用葱蒜<WP=7>间具有协同作用,有消化道肿瘤家族史而又不食用葱蒜者,其患病危险性将大大增加。分析了基因-环境交互作用后发现,CYP1A1突变基因型与吸烟间存在协同作用;XRCC1的突变基因型和喜食烫食或冷食对食管癌的发生有协同作用;GSTT1的缺失型与饮水类型间有协同作用;CYP2E1的突变基因型与有消化道肿瘤家族史间的协同作用,均使得上述人群食管癌的患病危险性升高。结论:本研究结果说明,尽管遗传因素在食管癌的发生中起一定作用,但食管癌的发病的危险主要来自环境因素,对基因与环境的交互作用应予以高度重视。本研究为明确淮安地区食管癌的高发病因,以及降低发病率和一级预防方案的制定提供了理论依据。更多还原

【Abstract】 Objective: The highest incidence rate of malignant tumor is esophageal cancer in Huai-an. It is the results of the interaction between environmental and genetic factors. The current study analyzed the interaction between genetic polymorphisms and environmental risk factors to esophageal cancer in Huai-an population.Methods: A hospital-based 1:1 case-control study was conducted among 106 esophageal cancer patients and 106 controls who had no disease history of cancer and digestive system. These patients were diagnosed as primary esophageal cancer. The questionnaire included items on smoking status, alcohol consumption, diet and drinking habit, et al. Each of cases and controls provided 5ml peripheral blood sample to extract DNA. PCR-RLFP technique was used for analyzing genotypes of CYP1A1, CYP2E1, GSTM1, GSTT1, XRCC1 and XPD. The risk factors were screened by multivariate conditional logistic regression model and the PAR was calculated. The interaction between genes and environmental risk factors was analyzed by multivariate logistic regression model.Results: The results showed that the polymorphisms of XRCC1 Arg399Gln were related to the susceptibility of esophageal cancer. The Gln/Gln genotype frequency was significantly higher in the cases than controls. The interaction between polymorphisms of metabolic enzyme genes and repair genes was analyzed. It was revealed the combined genotypes of both CYP2E1 (wt/mt+mt/mt) and GSTT1 (null) had an antagonistic joint action in risk of esophageal cancer. Similarly, there was an <WP=9>antagonistic joint action between XRCC1 399codon (Arg/Gln+Gln/Gln) and 194condon (Arg/Trp+Trp/Trp). The environmental risk factors related with esophageal cancer were deep of smoking, hobby of hot or cold food, frequent consumption of pickled food, kinds of drinking and family history of digestive tumor. The population attributable risk of the five factors was 23.56%, 18.07%, 29.58%, 29.29% and 25.13%, respectively. Summary population attributable risk for the five factors was 72.79%. Combination analysis of environmental risk factors and polymorphisms of genes showed that there was a synergistic effect on development of esophageal cancer between CYP1A1 mutation genotype and smoking; between XRCC1 399codon (Arg/Gln+Gln/Gln) and hobby of hot or cold food; between GSTT1 (null) and drinking well-water; between CYP2E1 and family history of digestive tumor. These synergistic effects increased the risk of esophageal cancer. Conclusion: The results of this study show that although genetic factors have an effect on the incidence of esophageal cancer, the main risk factors are environmental factors. The attention should focus on the interaction between genetic polymorphisms and environmental risk factors. These results provide foundation of theory on the etiology, decreasing morbidity and mortality of esophageal cancer, and making primary preventive project.更多还原