【作者】 袁天柱；

【导师】 周清华； 朱文； 杨俊杰； 刘伦旭；

【作者基本信息】 四川大学 ， 外科学， 2005， 博士

【摘要】 背景与目的 肺癌是发病率和死亡率增长最快,对人类健康和生命威胁最大的恶性肿瘤。肺癌已成为我国恶性肿瘤死因的首位。吸烟、职业暴露、环境污染等被认为是肺癌的危险因素。尽管绝大多数肺癌的发生与这些因素相关,但是仅有15%的吸烟者最终发生肺癌,有不足10%的肺癌患者则从不吸烟,而且生活在同一污染环境中的人群仅有小部分发生肺癌。产生这一结果的原因与人群或/和个体肿瘤易感性有关,即不同人群或/和个体对环境致癌物致癌的易患性不同。与肿瘤遗传易感性相关的基因主要有有两大类,即Ⅰ相与Ⅱ相代谢酶基因。这些基因均存在着遗传多态性,它们的产物往往具有不同的生物学活性,从而表现为机体对同一化学致癌物的易感性不同。 本研究首次通过病例-对照PCR-RFLP的方法研究CYP2A6、CYPlBl和GSTTl基因多态性与中国四川汉族人群患肺癌的易感性的关系,并更多还原

【Abstract】 Background and Objective Lung cancer is the most common malignant tumor which its incidence and mortality are increasing rapidness, and threaten the health and life of human furthest. Lung cancer is the first killer of cancer-related deaths both in men and women in the world. Cigarette smoking, various occupational exposures and carcinogens in heavily polluted air are the risk factors to lung cancer. Although it is well recognized that most of lung cancer are attributable to these factors, only 15% of all smokers develop lung cancer and under 10% of all diagnosed lung cancer are among never smokers. Genetic susceptibility is one of primary hypotheses used to explain why a minority of smokers develop lung cancer. Genetic polymorphism in metabolic enzyme gene, which are involved in themetabolism of environmental carcinogens, have been thought to be related to the susceptibility of lung cancer. There are two kinds of genes related to tumor susceptibility, namely phase I and phase II metabolic enzyme genes. All the metabolic enzyme genes have polymorphisms, and their products have different biologic activity, therefore the body have different susceptibility to cancer in different people or different individuals.Up to now, we have not seen any reports on the relationship between the genetic polymorphisms of CYP2A6, CYP1B1 and GSTT1 gene and lung cancer susceptibility of the Chinese Han Nationality population in Sichuan province in the world. Our study is the first one using case-control and restriction fragment length polymorphism ( PCR-RFLP) method to investigate the distribution and characteristics of CYP2A6, CYP1B1 and GSTT1 genetic polymorphisms, and the relationship between genetic polymorphisms of CYP2A6, CYP1B1 and GSTT1 gene and lung cancer susceptibility in Chinese Han Nationality population of Sichuan province in China. The key aim of this study are as follows:(1) to evaluate the potential role of separate single CYP2A6, CYP1B1 and GSTT1 genetic polymorphisms on lung cancer susceptibility; (2) to evaluate the potential role of the combination of CYP2A6, CYP1B1 and GSTT1 genetic polymorphisms on lung cancer susceptibility; (3) the interactions between genetic polymorphisms and smoking on lung cancer susceptibility. The results of this study firstly showed in the world as follows: 1 .The frequency of CYP2A6wt and CYP2A6del genotype was 96.0% and 4.0% in lung cancer group, and 87.5% and 12.5% in control group respectively. A highly significant difference was found between the twogroups ft2=7.184, /*=0.007).2.The results of Binary Logistic Regression showed that the people who carried with CYP2A6wt genotype had a 3.756 fold increased risk of lung cancer than those who carried with CYP2A6del genotype(95%CI=1.387~ 10.171, P=0.009).3.The people who carried with CYP2A6wt genotype had a 7.511 fold increased risk of SCC than those who carried with CYP2A6del genotype (95 %CI=1.601—35.230, P=0.011).4.The smokers who carried with CYP2A6wt genotype had a 28.879 fold increased risk of lung cancer than those who carried with CYP2A6del genotype(95%CI=3.537~235.763, P=0.002).5.The smokers who carried with CYP2A6wt genotype had a 10.307 fold increased risk of lung cancer than the nonsmokers who carried with CYP2A6wt genotype (95 %CI=5.199~20.434, P=0.000).6.The heavy smokers(YP^20) who carried with CYP2A6wt genotype had a 23.100 fold increased risk of lung cancer than those who carried with CYP2A6del genotype (95%CI=2.680~199.142, i>=0.004).7.The frequency of CYP1B1(C/C) and CYP1B1(G/C+G/G) genotypes was 67.3% and 32.7% in lung cancer group, and 71.9% and 28.3% in control group respectively. No significant difference was found between the two groups (x2=0.683, i>=0.409).8.No significant difference was found between the people who carried with CYP1B1(G/C+G/G) genotype and those people who carried with CYPlBl(C/C)genotype(OR=1.514, 95%CI=0.883~2.596, P=0.l32).9.No significant difference were found among polymorphisms ofCYP1B1 Val432Leu and the SCC(OR=2.012, 95 % Cl=0.957 - 4.234, P=0.065), AD(OR=1 474, 95%CI=0.727~2.988, P=0.282) and Other type lung cancer risk (OR-1.830, 95%CI=0.646—5.178, P=0.255).lO.The smokers who carried with CYP1B1(G/C+G/G) genotype had a 2.521 fold increased risk of lung cancer than those who carried with CYP1B1(C/C) genotype(95%CI=1.046~6.080, P=0.039).11.The smokers who carried with CYP1B1(C/C) genotype had a 5.764 fold increased risk of lung cancer than the nonsmokers who carried with CYP1B1(C/C) genotype (95%CI=2.690~12.350,P=0.000); The smokers who carried with CYP1B1(G/C+G/G) genotype had a 12.093 fold increased risk of lung cancer than the nonsmokers who carried with CYP1B1(G/C+G/G) genotype (95 %CI=3.713~39.388,P=0.000).12.The heavy smokers(YP^20) who carried with CYP1B1(G/C+G/G) genotype had a 4.762 fold increased risk of lung cancer than those who carried with CYP1B1(C/C) genotype (95 %CI= 1.300—17.444, /M).O18).13.The frequency of GSTT1(+) and GSTTl(-) genotype was 45.3% and 54.7% in lung cancer group, and 61.8% and 38.2% in control group respectively. A highly significant difference was found between the two groups (x2=8.274, P=0.004).14.The people who carried with GSTTl(-) genotype had a 1.715 fold increased risk of lung cancer than those who carried with GSTT1(+) genotype (95%CI= 1.038-2.853, P=0.038).15.The people who carried with GSTTl(-) genotype had a 2.565 (95% CI= 1.323-4.975, P=0.005) fold increased risk of SCC and 2.149 (95%CI = 0.365—2.863, ^=0.966) fold increased risk of AD than those whocarried with GSTT1(+) genotype.16.The smokers who carried with GSTTl(-) genotype had a 4.088 fold increased risk of lung cancer than those who carried with GSTT1(+) genotype (95%CI= 1.977—8.454, i>=0.000).17.The smokers who carried with GSTTl(-) genotype had a 58.518 fold increased risk of lung cancer than the nonsmokers who carried with GSTTl(-) genotype (95%CI= 12.868-266.119, />=0.000).18.The light smokers(YP<20) who carried with GSTTl(-) genotype had a 3.294 fold increased risk of lung cancer than those who carried with GSTT1(+) genotype(95 % CI = 1.022 -10.619, P =■ 0.046). The heavy smokers(YP$:20) who carried with GSTTl(-) genotype had a 4.296 fold increased risk of lung cancer than those who carried with GSTT1(+) genotype(95%CI= 1.649-11.190, P=0.003).19.The individuals who carried with combination of CYP2A6wt/GSTTl(+) and CYP2A6wt/GSTTl(-) genotypes had a 4.444(95%CI=1.240~ 15.926, P=0.022) and 11.782(95%CI = 2.955-46.985, P=0.000) fold increased risk of lung cancer than those who carried with combination of CYP2A6del /GSTT1(+) genotype respectively.2O.The smokers who carried with combination of CYP2A6wt/GSTTl(+) and CYP2A6wt/GSTTl(-) genotypes had a 13.739 (95%CI=1.396—98.737, P=0.023) fold and 46.255(95%CI =5.314-402.584, P=0.00l) fold increased risk of lung cancer than those carried with combination of CYP2A6del/GSTTl(+) genotype respectively.21.The individuals who carried with combination of CYP1B1 (C/C)/GSTT1(-) and CYP1B1(G/C+G/G)/GSTT1(-) genotypes had a1.915(95%CI=1.023-3.584, P=0.042) and 2.328(95%CI =1.146-4.728, P=0.019) fold increased risk of lung cancer than those who carried with combination of CYP1B1(C/C)/GSTT1(+) genotype respectively.22.The smokers who carried with combination of CYP1B1(C/C)/ GSTTl(-) and CYP1B1(G/C+G/G)/GSTT1(-) genotypes had a 4.592 (95%CI=2.024 — 10.415, /M).000) and 6.612 (95%CI=2.110-20.724, P=0.001) fold increased risk of lung cancer than those who carried with combination of CYP1B1(C/C)/GSTT1(+) genotype respectively.23 .The individuals who carried with combination of CYP2A6wt/ CYP1B1 (C/C) and CYP2A6wt/CYPlBl(G/C+G/G) genotypes had a 4.568 (95%CI=1.417—14.722, P=0.011) and 6.058 (95%CI=1.714-21.407, />=0.005) fold increased risk of lung cancer than those who carried with combination of CYP1B1(C/C)/GSTT1(+) genotype respectively.Conclusion: (1) CYP2A6wt genotype remarkably increases lung cancer susceptibility of Sichuan Han Nationality population in China, especially increases SCC susceptibility. In addition, a close interaction was existed between CYP2A6wt and smoking in the oncogenesis of lung cancer. (2) CYP1B1(G/C+G/G) genotype remarkably increases lung cancer susceptibility in the smokers of Sichuan Han Nationality population in China. Moreover, a close interaction was existed between CYP1B1(G/C+G/G) genotype and smoking in the oncogenesis of lung cancer. (3) GSTTl(-) genotype remarkably increases SCC and AD susceptibility of Sichuan Han Nationality population in China, especially increases lung cancer susceptibility in smokers. Moreover, there is a close interaction between GSTTl(-) genotype and smoking in the oncogenesis of lung cancer. (4) Thecombination of CYP2A6wt/GSTTl(+) , CYP2A6wt/GSTTl(-) > CYP1B1(C/C)/ GSTTl(-) and CYP1B1(G/C+G/G)/GSTT1(-) genotypes remarkably increases lung cancer susceptibility of Sichuan Han Nationality population in China respectively, especially increases lung cancer susceptibility in smokers. Moreover, there are close interactions between these genotypes and smoking in the oncogenesis of lung cancer. (5)The individuals who carried with combination of CYP2A6wt/CYPlBl(C/C) and CYP2A6wt/CYPlBl(G/C+G/G) genotypes remarkably increase lung cancer susceptibility of Sichuan Han Nationality population in China respectively. (6) CYP2A6wt genotype is the strongest genotype in increasing lung cancer risk of Sichuan Han Nationality population in China in our study, the GSTTl(-) genotype take second place, and the role of CYP1B1(G/C+G/G) genotype is unclear.更多还原