A Case Control Study On The Association Between Genetic Polymorphisms Of CYP1A1, CYP2E1, GSTM1 And Lung Cancer Susceptibility

Lung cancer is the leading cause of malignant tumor death among Chinese population. Epidemiological studies have demonstrated that tobacco smoke and environmental carcinogens plaied an important role in the oncogenesis of lung cancer. Most carcinogens are metabolized to their ultimate carcinogens depended on the action of phase I and phase II enzymes. Genetic polymorphisms existed in most metabolizing genes encoding metabolizing enzymes. Since metabolizing enzymes play an important role in the metabolic activation and detoxication of precarcinogens and polymorphisms of metabolizing enzymes can change their activities, it is necessary to elvaluate the correlation between the polymorphisms of metabolizing enzyme gene and the susceptibility of lung cancer, which willnot only illuminate the molecular mechanism of lung cancer, but also provide a new route for screening and early diagnose of lung cancer. Recently, it has been proved that polymorphisms of CYP1A1, CYP2E1 and GSTM1 genes were closely associated with the risk of lung cancer. In order to explore the effects of combined polymorphisms of these genes on lung cancer susceptibility in Chinese population, polymorphisms of CYPlAl Exon 7.CYP2E1 RsaI/PstI and DraI, GSTM1 gene were detected in 150 patients with lung cancer and 152 healthly controls in Chinese Sichuan Han subjects by PCR,AS-PCR and PCR-RFLP.The associations between genetic polymorphisms and susceptibility of lung cancer in Chinese Sichuan Han subjects were analyzed. The interaction among genotype, smoking status and lung cancer susceptibility were also analyzed. The feasibility of different histology samples used in evaluating genetic polymorphism were discussed, too.The results in this study first showed in the world as follows:1. The frequency of CYP1A1 Exon 7 genotypes in lung cancer group and control group were 21.3%, 69.3%,9.3% and 25.7%, 69.1%, 5.3%,respectively.No significant differences in CYP1A1 Exon 7 genotype distributions were found between the two groups (X2=0.634, P=0728) .2. The individuals who carried with mutated Val allele had an increased risk of lung cancer than those who carried with Ile/Ile wild genotype. The OR for Ile/Val and Val/Val genotypes were 1.104 and 1.529, respectively. When data were stratified by smoking status, this trend still existed.3. When data were stratified by smoking status, The risk of lung cancer in the individuals who carried with Ile/Val and Val/Val genotype increased gradually with the smoking dose increasing .The estimated relative risk in thelight smoker and heavy smoker was 1.231 and 1.842, respectively.4. The individuals who carried with Ile/Val and Val/Val genotypes had an increased risk for lung squamous cell carcinoma than those who carried with Ile/Ile genotype (OR=3.510, 95%CI =1.326-9.293, p=0.011) .But no significant relationship was observed in adenocarcinoma of the lung (OR=1.398,95%CI=0.690-2.832).5. The frequency of c1/c1,c1/c2 and c2/c2 genotype was 62.7%,34.7% and 2.7% in lung cancer group and 54.6%,41.4% and 3.9% in control group,respectively.No significant difference in frequencies of CYP2E1 RsaI/PstI genotypes was found between the two groups (X2=3.186, P= 0.203).6. Compared with c1/c1 genotype carriers , the estimated relative risk for c1/c2 and c2/c2 genotype carriers was 0.729 and 0.589 ,respectively.Even after adjusted by age ,gender and smoking status,the risk in the individuals who carried with at least one c2 allel genotype(OR=0.635, 95%CI = 0.690-2.832) was lower than those who carried with cl/cl genotype.7. Considering smoking status and smoking level, the individuals who carried with cl/cl genotype had increased lung cancer risk than those who carried with at least one c2 genotypes,but no sifhificant difference was observed between the two groups(.P>0.05). No remarkable association was observed between RsaI/PstI genotypes and smoking on susceptibility of lung cancer,too.8. Compared with cl/c2 and c2/c2 genotypes carriers, the risk of adenocarcinoma in the individuals who carried c1/c1genotype was significantly increased (OR=2.152,95%CI=1.130-4.099, P=0.02 and adjustedOR=2.44, 95%CI=1.235-4.820,P=0.01). But no simificant relationship was found between c1/c1 genotype and susceptibility of squamous cell cancer.9. The frequency of DD,DC and CC genotype were 58.7%,35.3% and 6% in lung cancer group,and 52.0%,40.1% and 7.9% in control group,respectively.No significant differences in CYP2E1 DraI genotype distributions were found between lung cancer and control group (X2=1 .756, P=0.416) .10. The individuals who carried with at least one mutated C allele had a lower risk of lung cancer compared with those carried with DD genotype, despite of smoking status and smoking level (P>0.05).11. Compared with individuals who carried with DC and CC genotypes, people carried with DD genotype had an increased adenocarcinoma risk (OR=1.638, 95%CI=0.873-3.073, P=0.125). The OR for squamous cell cancer was 1.206(95%CI=0.670-2.172) in the individuals carried with DD genotype.12. GSTM1 genotype among cancer tissue, adjacent cancer tissue, distant cancer tissue, lymph node tissue ,bronchial tissue and peripheral blood sample in the same individual was the same.13. The frequency of GSTM1-null genotype in lung cancer group was significantly higher than that in control group (53.3% vs 40.91%, adjusted X2=6.646,P=0.010).14. The individuals who carried with GSTM1-null genotype had a 1.9 fold increased risk of lung cancer (95%CI=1.171-3.191, P=0.010) than those carried with GSTM1(+) genotype.15. GSTM1(-) genotype remarkably increased lung cancer risk in bothsmokers and non-smokers.The individuals who carried with GSTM1(-) genotype had increased lung cancer risk than those carried with GSTM1(+) genotype in smoking group, which were also higher than overall lung cancer(OR=1.933).16. The carriers with GSTM1(-) genotype had gradually increased lung cancer risk with smoking dose increasing.OR with lung cancer were 1.823 for non-smoker and 2.184 (95%CI=0.820-5.818)for light smoker,and increased to 2.958 (95%CI=0.933-9.383) for heavy smoker.17. GSTM1(-) genotype significantly increased the risk suffering from other histology type of lung cancer (included small cell cancer and mixed cancer) (OR=4.204, 95%CI=1.429-12.365), but no association was existed between GSTM1 genotype and the risk for adenocarcinoma and squamous cell cancer.18. Compared with the individuals who carried with combination of GSTM1(+) and Ile/Ile genotype,the OR of lung cancer was 3.683(P=0.021) in the peoples carried with combination of GSTM1 null and Ile/Ile genotype ,and 2.307(P=0.031)for those carried with either GSTM1 null and Ile/Val genotype or GSTMl null and Val/Val genotype.Combination of GSTM1(-) and Val genotype significiantly increased lung cancer susceptibility.19. The combination of GSTM1(+) and at least one c2 allele genotype was remarkably higher in the control group than that in the lung cancer group. (13.3% vs 27.6%, P=0.014).20. Compared with individuals carried with combination of GSTM1(+) and mutated allele c2, the estimated relative risk was increased 2.477 foldthan those carried with combination of GSTM1(+) and c1/c1 genotype (95%CI=1.211-5.064,P=0.013).The combination of GSTM1 null and either of RsaI/PstI genotypes was closely associated with increased lung cancer risk. The OR of lung cancer for the combination of GSTM1 null and c1/c1 genotype was the highest in the different combination of GSTM1 and CYP1A1 genotype (OR=3.523,P=0.001). The OR for the combination of GSTM1 null and at least one c2 genotype was 3.232 (P=0.003).21. Compared with people who had the combination of GSTM1(+) and DC or CC genotype,the OR of lung cancer for the combination of GSTMl null and DC or CC genotype was 2.504(P=0.016).The OR for GSTM1 null and DD genotype increased 2.763 fold (P=0.006).Conclusion:(1) GSTMl (+) and c2 mutated genotype are the protective genes for lung cancer in Chinese Sichuan Han population in China.However, the GSTM1(-), c1/c1 and Val mutated allele genotypes are susceptible genes for lung cancer in Chinese Sichuan Han population in China;(2) GSTMl null remarkably increase lung cancer susceptibility in smoker; (3) Polymorphisms of CYP1A1 Exon 7 may play an important role in the oncogenesis of squamous cell carcinoma of the lung.The polymorphisms of CYP2E1 RsaI/PstI are closely associated with increased risk for adenocarcinoma in Chinese Sichuan Han population; (4 ) Combined GSTM1(-) and Val and c1/c1 genotype signisicantly increase lung cancer susceptibility in Chinese Sichuan Han population in China;(5)Blood sample and lung tissues sample is equivalent in the evaluation of CYP1A1,CYP2E1 and GSTM1 polymorphisms...