Case Control Study Of The Association Between CYP1A1 NAT2 GSTM1 Genetic Polymorphism And Lung Cancer Risk

Objective:Lung cancer poses a major threat to human survival and health, both the incidence and death rate of lung cancer are in the first place among cancers worldwide. The rapid development of medical technology greatly improved health care quality, however, the recent situation in the diagnosis and treatment of lung cancer is far beyond what we have expected. Statistics showed that the incidence and death rate of lung cancer had increased tens of times than 50 years ago, and the overall recovery rate of lung cancer remained less than 15% percent at the same time. So it is of great significance to conduct researches on early diagnosis of lung cancer. Studies have shown that lung cancer is affected comprehensivly by smoking, environment pollution, individual genetic factors and so on. The Human Genome Project and the following HapMap Project facilitate the study on the association between SNPs or haplotypes and lung cancer susceptibility to a great extent. CYP1A1,NAT2,GSTM1 are key human Phaseâ… or Phaseâ…¡metabolic enzyme genes whose genetic polymorphism are considered to be predisposition factors to lung cancer. Thus, in our study,we selected five SNPs (rs1048943,rs4646422,rs1799930,rs1208,rs1799931) of the CYP1A1 and NAT2 gene, which were all non-synonymous mutations. We applied high sensitive, high specific and high through-out methods to analyze the genetic polymorphism of the CYP1A1,NAT2,GSTM1 gene, and constructed haplotypes of the CYP1A1 and NAT2 gene, and finally analyzed the relationship between genetic polymorphisms of these gene and lung cancer risk.Methods:This case control study that we conducted included 266 histological confirmed lung cancer patients and 307 control subjects. The lung cancer patients were recruited from Tianjin general hospital and the controls were local citizens from Tianjin taking part in health screening survey at the Health managing center of Tianjin medical university general hospital. We applied the Taqman assay to explore the genetic polymorphism of the CYP1A1 and NAT2 gene, and used the SYBR green I real-time PCR combined with melting curve analysis method to detect the GSTM1 genetic polymorphism. PHASEv2.0 software was used to construct haplotypes of the CYP1A1 and NAT2 gene. The logistic regression analysis was carried out to estimate the association between genetic polymorphisms of these gene and lung cancer risk which was manifested by Odds Ratio(OR) and 95% confidential interval(95%CI). Further stratification analysis by smoking status and lung cancer histological types were also conducted. Results:1.Our study shows that there was no overall relationship between CYP1A1 rs1048943 polymorphism and lung cancer risk. And carriers of the rs4646422 TT genotype was in a relationship with lung cancer risk with a marginal statistical significance. Among subject more than 60 years old, the CG haplotype increased lung cancer risk and reached the statistical significance level.2. There were no overall association between NAT2 rs1799930,rs1799931 polymorphism and lung cancer risk. No assciation was found between NAT2 intermediate and slow acetylation genotypes and lung cancer risk. The NAT2*12A alle was found to be associated with reduced lung cancer risk in our study.3. The frequencies of the GSTM1(-) genotype in lung cancer group and control group was 56.6% and 57.0% respectively, no statistically significance was found in the frequency distribution of these two groups. Compared to the GSTM1(+) genotype, no association was found between GSTM1(-) genotype and lung cancer risk, and also no association was found between GSTM1(-) genotype and lung cancer risk when stratified by lung cancer histological types. As for the group of non-smokers, the GSTM1(-) was shown to be associated with reduced lung cancer risk which reached the statistical significance level, and on the other hand, the GSTM1(-) was observed to be associated with increased lung cancer risk, but with no statistical significance.Conclusion:The CYP1A1 rs4646422 TT polymorphism was associated with increased lung cancer risk. The CYP1A1 CG haplotype was associated with increased lung cancer risk among subjects more than 60 years old. The NAT2 rs1208 SNP was associated with reduced lung cancer risk in non-smokers, and the NAT2*12A haplotype was associated with reduced lung cancer risk.