| Backgroud and Objective 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 of 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 ~ 10% of all diagnozed lung cancer are among never smokers. Genetic susceptibility is one of primary hypotheses used to explain why a minority of smokers develops lung cancer. Genetic polymorphism in metabolic enzymes, which are involved in the metabolism of environmental carcinogens, have been thought to be related to susceptibility of lung cancer. However, the previously results about the relationship between metabolic gene polymorphisms and lung cancersusceptibility have been conflicting. Up to now, we have not seen any reports on the relationship between the genetic polymorphisms of CYP2D6, NAT2, and GSTP1 gene and lung cancer susceptibility of the Chinese Han Nationality population in Sichuan Province in the world. The aim of this study is as following: (1) to investigate the distribution and characteristics of CYP2D6, NAT2 and GSTP1 genetic polymorphisms in Chinese Han nationality population of Sichuan Province in China;(2) to evaluate the potential role of the separately CYP2D6, NAT2 and GSTP1 genetic polymorphisms on lung cancer susceptibility; (3) to evaluate the potential role of the combination of CYP2D6, NAT2 and GSTP1 genetic polymorphisms on lung cancer susceptibility; (4) to provide the theoretical and experimental ground of biomarker for lung cancer screening and early diagnosis.Material and Methods The experimental subjects were composed of 150 cases of primary lung cancer and 152 healthy controls from Chinese Han nationality population in Sichuan Province in China. Genotypes of the CYP2D6, NAT2 and GSTP1 were determined by genomic amplification and restriction fragment length polymorphism analysis. DNA extracted from blood samples was used for genotyping, and the case-control study was used to analyze the relationship between genetic polymorphism and lung cancer susceptibility.Results 1.The frequences of CYP2D6ch C and T allele were 60.5% and 39.5% in control group, and 46.3% and 56.7% in lung cancer group, respectively. There was no significant difference between the two groups(P=0.089).2.The frequence of the CYP2D6ch C/C, C/T, T/T genotypes were 18.4 %, 42.1 % and 39.5% in control group, and 22.7%, 47.3% and 30% in lung cancer group, respectively. No significant difference was found between the two groups(P=0.215).3. The frequence of the CYP2D6ch Non-T/T genotypes was 60.5% in control group and 70.0% in lung cancer group, respectively. No significant difference was found in the two groups(P=0.262).4.The people who carried with Non-T/T genotypes had a 2.08 fold increased risk of squamous cell carcinoma (95%CI 1.024-4.244, P=0.043) than those who carried with T/T genotypes.5.The lightly smokers who carried with Non-T/T genotypes had a 2.92 fold increased risk of lung cancer (95%CI 1.087—7.828, i*=O.O33) than those who carried with T/T genotypes.6.The frequences of NAT2 WT, Ml, M2 and M3 allele were 54.9%, 3.3%, 23.0% and 18.8% in control group, and 44.7%, 4.3%, 28.3% and 22.7% in lung cancer group, respectively. There was no significant difference between the two groups(/)=0.094).7.The frequences of the NAT2 WT/WT, WT/MX and Mx/Mx genotypes were 28.9%, 52.0% and 19.1% in control group, and 22.0%, 45.3% and 32.7% in lung cancer group, respectively. A highly significant difference was observed between the two groups (^=0.023).8.The people who carried with slow NAT2 genotypes had a 1.84 fold increased risk of lung cancer(95%CI 1.044-3.231, />=0.035) than those who carried with fast NAT2 genotypes. The people who carried with slow NAT2 genotypes had a 2.05 fold increased risk of adenocarcinoma(95%CI1.242-4.973, P=0.010) than those who carried with fast NAT2 genotypes.9. The smokers who carried with slow NAT2 genotypes had a 2.34 fold increased risk of lung cancer (95%CI 1.007-5.424, P=0.048) than those who carried with fast NAT2 genotypes.lO.The frequences of GSTP1 A and G allele were 77.0% and 23.0% in control group, and 71.7%, 28.3% in lung cancer group, respectively. No significant difference was existed between the two groups (/*=0.135).1 l.The frequence of the GSTP1 A/A, A/G and G/G genotypes were 56.6 %, 40.8% and 2.6% in control group, and 49.3%, 44.7% and 6.0% in lung cancer group. No significant difference was found between the two groups(P=0.223).12.There was no significant association between polymorphisms of GSTPl and the overall lung cancer risk (OR=1.43, 95%CI 0.890-2.306, i*=0.138). However, the people who carried with Non-A/A genotypes had a 2.31 fold increased risk of squamous cell carcinoma (95%CI 1.024-4.244? /M).015) than those who carried with A/A genotypes.13.The individuals carried with CYP2D6ch Non-T/T and slow NAT2 genotypes had a 2.76 fold increased risk of lung cancer(95% CI 1.229— 6.177, P=0.014) than those carried with CYP2D6ch T/T and fast NAT2 genotypes.14. The individuals carried with CYP2D6ch T/T and GSTPl Non-A/A genotypes had a 2.64 fold increased risk of lung cancer(95% CI 1.017-6.306, P = 0.029) than those carried with CYP2D6ch T/T and GSTPl A/A genotypes.15 The individuals carried with CYP2D6ch Non-T/T and GSTPlNon-A/A genotypes had a 2.81 fold increased risk of lung cancer(95% CI 1.271-6.206, /)=0.010) than those carried with CYP2D6ch T/T and GSTPl A/A genotypes.16. The individuals carried with slow NAT2 and GATP1 Non-A/A genotypes had a 3.68 fold increased risk of lung cancer (95% CI 1.622-8.331, P = 0.002) than those carried with fast NAT2 and A/A genotypes.Conclusion (1) The genetic polymorphism distribution of CYP2D6, NAT2, GSTPl of the Chinese Han Nationality population in Sichuan was coincident with other Han Nationality population in China, but different from Western population. (2)A significant association was existed between the polymorphism of NAT2 and overall lung cancer risk. Slow NAT2 genotypes significantly increase risk of lung cancer in Sichuan Han Nationality population, especially increasing adenocarcinoma risk and risk of lung cancer in the smokers. (3)There was no significant association between the polymorphism of CYP2D6, GSTPl and overall lung cancer risk in Sichuan Han Nationality population. However, CYP2D6 Non-T/T and GATP1 Non-A/A genotypes significantly increase risk of squamous cell lung cancer. Moreover, CYP2D6 Non-T/T genotype remarkably increase risk of lung cancer in the lightly smokers of Sichuan Han Nationality population. (4)The combination of CYP2D6, NAT2 and GSTPl genetic polymorphisms more significantly increase lung cancer risk than single genetic polymorphism of CYP2D6, NAT2 and GSTPl does in the Chinese Han Nationality population in Sichuan.
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