Association Study Of TP73-AS1 And EZH2 Single Nucleotide Polymorphisms And Genetic Susceptibility To Lung Cancer In Non-Smoking Women

Objective:Lung cancer is the leading cause of cancer death in the world,which greatly threatens people’s health.Most of them have no obvious clinical symptoms in the early stage,so it is very important to explore molecular markers for early diagnosis of lung cancer.Genome-wide association studies have identified multiple single nucleotide polymorphism(SNP)markers associated with the risk of lung cancer.Lnc RNA P73antisense RNA1(TP73-AS1)and Enhancer of zeste homolog2(EZH2)has been proven to be associated with the occurrence and development of cancer.The purpose of this study was to investigate the relationship between TP73-AS1 rs3737589,EZH2rs12670401 and rs3757441 polymorphisms and genetic susceptibility to lung cancer in non-smoking women.Methods:This study is a hospital-based case-control study.According to the uniform inclusion and exclusion criteria,778 samples(including 389 non-smoking female lung cancer patients and 389 non-smoking female controls)were selected.All cases were confirmed by histological diagnosis.DNA was extracted from venous blood using the classical phenol-chloroform method,and then the single nucleotide polymorphisms of TP73-AS1 rs3737589 and EZH2 rs12670401 and rs3757441 were detected by Taq Man probe genotyping technology.T test andχ~2 test were used to analyze the differences between groups in age and exposure status of oil fume andχ~2 test was used to test whether the control group was in line with Hardy-Weinberg equilibrium(HWE)to judge the representability of the control population.Logistic regression analysis was performed to evaluate the association and cumulative effect of polymorphisms at the three loci with lung cancer susceptibility.The interaction between SNPs of TP73-AS1and EZH2 and oil fume exposure status was assessed using a crossover analysis,and additive and multiplicative interactions were assessed separately.Results:1.The TP73-AS1 rs3737589 polymorphism was associated with the risk of lung cancer:AG genotype carriers had a 33.2%lower risk of lung cancer than AA genotype individuals(AG vs.AA:OR=0.668,95%CI=0.495-0.901,P=0.008).The susceptibility of AG and GG genotype individuals to lung cancer was 32.2%lower than AA genotype individuals(AG+GG vs.AA:OR=0.678,95%CI=0.509-0.904,P=0.008).The susceptibility of lung cancer in G allele carriers was 0.778 times of that in A allele carriers(G vs.A:OR=0.778,95%CI=0.623-0.972,P=0.027).When analyzed by different pathological subtypes of lung cancer,rs3737589 polymorphism can reduce the risk of lung adenocarcinoma,showing statistically significant association in the three models(AG vs.AA:OR=0.579,95%CI=0.414-0.810,P=0.001;AG+GG vs.AA:OR=0.591,95%CI=0.429-0.814,P=0.001;G vs.A:OR=0.714,95%CI=0.555-0.918,P=0.008).The rs3737589 polymorphism is associated with the risk of non-small cell lung cancer,and is a protective factor for non-small cell lung cancer,showing similar results as lung cancer and lung adenocarcinoma(AG vs.AA:OR=0.669,95%CI=0.490-0.915,P=0.012;AG+GG vs.AA:OR=0.672,95%CI=0.499-0.907,P=0.009;G vs.A:OR=0.773,95%CI=0.613-0.976,P=0.030).Stratified analysis by age,in the subgroup older than 55 years,the rs3737589 polymorphism in heterozygous,dominant,and allelic models significantly reduced the risk of lung cancer.Stratified analysis by lampblack exposure status showed that rs3737589 polymorphism could significantly reduce the risk of lung cancer in lampblack exposure.The interaction between rs3737589 polymorphism and lampblack exposure was not statistically significant.2.No statistical association was found between EZH2 rs12670401 and rs3757441 and lung cancer susceptibility.However,stratified analysis showed that in the subgroup of less than or equal to 55 years old,the risk of lung cancer in individuals with EZH2 rs12670401 CT genotype was 53.5%of that in individuals with EZH2 rs12670401TT genotype(OR=0.535,95%CI=0.320-0.897,P=0.018);individuals with CT and CC genotypes had a 41.5%lower risk of lung cancer than those with TT genotype(OR=0.585,95%CI=0.360-0.950,P=0.030).3.Further analysis of the cumulative effect of the three risk genotypes(rs3737589-A,rs12670401-C,rs3757441-T)showed that the number of risk alleles had no significant effect on the risk of lung cancer(P=0.168).Conclusion:1.TP73-AS1 rs3737589 was statistically associated with the susceptibility to lung cancer,lung adenocarcinoma and non-small cell lung cancer in non-smoking women.2.EZH2 rs12670401 may be associated with lung cancer susceptibility in non-smoking women≤55 years of age.3.There was no statistical association between EZH2 rs3757441 and lung cancer susceptibility in non-smoking women.4.The interaction between TP73-AS1,EZH2 gene polymorphisms and oil fumes exposure was not statistically associated with the risk of lung cancer.5.No statistical association was found between the cumulative effect of rs3737589,rs12670401 and rs3757441 risk alleles and lung cancer risk.