Associations Between Genetic Variations On Chromosome 5p15.33 And Risk Of Lung Cancer

PartⅠAssociation between Candidate Genetic Variations on5p15.33 and the Risk of Lung CancerObjectives:Lung cancer is a complex disease caused by environmental factors and genetic factors.Genome-wide association studies(GWAS)have shown that the 5p15.33 region are significantly associated with the risk of lung cancer.In this region,there were two genes-human telomerase reverse transcriptase(TERT)and Cleft lip and palate transmembrane protein 1-like protein(CLPTM1L).Studies of European population have shown that single nucleotide polymorphism(SNP)rs7725218 and rs7705526 in the 5p15.33 region was significantly associated with several tumors respectively.However,no study has yet explored on the association of the two SNPs with the risk of lung cancer in Chinese population.Hence we investigated the association between SNPs and the risk of lung cancer in Chinese patients based on a case-control design.Methods: 1000 lung cancer cases and 1000 controls were recruited from the same area.Candidate polymorphisms were genotyped by TaqMan assay.The association between genetic variation and lung cancer risk were analyzed by using software SPSS16.0.Results: We found that rs7725218 and rs7705526 was significantly associated with the risk of lung cancer respectively(p <0.05).rs7725218 A allele increased the risk of lung cancer: compared with subjects carrying GG genotype,the lung cancer risk of the subjects carrying GA genotype increased by 39%(OR = 1.39,95% CI = 1.14-1.70;p = 0.001),the lung cancer risk of the subjects carrying AA genotype increased by 55%(OR = 1.55,95% CI = 1.20-2.00;p=0.001);rs7725218 A allele demonstrated more susceptibility to lung cancer,with an adjusted OR of 1.26(OR = 1.26,95% CI = 1.12-1.43;p =2.474×10-4);Dominant model((GA+AA)vs GG)and recessive model(AA vs(GA+GG))showed similar results(Dominant model: OR=1.43,95%CI=1.19-1.73;p=1.678×10-4 recessive model: OR=1.28,95%CI=1.02-1.61;p=0.035).rs7705526 A allele increased the risk of lung cancer: compared with subjects carrying CC genotype,individuals with CA genotype showed a 1.42-fold higher risk(OR = 1.42,95% CI = 1.16-1.74;p = 0.001),homozygous AA showed a 1.68-fold higher risk(OR=1.68,95%CI=1.30-2.18;p=7.430×10-5);rs7705526 were associated with a 31% increase in lung cancer risk with each additional A allele(OR=1.31,95%CI=1.20-1.50;p=2.464×10-5).dominant model and recessive model showed similar results(dominant model: OR=1.50,95%CI=1.23-1.80;p=3.910×10-4;recessive model : OR=1.36,95%CI=1.09-1.71;p=0.008).We did not observed the interaction between thses two SNPs and smoking status(p >0.05).Conclusions: rs7725218 and rs7705526 were significantly associated with susceptibility to lung cancer.PartⅡ Association between Genetic Variations on 5p15.33 and Leukocyte Telomere Length in Lung Cancer PatientsObjectives:Human chromosome 5p15.33 region contains two genes: TERT and CLPTM1 L.h TERT regulates telomerase activity and thus affects telomere length.Studies have shown that leukocyte telomere length(LTL)is associated with the risk of several tumor.In order to study the association of the SNPs in 5p15.33 region and leukocyte telomere length in lung cancer patients,We have re-sequenced this region.Methods: We collected blood samples from 400 patients with lung cancer from 2014 to 2016.The 5p15.33 region was reconstructed by PGM sequencing platform of ABI.The data were analyzed by Ion Report.At the same time,LTL in peripheral blood was measured by real-time PCR.The positive loci were selected by plink software.The selected positive loci were validated by sanger sequencing.Results: We found that five SNPs in the 5p15.33 region were significantly associated with LTL,they are rs2853676,rs7712562,rs7449190,rs2735948 and rs2736098.For rs2853676,LTL was shortened by 0.107 with each additional variant allele(p= 0.032);the LTL of(CT+ TT)genotype was shortened by 0.123(p = 0.014)compared with CC genotype.For rs7712562,the LTL of(AG + AA)genotype was shortened by 0.102(p = 0.042)compared with the GG genotype.For rs7449190,LTL was shortened by 0.115 with each additional variant allele(p=0.022),the LTL of(CT+TT)genotype was shortened by 0.123(p = 0.014)compared with the CC genotype.For rs2735948,LTL was shortened by 0.134 with each additional variant allele(p=0.007),the LTL of(AG + AA)genotype was shortened by 0.140(p = 0.005)compared with the GG genotype.For rs2736098,LTL was increased by 0.117 with each additional variant allele(p=0.019),the LTL of TT genotype was increased by 0.133(p=0.008)compared with(CC+CT)genotype.Stratified analysis based on tumor stage found that rs2853676,rs7449190,rs2735948 and rs2736098 were all associated with LTL in advanced lung cancer(all p <0.05).Bioinformatics analysis found that rs2853676,rs7712562,rs7449190,rs2735948 may affect the transcription factor binding site and rs2736098 may influence the exon splicing enhancer(ESE).Conclusions: Genetic polymorphisms on 5p15.33 are associated with LTL in lung cancer patients.