DNA双链断裂修复基因XRCC4多态性与肺癌易感性的关系

Association of the polymorphisms in DNA double-strand break repair gene XRCC4 with susceptibility of lung cancer

目的:探讨DNA双链断裂修复基因X-射线修复交叉互补4(X-ray repair cross-complementing 4, XRCC4)基因单核甘酸多态性(single nucleotide polymorphism, SNP)与肺癌发生风险的关系.方法:采用病例-对照研究的方法,应用聚合酶链反应-限制性片段长度多态性(polymerase chain reaction-restriction fragment length polymorphism, PCR-RFLP)技术和TaqMan探针基因分型技术对781例肺癌患者和781健康志愿者(作为对照)进行XRCC4 rs6869366、rs3734091和rs1056503多态性的检测;结合PCR和定点突变技术,分别构建含有XRCC4基因启动子rs6869366位点不同等位基因的重组质粒,以双荧光素酶报告系统检测SNP位点碱基突变对启动子活性的影响.结果:XRCC4 rs6869366位点携带G等位基因的基因型(T/G+G/G)可显著增加肺癌的患病风险[比值比(odds ratio, OR)=1.607, 95%可信区间(confidence interval,CI): 1.138~2.270];rs6869366与rs3734091存在连锁不平衡,携带由其构建的单体型GC或单体型对TC/GC者患肺癌的风险增加(OR=1.993,95%CI:1.194~3.329;OR=2.013,95%CI:1.174~3.452);含rs6869366不同等位基因的启动子转录活性差异无统计学意义.结论:XRCC4 rs6869366位点多态性与肺癌的易感性有关,其影响机制还需进一步研究.

Objective:To investigate the relationship between single nucleotide polymorphism(SNP) of the DNA double-strand break repair gene X-ray repair cross-complementing gene 4(XRCC4) and the risk of developing lung cancer.Methods:Case-control study was performed.Polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP) and TaqMan probe were applied to determine the genotype of XRCC4 rs6869366,rs3734091 and rs1056503 in 781 lung cancer patients and 781 healthy volunteers.The plasmids of XRCC4 promoters with different genotypes of rs6869366 were constructed using PCR combined with the site-directed mutagenesis technology.The effects of gene mutation at SNP point on the promoters'activity were evaluated using dual luciferase reporting system.Results:The G/G or G/T genotype of rs6869366 were associated with increased risk of developing lung cancer [odds ratio(OR)=1.607,95% confidence interval(CI): 1.138-2.270].There existed linkage disequilibrium between rs6869366 and rs3734091,and the individuals with GC haplotype or TC/GC diplotype were at greater risks of developing lung cancer(OR=1.993,95%CI :1.194-3.329 and OR=2.013,95%CI:1.174-3.452),respectively.The result of functional study indicates that the transcriptional activity of the promoters with different genotypes of rs6869366 had no statistical significance.Conclusion:The rs6869366 polymorphisms of XRCC4 contributed to the susceptibility of lung cancer and the mechanism needs further study.