XRCC1、PARP1和APE1多态性与晚期非小细胞肺癌铂类药物化疗敏感性的关系

Relationship of XRCC1,PARP1 and APE1 polymorphisms with efficacy of platinum-based chemotherapy for patients with advanced non-small cell lung cancer

目的:探讨碱基切除修复系统(BER)3个重要基因——X线修复互补基因(XRCC1)、多(ADP核糖)聚合酶(PARP1)及脱嘌呤/脱嘧啶核酸内切酶(APE1)的单核苷酸多态性(SNPs)与晚期非小细胞肺癌(NSCLC)患者铂类药物化疗疗效的相关性。方法:对151例接受以铂类药物为基础化疗的晚期NSCLC患者进行临床疗效评价。采用TaqMan探针法对XRCC1G28152A(Arg399Gln)、XRCC1 C26304T(Arg194Trp)、PARP1 T2444C(Val762Ala)及APE1 T1349G(Asp148Glu)多态性位点进行基因型分析。比较不同基因型与铂类药物化疗效果之间的关系。结果:XRCC1 G28152A多态性与铂类化疗敏感性密切相关,GA杂合型患者临床受益率明显高于野生型,其化疗有效率为GG野生型的2.85倍(调整的OR=2.85,95%CI:1.291～6.277,P<0.05);至少携带1个变异等位基因A的患者(GA/AA)临床受益率为GG野生型携带者的2.48倍(调整的OR=2.48,95%CI:1.330～6.075,P<0.05)。XRCC1 26304位点及PARP1 2444位点的突变纯合基因型携带者,其化疗有效率都明显下降,XRCC126304的TT基因型有效率是CT/CC基因型的0.36倍(调整的OR=0.36,95%CI:0.040～3.298),PARP1 2444 CC基因型有效率是CT/TT基因型的0.37倍(调整的OR=0.37,95%CI:0.118～1.170),但均未见有统计学差异。未发现APE1 T1349G多态性与铂类化疗疗效之间存在关联。结论:BER修复通路XRCC1 G28152A多态性与晚期NSCLC患者铂类药物化疗临床受益相关,XRCC1 28152位点基因型检测有可能作为晚期NSCLC铂类化疗敏感性的预测指标。

Objective：To investigate the relationship of X-ray repair cross complement gene 1（XRCC1）,poly（ADP-ribose）polymerase-1（PARP1） and apurinic/apyrimidinic endonuclease 1（APE1） polymorphisms with the efficacy of platinum-based chemotherapy for treatment of the patients with advanced non-small-cell lung cancer（NSCLC）.Methods：A total of 151 patients with advanced NSCLC were routinely treated with platinum-based chemotherapy,and their clinical responses were evaluated.XRCC1 G28152A（Arg399Gln）,XRCC1 C26304T（Arg194Trp）,PARP1 T2444C（Val762Ala） and APE1 T1349G（Asp148Glu） of the patients were genotyped using the TaqMan method.The association of these polymorphisms with the clinical responses was analyzed using unconditional logistic regression model.Results：XRCC1 G28152A polymorphism was significantly correlated with clinical benefit.The efficacy of chemotherapy of XRCC1 28152 GA genotype carriers significantly increased compared with patients with GG genotype（adjusted OR=2.85,95%CI：1.291～6.277,P 0.05）.Patients carrying XRCC1 28152 A allele（GA/AA） had better clinical response than patients with wildtype allele（adjusted OR=2.48,95%CI：1.330～6.075,P 0.05）.Compared with CC and CT genotypes,XRCC1 26304 TT genotype carriers had a roughly 64% decreased efficiency but with no statistical significance（adjusted OR=0.36,95%CI：0.040～3.298）.A similar result was found in polymorphism of PARP1 T2444C,the response rate of chemotherapy of the patients with CC genotype significantly decreased compared with other（adjusted OR = 0.37,95%CI：0.118～1.170）.No significant association was found between APE1 T1349G polymorphism with clinical response.Conclusion：The XRCC1 G28152A（Arg399Gln） polymorphism is significantly associated with the clinical benefit of NSCLC patients receiving platinum-based chemotherapy,and the XRCC1 G28152A genotypes detected by TaqMan method may be useful in clinical applications to predict the sensitivity of chemotherapy in NSCLC patients.