XRCC1、XPD单核苷酸多态性与肺癌铂类化疗的临床预后研究

Single nucleotide polymorphisms in XRCC1,XPD and platinum prognosis in non-small-cell lung cancer patients

目的DNA修复基因XRCC1和XPD是参与铂-DNA加合物修复中的关键因子。探讨肿瘤石蜡组织中XR- CC1、XPD单核苷酸多态性与接受铂类药物化疗非小细胞肺癌(NSCLC)患者临床预后之间的关系。方法采用TaqMan探针Real-time PER方法评价53例石蜡包埋NSCLC组织中DNA修复基因XRCC1第399位密码子、XPD第751位密码子的多态性,并比较不同基因型与NSCLC肿瘤组织临床病理及铂类化疗预后之间的关系。结果XRCC1 Arg399Gln、XPD Lys751Gln基因多态性与NSCLC患者临床及肿瘤病理特征均未见相关性。携带XRCC1 Arg/Arg或Arg/Gln基因型NSCLC患者经铂类化疗后的平均总生存时间为24.0月,而携带Gln/Gln基因型患者仅为8.0月,两者有统计学差异(P=0.02)。XPD Lys751Gln与NSCLC患者无进展生存期和总生存时间均未见显著性差异(P>0.05)。XPD和XRCC1的多态性联合分析显示变异型等位基因的个数增加与总生存时间(P=0.015)相关。Cox比例风险模型显示XRCC1 Arg399Gln可以独立预测NSCLC患者的总生存时间(P=0.011)。结论XRCC1 Arg399Gln、XPD Lys751Gln基因多态性与NSCLC肿瘤临床病理特征无关。XRCC1 Arg399Gln基因多态性与NSCLC患者的总生存时间有关,在一定程度上可以作为判断NSCLC患者铂类药物化疗的预后指标。XRCC1和XPD SNP在铂类药物化疗预后方面可能存在一定的联合作用。

Objective XPD and XRCC1 are emerging as essential elements in repair of platimun-DNA adducts. To investigate whether the single nucleotide polymorphism （SNP） in DNA repair gene XRCC1 （X-ray repair cross-complementing 1） and XPD are associated with the clinical prognosis of platinum-containing combination chemotherapy in the paraffin-embedded tissue of nonsmall-cell lung cancer. Methods XRCC1 and XPD genotypes were assessed using 5＇nuclease allelic discrimination assay （TaqMan） by real-time PCR. The pathological parameters and survival data were evaluated according to the different genotypes in 53 NSCLC. Results The median survival time of patients with Arg/Arg or Arg/Gln genotypes was 24 months compared with 8.0 months of others （P=0.02）. No significant association was found between XPD 751 SNP and survival （P〉 0.05）. When we compared combinations of variant alleles across both polymorphisms, we found that a greater number of variant alleles were associated with decreasingoverall survival （P = 0. 015, log-rank test）. In Cox ratio hazard models, XRCC1 Arg399Gln could independently predict overall survival time of lung cancer（P = 0.011 ）. Conclusions It suggested that XRCC1 399 SNP might be prognostic marker of survival for lung cancer patients receiving platinum-based chemotherapy. The two polymorphism of XRCC1 and XPD might have synergic effect on the prognosis of platinum agents.