DNA修复基因RAD52遗传变异与小细胞肺癌铂类药物化疗疗效的关系

摘要

目的：探讨DNA双链断裂修复基因RAD52遗传变异与小细胞肺癌（ SCLC）患者铂类药物化疗疗效及预后的关系。方法采用Sequenom MassARRAY平台检测939例接受铂类药物化疗SCLC患者RAD52基因9个标签单核苷酸多态（ htSNP ）位点的基因型，分析其与患者化疗疗效和总生存时间的关系。采用Logistic回归分析和Cox比例风险模型分析影响SCLC患者疗效和预后的独立因素。结果939例患者中，采用EP方案（足叶乙甙＋顺铂）化疗483例（51．4％），采用CE方案（卡铂＋足叶乙甙）化疗456例（48．6％），其中有效682例，无效257例，有效率为72．6％。全组患者死亡594例，生存200例，中位生存时间为25个月。位于RAD52基因5′近基因区rs10774474位点与铂类药物化疗疗效有关（ P＜0．05），与携带TT基因型患者比较，携带TA或AA基因型的患者化疗有效率降低（P＝0．004）。卡氏体力状态（KPS）评分＞80分患者的化疗有效率高于 KPS评分≤80分患者（P＝0．001）。广泛期患者的化疗有效率低于局限期患者（P＜0．001）。9个htSNP 与患者铂类药物化疗后的预后均无关（均P＞0．05）。年龄≤56岁、KPS评分＞80分、局限期、化疗有效和放射治疗可延长患者的总生存时间（均P＜0．05）。结论 DNA修复基因RAD52遗传变异位点rs10774474为影响SCLC患者铂类药物化疗疗效的独立因素，可能成为预测SCLC患者铂类药物化疗疗效的遗传标志和SCLC个体化治疗的重要标志物。%Objective To explore the associations between genetic variations of DNA repair gene RAD52 and response to platinum⁃based chemotherapy of small cell lung cancer ( SCLC) , and to analyze the influencing factors on survival. Methods Nine haplotype⁃tagging single nucleotide polymorphisms ( htSNPs) of RAD52 were genotyped by Sequenom Mass ARRAY technology in 939 SCLC patients who received platinum⁃based chemotherapy, and had different response and survival time. The associations between genotypes and platinum⁃based chemotherapy response were analyzed by odds ratios ( ORs) and 95%confidence intervals ( CIs) , adjusted for sex, age, smoking, KPS, staging and chemotherapy regimens, by unconditional logistic regression model. The relative ratios ( RRs ) were estimated using Cox proportional hazards regression model. Results Among the 939 cases, 483 ( 51. 4%) cases received cis⁃platinum and etoposide treatment while others treated with carboplatin and etoposide. Six hundred and eighty two patients were chemotherapy responders in the study with a response rate of 72.6%. Patients were followed up to get their survival information. The median survival time ( MST) of these patients was 25 months. We found that rs10774474 SNP which located in the 5′⁃flanking region of RAD52 was significantly associated with chemotherapy response. Compared with the TT genotype, patients with TA and AA genotype had a worse chemotherapy response and increased risk of no⁃response ( P=0. 004 ) . Correlation analysis showed that patients with KPS >80 had a better chemotherapy response than those with KPS≤80 (P=0.001). The patients with extensive⁃stage had a worse chemotherapy response than those with limited⁃stage (P<0.001). Cox proportional hazards regression model analysis showed that nine htSNPs of RAD52 were not associated with the overall survival ( OS) of SCLC patients who received platinum⁃based chemotherapy. Age≤56, KPS>80, limited⁃stage, chemotherapy response and radiation therapy can remarkably prolong OS ( all P<0.05) . Conclusions These results suggest that RAD52 genetic polymorphism rs10774474 plays an important role in the response to platinum⁃based chemotherapy, and may be a potential genetic biomarker for SCLC personalized treatment.