摘要目的 探讨参与跨损伤DNA合成的POLK基因的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 通过Sequenom MassARRAY检测1030例接受铂类药物化疗的SCLC患者POLK基因的5个标签单核苷酸多态(htSNP)的基因型,比较不同基因型与化疗疗效及预后的关系.基因型与化疗疗效之间的关联分析采用非条件Logistic回归模型,基因型与远期生存之间的关联分析采用Cox比例风险回归模型.结果 1030例SCLC患者中接受顺铂+依托泊苷(EP方案)化疗558例,接受卡铂+依托泊苷(CE方案)化疗472例,其中化疗有效788例,无效242例,有效率为76.5％.中位随访22.0个月,全组死亡673例,生存224例,失访133例,中位生存时间为22.5个月.Karnofsky功能状态(KPS)评分≤80分患者的有效率为72.0％,低于KPS评分＞80分的患者(80.1％;0R=0.64,P=0.002).局限期患者的有效率为81.6％,高于广泛期患者(71.0％;OR=1.81,P＜0.001).POLK基因5个htSNP位点遗传变异与SCLC患者化疗近期疗效均无关(均P＞0.05).年龄＞56岁(HR=1.25,P=0.005)、广泛期(HR=1.67,P＜0.001)、化疗无效(HR=1.72,P＜0.001)患者死亡风险增加,KPS评分＞80分(HR=0.84,P=0.021)、有放射治疗(HR=0.70,P＜0.001)的患者死亡风险降低.POLK基因rs73120833位点与SCLC患者铂类药物化疗后的总生存有关,与携带T等位基因的患者相比,携带C等位基因患者的死亡风险降低(HR=0.87,P=0.021),而rs10077427、rs3756558、rs4549504和rs5744545位点与总生存无关(均P＞0.05).携带rs73120833 TC基因型和CC基因型的患者合并后,与携带TT基因型的患者比较,死亡风险明显降低(HR=0.84,P=0.024).结论 POLK基因rs73120833位点遗传变异与SCLC患者总生存有关,可能是预测SCLC患者含铂类药化疗预后的潜在遗传标志.

abstractsObjective To investigate the associations between genetic variations of DNA polymerase kappa (POLK) and treatment response to platinum-based chemotherapy of small cell lung cancer (SCLC),and to analyze the influencing factors on survival.Methods Five haplotype-tagging single nucleotide polymorphisms (htSNPs) of POLK were genotyped by Sequenom MassARRAY methods in 1 030 SCLC patients who received platinum-based chemotherapy,and had different response and survival time.The associations between SNPs and treatment response were analyzed by computing the odds ratios (ORs) and 95％ confidence intervals (CIs) from logistic regression model.Cox regression was used for survival analysis between SNPs and overall survival by computing the hazard ratios (HRs) and 95％ CIs.Results Among 1 030 cases,558 (54.2％) cases received cis-platinum and etoposide treatment while others treated with carboplatin and etoposide.Seven hundred and eighty eight patients were chemotherapy responders in the study with a response rate of 76.5％.The median follow-up time of these patients was 22.0 months.Patients were followed up to get their survival information.The median survival time of these patients was 22.5 months.Six hundred and seventy three patients (65.3％) had died by the last date of follow-up to get their survival information (Dec 21,2017).Five htSNPs of POLK were not associated with the chemotherapy response of SCLC patients who received platinum-based chemotherapy (all P ＞ 0.05).Multivariate Cox proportional hazards regression model analysis showed that,rs73120833 of POLK was significantly associated with the overall survival (OS) of SCLC patients,compared with POLK rs73120833 T allele,C allele can prolong OS (adjusted HR =0.87,95％ CI=0.77-0.97,P =0.021).The remaining 4 SNPS,including rs10077427,rs3756558,rs4549504 and rs5744545,were not significantly associated with overall survival.Age ≤ 56,KPS＞ 80,limited-stage,chemotherapy response and radiation therapy can remarkably prolong OS (all P＜0.05).Conclusion These results suggest that POLK genetic polymorphism rs73120833 plays an important role on the prognosis of SCLC patients,which can be potential genetic biomarker for SCLC personalized treatment.