晚期非小细胞肺癌中SOD2基因多态性与含铂方案化疗敏感性的研究

Study of SOD2 gene polymorphism and chemotherapy sensitivity in advanced non-small cell lung cancer

目的探讨超氧化物歧化酶2(SOD2)基因多态性与晚期非小细胞肺癌(NSCLC)患者含铂方案化疗疗效的关系。方法采用直接测序法检测162例以含铂方案化疗的晚期NSCLC患者外周血DNA中SOD2 rs7855、rs5746151、rs5746136、rs2758331和rs4880的基因多态性;162例患者中,43例接受多西他赛联合顺铂方案,63例接受吉西他滨联合顺铂方案,56例接受培美曲塞联合顺铂方案化疗,2个周期后采用RECIST 1.0版标准评价疗效并将患者分为化疗敏感组(CR+PR)和不敏感组(SD+PD),分析疗效与临床病理特征及以上多态性位点的关系。结果 162例晚期NSCLC患者SOD2rs7855、rs5746151、rs5746136、rs2758331和rs4880位点基因型频率均符合Hardy-Weinberg平衡(P>0.05)。162例患者经2个周期化疗后,获PR 43例、SD 68例、PD 51例,分为化疗敏感组43例和不敏感组119例,化疗敏感率为26.5%。年龄、性别、病理类型、分期、ECOG评分和化疗方案与化疗敏感性均无关。SOD2 rs7855、rs5746151、rs5746136和rs2758331位点中,各基因型及等位基因化疗敏感率的差异无统计学意义,且突变型等位基因相对于野生型等位基因及携带突变等位基因的基因型相对于野生型纯合子化疗不敏感的风险未升高(P>0.05);SOD2 rs4880 TT、TC、CC基因型的敏感率依次为42.1%、19.6%和16.7%,差异有统计学意义(P<0.05);T、C等位基因的敏感率分别为35.2%和17.6%,差异有统计学意义(P<0.05);以野生型TT型为参照,TC、CC基因型化疗不敏感的风险升高,且C等位基因相对于T等位基因化疗不敏感的风险亦升高,差异均有统计学意义(P<0.05)。结论 SOD2 rs4880多态性与晚期NSCLC患者含铂方案的疗效有关,且携带突变等位基因者化疗不敏感的风险较高,SOD2 rs4880多态性可用于预测晚期NSCLC患者对含铂方案的疗效。

Objective To investigate the relationship between superoxide dismutase 2（ SOD2） gene polymorphism and platinum-based chemotherapy in patients with advanced non-small cell lung cancer（ NSCLC）. Methods The polymorphisms of five SOD2variants（ rs7855,rs5746151,rs5746136,rs2758331 and rs4880） were detected by direct sequencing in peripheral blood DNA of 162 patients with NSCLC receiving platinum-based chemotherapy. Among the 162 patients,43 cases received docetaxe plus cisplatinum regimen,63 cases received gemcitabine plus cisplatinum regimen,and 56 cases received pemetrexed plus cisplatinum regimen. After 2 cycles,the patients were divided into chemotherapy sensitive group（ CR＋PR） and non-sensitive group（ SD＋PD） by using the RECIST1. 0 standard. The relationship between different efficacy and clinical pathological parameters,as well as the above polymorphisms were analyzed. Results The frequencies of rs7855,rs5746151,rs5746136,rs2758331 and rs4880 loci in 162 patients with NSCLC were in line with the Hardy-Weinberg equilibrium（ P〈0. 05）. After 2 cycles of chemotherapy,there were 43 cases of PR,68 cases of SD and51 cases of PD. The patients were divided into 43 cases of sensitivity group and 119 patients of non-sensitivity group. The sensitivity rate was 26. 5%. There was no relation of chemotherapy sensitivity with age,sex,pathological type,clinical stage,ECOG score and chemotherapy regimen. In the rs7855,rs5746151,rs5746136 and rs2758331 sites of SOD2,genotypes and alleles had no significant influence on chemotherapy sensitivity. There were little risks of the mutant allele relative to the wild-type allele or genotype carrying a mutation allele to wild type homozygotes（ P〈0. 05）. The sensitive rates of TT,TC and CC genotypes in SOD2 rs4880 were 42. 1%,19. 6% and 16. 7% with statistical difference（ P〉0. 05）. The sensitive rates of T and C allele were 35. 2% and 17. 6%,and the difference was statistically significant（ P〈0. 05）. Taking wild type TT as the reference,the risks of less sensitive were increased in TC and CC genotypes（ P〈0. 05）. Taking T allele as the reference,the risk of less sensitive was increased in C allele（ P〈0. 05）. Conclusion SOD2 rs4880 polymorphism is associated with the efficacy of platinum containing regimen in patients with NSCLC. The risk of patients carrying the mutant allele not sensitive to chemotherapy is high,and rs4880 SOD2 polymorphism can be used to predict the efficacy of advanced NSCLC patients receiving platinum-based regimen.