Objective: To explore the associations between genetic variations of glutathione synthetase gene (GSS) and response to platinum-based chemotherapy of small cell lung cancer(SCLC), and to analyze the influencing factors on survival. Methods: Four haplotype-tagging single nucleotide polymorphisms (htSNPs) of GSS were genotyped by Sequenom MassARRAY methods in 903 SCLC patients who received platinum-based chemotherapy, and had different response and survival time. The associations between genotypes and platinum-based chemotherapy response were measured by odds ratios (OR) and 95% confidence intervals (CI), adjusted for sex, age, smoking, KPS, staging and chemotherapy regiments, by unconditional logistic regression model. The hazard ratios (HR) were estimated by Cox proportional hazards regression model. Results: Among the 903 patients, 462(51.2%) cases received cis-platinum and etoposide treatment while others were treated with carboplatin and etoposide. 656 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 25.0 months.We found that rs725521 located in the 3' near gene region of GSS was significantly associated with chemotherapy response. Compared with the T allele, patients with C allele had a worse chemotherapy response and an increased risk of no-responders (P=0.027). Rs7265992 and rs725521 of GSS were associated with the overall survival (OS) of SCLC patients who received platinum-based chemotherapy (HR=1.16, 95% CI=1.02-1.33, P=0.027; HR=1.17, 95% CI=1.05-1.31, P=0.006, respectively). The patients carrying 1 or 2 risk alleles and the patients carrying 3 or 4 risk alleles had worse MST than the patients without the rs7265992A and rs725521C risk alleles (24.0 and 22.0 versus 30.0 months), with the HR for death being 1.26 (95% CI=1.04-1.54) and with the HR of 1.52 (95%CI=1.18-1.97, P=0.001). Rs2025096 and rs2273684 were not associated with the OS of SCLC patients who received platinum-based chemotherapy. Age ≤ 56, KPS> 80, limited-stage, chemotherapy response and radiation therapy had a remarkably prolonged OS (all P<0.05). Conclusions: These results suggest that GSS genetic polymorphism rs725521 plays an important role in the response to platinum-based chemotherapy, while rs7265992 and rs725521 have important effect on the prognosis of SCLC patients, which may be potential genetic biomarkers for personalized treatment of SCLC.
目的： 探讨谷胱甘肽合成酶(GSS)基因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903例接受铂类药物化疗的SCLC患者GSS基因4个标签单核苷酸多态位点(htSNP)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： 903例患者中，采用EP方案(足叶乙甙＋顺铂)化疗462例(51.2%)，采用CE方案(卡铂＋足叶乙甙)化疗441例(48.8%)，其中有效656例，无效247例，有效率为72.6%。至随访结束，全组患者死亡626例，生存150例，中位生存时间(MST)为25.0个月。位于GSS基因3′近基因区的rs725521位点与铂类药物化疗疗效有关，与携带T等位基因比较，携带C等位基因的患者化疗无效的风险增加(OR＝1.28，95% CI为1.03～1.59，P＝0.027)。rs7265992和rs725521位点与SCLC患者铂类药物化疗后的总生存时间有关(HR＝1.16，95% CI为1.02～1.33，P＝0.027；HR＝1.17，95% CI为1.05～1.31，P＝0.006)。不携带rs7265992A和rs725521C风险等位基因患者MST为30.0个月，携带1～2个风险等位基因和携带3～4个风险等位基因患者MST分别为24.0和22.0个月，随着携带的风险等位基因增多，患者死亡风险显著增加(P(trend)＝0.001)，HR分别为1.26(95% CI为1.04～1.54)和1.52(95% CI为1.18～1.97)。rs2025096和rs2273684这两个htSNP位点与铂类药物化疗疗效及患者的总生存时间无关。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： GSS基因遗传变异位点rs725521为影响SCLC患者铂类药物化疗疗效的独立因素，rs7265992和rs725521位点遗传变异影响患者总生存时间，可能成为预测SCLC患者铂类药物化疗疗效及预后的遗传标志和SCLC个体治疗的重要标志物。.
Keywords: Carcinoma, small-cell lung; Drug therapy; Glutathione synthetase; Polymorphism, single nucleotide; Prognosis; Treatment outcome.