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ENGLISH ABSTRACT
谷胱甘肽合成酶基因遗传变异与小细胞肺癌患者铂类药物化疗疗效及预后的关系
封婷
李洪敏
袁芃
于典科
马飞
谭文乐
杜忠礼
杨洁
黄莹
林东昕
徐兵河
谭文
作者及单位信息
·
DOI： 10.3760/cma.j.issn.0253-3766.2017.02.008
Correlations between genetic variations of glutathione synthetase gene and the response to platinum-based chemotherapy and prognosis of small cell lung cancer patients
Feng Ting
Li Hongmin
Yuan Peng
Yu Dianke
Ma Fei
Tan Wenle
Du Zhongli
Yang Jie
Huang Ying
Lin Dongxin
Xu Binghe
Tan Wen
Authors Info & Affiliations
Feng Ting
Department of Etiology & Carcinogenesis, Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, National Cancer Centre/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
Li Hongmin
Department of Etiology & Carcinogenesis, Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, National Cancer Centre/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
Yuan Peng
Department of Medical Oncology, National Cancer Centre/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing100021, China
Yu Dianke
Department of Etiology & Carcinogenesis, Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, National Cancer Centre/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
Ma Fei
Department of Medical Oncology, National Cancer Centre/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing100021, China
Tan Wenle
Department of Etiology & Carcinogenesis, Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, National Cancer Centre/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
Du Zhongli
Department of Etiology & Carcinogenesis, Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, National Cancer Centre/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
Yang Jie
Department of Etiology & Carcinogenesis, Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, National Cancer Centre/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
Huang Ying
Department of Etiology & Carcinogenesis, Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, National Cancer Centre/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
Lin Dongxin
Department of Etiology & Carcinogenesis, Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, National Cancer Centre/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
Xu Binghe
Department of Medical Oncology, National Cancer Centre/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing100021, China
Tan Wen
Department of Etiology & Carcinogenesis, Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, National Cancer Centre/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
·
DOI： 10.3760/cma.j.issn.0253-3766.2017.02.008
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摘要

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。

癌，小细胞肺;多态性，单核苷酸;谷胱甘肽合成酶;药物疗法;治疗结果;预后
ABSTRACT

ObjectiveTo 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.

MethodsFour 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.

ResultsAmong 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).

ConclusionsThese 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.

Carcinoma, small-cell lung;Polymorphism, single nucleotide;Glutathione synthetase;Drug therapy;Treatment outcome;Prognosis
Tan Wen, Email: mocdef.labiamtoh86newnat
Xu Binghe, Email: nc.defgrabo.ocscehgnibux
National High Technology Project and Development Program of China(2012AA02A502)
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引用本文

封婷,李洪敏,袁芃,等. 谷胱甘肽合成酶基因遗传变异与小细胞肺癌患者铂类药物化疗疗效及预后的关系[J]. 中华肿瘤杂志,2017,39(2)：115-120.

DOI:10.3760/cma.j.issn.0253-3766.2017.02.008

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小细胞肺癌(small cell lung cancer, SCLC)是一种神经内分泌肿瘤，尽管只占全部肺癌的15%～20%，但是恶性程度高、倍增时间短、转移较早且广泛，严重威胁患者的生命健康 [ 1 ]。在临床治疗中，卡铂或顺铂加足叶乙甙的联合治疗作为SCLC的一线化疗方案，治疗效果有明显的个体差异性，遗传背景的不同可能影响SCLC的化疗疗效和患者的预后 [ 2 , 3 , 4 , 5 ]。
影响化疗药物疗效的分子机制涉及多个方面，包括细胞内药物浓度降低、细胞解毒能力提高、DNA损伤修复能力增强等 [ 6 ]。谷胱甘肽可以通过干扰DNA加合物的形成等途径来使铂类药物失去药效。谷胱甘肽合成酶(glutathione synthetase, GSS)基因位于人类基因组20q11.2区域，编码谷胱甘肽合成酶蛋白，在谷胱甘肽合成的生物学过程中发挥重要作用。目前，有关GSS遗传变异与SCLC化疗疗效和预后关系的研究报道较少。在本研究中，我们通过筛选GSS基因的4个标签单核苷酸多态位点(haplotype－tagging SNP, htSNP)，探讨其遗传变异与SCLC患者铂类药物化疗疗效及预后的关系，旨在为SCLC的铂类药物化疗提供依据。
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备注信息
A
谭文，Email: mocdef.labiamtoh86newnat
B
徐兵河，Email: nc.defgrabo.ocscehgnibux
C
无
D
国家高技术研究发展计划（863计划）课题 (2012AA02A502)
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