title: [Correlations between genetic variations of glutathione synthetase gene and the response to platinum-based chemotherapy and prognosis of small cell lung cancer patients].
abstract: 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 theHRof 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 (allP<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.
authors.affiliation: 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.
authors.forename: T
authors.initials: T
authors.lastname: Feng
authors.affiliation: 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.
authors.forename: H M
authors.initials: HM
authors.lastname: Li
authors.affiliation: Department of Medical Oncology, National Cancer Centre/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing100021, China.
authors.forename: P
authors.initials: P
authors.lastname: Yuan
authors.affiliation: 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.
authors.forename: D K
authors.initials: DK
authors.lastname: Yu
authors.affiliation: Department of Medical Oncology, National Cancer Centre/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing100021, China.
authors.forename: F
authors.initials: F
authors.lastname: Ma
authors.affiliation: 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.
authors.forename: W W
authors.initials: WW
authors.lastname: Tan
authors.affiliation: 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.
authors.forename: Z L
authors.initials: ZL
authors.lastname: Du
authors.affiliation: 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.
authors.forename: J
authors.initials: J
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Y
authors.initials: Y
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: D X
authors.initials: DX
authors.lastname: Lin
authors.affiliation: Department of Medical Oncology, National Cancer Centre/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing100021, China.
authors.forename: B H
authors.initials: BH
authors.lastname: Xu
authors.affiliation: 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.
authors.forename: W
authors.initials: W
authors.lastname: Tan
mesh_terms: D000368:Aged; D000483:Alleles; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D002945:Cisplatin / Q000008:administration & dosage; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D005981:Glutathione Synthase / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000401:mortality; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D017671:Platinum Compounds / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D016016:Proportional Hazards Models; D012306:Risk; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000401:mortality; D016896:Treatment Outcome
chemical_list: D017671:Platinum Compounds; D005047:Etoposide; D016190:Carboplatin; D005981:Glutathione Synthase; D002945:Cisplatin
keywords: Carcinoma, small-cell lung; Drug therapy; Glutathione synthetase; Polymorphism, single nucleotide; Prognosis; Treatment outcome