title: Variations within 3'-UTR of MDM4 gene contribute to clinical outcomes of advanced non-small cell lung cancer patients following platinum-based chemotherapy.
abstract: Single-nucleotide polymorphism (SNPs) in microRNA (miRNA)-binding sites may modulate the posttranscriptional regulation of gene expression and explain individual sensitivity to platinum agents. This study aimed to investigate the impact of SNPs located at 3'-untranslated region (UTR) of MDM4 gene, on clinical outcomes of advanced non-small cell lung cancer (NSCLC) patients. Four SNPs were genotyped by using DNA from blood samples of advanced NSCLC patients (642 in the Discovery set and 330 in the Replication set) and were analyzed the relationships with clinical outcomes. Carriers with rs10900598 CC genotype and rs4245739 AC genotype showed increased overall survival (OS) than those with AA genotype (P = 0.017 and P = 0.037, respectively) in the Discovery set and after pooling results from the Replication set. A combined effect on survival of variant alleles was also concluded and validated. Stratification analysis revealed that the effect of MDM4 SNPs was more pronounced in lung adenocarcinoma (LAC) subgroups. A reduced expression of the reporter gene for the C allele of rs4245739 was observed in NSCLC cells using luciferase reporter gene assays. Taken together, our results demonstrate that genetic variations in 3'-UTR of MDM4 gene may influence outcomes of advanced NSCLC by miRNAs-mediated regulation.
authors.affiliation: Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, P.R. China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, P.R. China.
authors.forename: Wen
authors.initials: W
authors.lastname: Gao
authors.affiliation: Central Laboratory, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, P.R. China.
authors.forename: Xi
authors.initials: X
authors.lastname: Ding
authors.affiliation: Central Laboratory, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, P.R. China.
authors.forename: Wen
authors.initials: W
authors.lastname: Xu
authors.affiliation: Central Laboratory, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, P.R. China.
authors.forename: Di
authors.initials: D
authors.lastname: Liu
authors.affiliation: Central Laboratory, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, P.R. China.
authors.forename: Bo
authors.initials: B
authors.lastname: Su
authors.affiliation: Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, P.R. China.
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Sun
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018797:Cell Cycle Proteins; D002945:Cisplatin / Q000008:administration & dosage; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000235:genetics; D008875:Middle Aged; D015999:Multivariate Analysis; D009687:Nuclear Proteins / Q000235:genetics*; D017063:Outcome Assessment, Health Care / Q000379:methods / Q000706:statistics & numerical data; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D011518:Proto-Oncogene Proteins / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; D018797:Cell Cycle Proteins; C482775:MDM4 protein, human; C000603103:MIRN887 microRNA, human; D035683:MicroRNAs; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016190:Carboplatin; D002945:Cisplatin
keywords: MDM4; chemotherapy; non-small cell lung cancer; platinum; single nucleotide polymorphisms