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MDM4基因3'-非翻译区的变异影响晚期非小细胞肺癌患者铂类化疗后的临床结局。

Variations within 3'-UTR of MDM4 gene contribute to clinical outcomes of advanced non-small cell lung cancer patients following platinum-based chemotherapy.

作者信息

Yang Yang, Gao Wen, Ding Xi, Xu Wen, Liu Di, Su Bo, Sun Yifeng

机构信息

Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, P.R. China.

Central Laboratory, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, P.R. China.

出版信息

Oncotarget. 2017 Mar 7;8(10):16313-16324. doi: 10.18632/oncotarget.10771.

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.

摘要

微小RNA(miRNA)结合位点的单核苷酸多态性(SNP)可能会调节基因表达的转录后调控,并解释个体对铂类药物的敏感性。本研究旨在探讨位于MDM4基因3'非翻译区(UTR)的SNP对晚期非小细胞肺癌(NSCLC)患者临床结局的影响。通过使用晚期NSCLC患者血样中的DNA对4个SNP进行基因分型(发现组642例,复制组330例),并分析其与临床结局的关系。在发现组以及合并复制组结果后,携带rs10900598 CC基因型和rs4245739 AC基因型的患者总生存期(OS)较携带AA基因型的患者有所延长(分别为P = 0.017和P = 0.037)。还得出并验证了变异等位基因对生存的联合效应。分层分析显示,MDM4 SNP的效应在肺腺癌(LAC)亚组中更为明显。使用荧光素酶报告基因检测法在NSCLC细胞中观察到rs4245739的C等位基因的报告基因表达降低。综上所述,我们的结果表明,MDM4基因3'-UTR的遗传变异可能通过miRNAs介导的调控影响晚期NSCLC的结局。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8db7/5369965/91cb48c06873/oncotarget-08-16313-g001.jpg

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