Delta样典型Notch配体3基因在脑胶质瘤中的表达及其临床意义  

The expression and clinical significance of delta like canonical notch ligand 3 in gliomas

作　　者：赵征 孙志延 吴凡[1] 刘玉清 张莹[1] Zhao Zheng;Sun Zhiyan;Wu Fan;Liu Yuqing;Zhang Ying(Beijing Neurosurgical Institute,Capital Medical University,Beijing 100070,China)

机构地区：[1]首都医科大学,北京市神经外科研究所,100070

出　　处：《中华神经外科杂志》2021年第7期721-727,共7页Chinese Journal of Neurosurgery

基　　金：国家自然科学基金(82002647)。

摘　　要：目的:研究Delta样典型Notch配体3(DLL3)基因在脑胶质瘤中的表达特征及其临床意义,进而探索其在脑胶质瘤中的生物学功能。方法:回顾性分析中国脑胶质瘤基因组图谱计划数据库(CGGA)的两套mRNA测序数据集及其匹配的临床数据,其中数据集1包含325例样本,数据集2包含693例样本。应用R软件分析DLL3在不同世界卫生组织(WHO)分级、不同分子分型脑胶质瘤的表达模式,并应用免疫组织化学染色检测方法验证DLL3蛋白在不同WHO级别脑胶质瘤中的表达水平。通过Kaplan-Meier生存曲线评价DLL3不同表达水平的脑胶质瘤患者的生存差异。采用单因素和多因素Cox回归分析法分析影响脑胶质瘤患者总体生存期的因素。通过Pearson相关性检验分析与DLL3表达相关的基因。采用功能富集分析方法分析与DLL3表达相关基因的生物学功能。结果:在数据集1中,DLL3的表达随着WHO级别的升高而下调,差异有统计学意义(P<0.001);DLL3在异柠檬酸脱氢酶(IDH)突变型患者中的表达量高于IDH野生型患者(P<0.001);DLL3在IDH野生型患者中的表达量低于IDH突变型且染色体1p/19q共缺失患者和IDH突变型且染色体1p/19q非共缺失患者(P<0.001);DLL3在O 6-甲基鸟嘌呤DNA甲基转移酶(MGMT)启动子甲基化患者中的表达量高于非甲基化患者(P<0.001);通过免疫组织化学染色方法验证DLL3表达随着WHO级别的升高而下调(P<0.01);DLL3的上述结果在数据集2中得到相似结果。在两个数据集中,DLL3高表达组患者的总体生存期均长于低表达组患者(均P<0.01)。多因素Cox回归分析结果显示,WHO分级(WHOⅢ级:HR=2.861,95%CI:1.910~4.287;Ⅳ级:HR=4.655,95%CI:3.010~7.199)、染色体1p/19q共缺失(HR=0.439,95%CI:0.293~0.657)以及DLL3高表达(HR=0.593,95%CI:0.427~0.823)均为脑胶质瘤患者预后的独立影响因素(均P<0.001)。与DLL3表达相关的基因有661个(|r|≥0.4,P<0.05);生物信息学分析提示,DLL3可能与脑胶质瘤Objective To explore the expression characteristics and clinical significance of delta like canonical notch ligand 3(DLL3)gene in gliomas,and to explore its biological functions in gliomas.Methods Two sets of mRNA sequencing datasets and their matched clinical data from the Chinese Glioma Genome Atlas(CGGA)database were retrospectively analyzed,among which dataset 1 contained 325 samples and dataset 2 contained 693 samples.The expression patterns of DLL3 in gliomas with different WHO grades and different molecular types were analyzed using the R software,and the expression levels of DLL3 protein in gliomas with different grades were verified by immunohistochemical assay.Kaplan-Meier survival curve was used to evaluate the survival differences among glioma patients with different DLL3 expression levels.Univariate and multivariate Cox regressions were used to analyze the factors associated with the overall survival of glioma patients.The genes associated with DLL3 expression were identified by Pearson correlation analysis.Functional enrichment analysis was used to analyze the biological functions of genes related to DLL3 expression.Results In dataset 1,the expression of DLL3 gene was down-regulated with the increase of WHO grade,and the difference was statistically significant(P<0.001).The expression of DLL3 in IDH mutant patients was significantly higher than that in IDH wild-type patients(P<0.001).The expression of DLL3 in IDH wild-type patients was significantly lower than that in IDH mutant with chromosome 1p/19q co-deletion group or IDH mutant without chromosome 1p/19q co-deletion group(P<0.001).The expression of DLL3 in patients with O6-methylguanine-DNA methyltransferase(MGMT)promoter methylation was significantly higher than that in non-methylated patients(P<0.001).The immunohistochemical staining confirmed that the expression of DLL3 gene was down-regulated with the increase of WHO grade(P<0.01).The above results of DLL3 were similar in dataset 2.Patients with high DLL3 expression had longer overall surviv

关 键 词：神经胶质瘤 基因表达 预后 Delta样典型Notch配体3 突触功能 

分 类 号：R739.41[医药卫生—肿瘤]