Fermitin家族成员1在脑胶质瘤中的表达及其临床意义
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国家自然科学基金项目(82003193)


The expression and clinical significance of FERMT1 in gliomas
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    摘要:

    目的 分析Fermitin 家族成员1(FERMT1)在脑胶质瘤中的表达特征,并探讨其临床意义及 在脑胶质瘤发生发展中的生物学作用。方法 纳入中国脑胶质瘤基因组图谱计划(CGGA)mRNA测序数 据库中309 例样本,按照FERMT1 表达量分为高表达组和低表达组,分析其表达特征。将癌症基因组图 谱计划(TCGA)mRNA 测序数据库的609 例样本作为对照,验证FERMT1 在脑胶质瘤患者中的表达特征。 采用Kaplan-Meier 法、Log-rank 检验和Cox 回归模型评价FERMT1 表达与脑胶质瘤患者生存期的关系。 通过基因本体(GO)分析和京都基因和基因组百科全书(KEGG)通路富集分析获得FERMT1 表达相关基 因的功能。结果 在CGGA 数据库(309 例)和TCGA 数据库(609 例)中,FERMT1 在世界卫生组织(WHO) Ⅱ、Ⅲ及Ⅳ级组间表达量的差异均有统计学意义(F 值分别为30.08、91.72,均P< 0.01),其中Ⅳ级中表 达量最低,Ⅱ级中表达量最高;FERMT1 在异柠檬酸脱氢酶(IDH)突变型脑胶质瘤中表达水平更高(t 值 分别为19.87、30.72,均P < 0.01);受试者工作特征(ROC)曲线显示,FERMT1 表达量可以很好地预测 IDH突变型脑胶质瘤,其曲线下面积(AUC)分别为92.7%和94.8%;FERMT1 在四分型组间表达量的差 异均有统计学意义(F 值分别为94.04、300.20,均P < 0.01),其中在前神经元型中表达最高;FERMT1 在 O6- 甲基鸟嘌呤甲基转移酶(MGMT)启动子甲基化组的表达量更高,差异有统计学意义(t值分别为6.65、 13.41,均P< 0.01);在CGGA 和TCGA 数据库中,FERMT1 低表达组患者较高表达组生存期短(P< 0.01); 单因素和多因素Cox 回归分析结果显示,FERMT1 表达水平和病理级别为影响胶质母细胞瘤患者预后 的独立危险因素(RR=0.718,95%CI:0.517~0.996,P=0.047;RR=2.519,95%CI:1.763~3.599,P< 0.001)。 GO富集分析显示,与FERMT1 负相关的基因可能与脑胶质瘤的细胞黏附、细胞外基质组成、炎性反应、 白细胞迁移和趋化作用等生物学过程有关。KEGG 通路富集分析显示,与FERMT1 负相关的基因与细 胞骨架调控、黏着斑和细胞外基质受体相互作用等通路相关。结论 FERMT1是可作为判断患者预后的 一个潜在指标,可能为胶质瘤的研究和个体化治疗提供一个新的视角。

    Abstract:

    Objective To determine the expression profile of FERMT1 in gliomas, and to explore the clinical significance and its biological processes involved in the development and progression of gliomas. Methods Clinical data and RNA sequencing expression data from 309 glioma patients was obtained from the Chinese Glioma Genome Atlas( CGGA) database. According to FERMT1 expression, they were divided into high expression group and low expression group, and the expression characteristics were analyzed. While 609 samples from the Cancer Genome Atlas( TCGA) mRNA sequencing database were used as controls to verify the expression characteristics of FERMT1 in glioma patients. Kaplan Meier method, Log-rank test and Cox regression model were used to evaluate the relationship between FERMT1 expression and the survival of glioma patients. Gene oncology( GO) and Kyoto Encyclopedia of Genes and Genomes( KEGG) were performed for the functional analysis of FERMT1. Results In the CGGA( 309 cases) and TCGA datasets( 609 cases), the expression of FERMT1 was distinct from WHO Ⅱ, Ⅲ and Ⅳ grade with statistical significance( F=30.08, 91.72, respectively, P< 0.01), with the lowest expression in WHO Ⅱ grade and the highest in WHO Ⅳ grade. FERMT1 expression is higher in isocitrate dehydrogenase( IDH) mutant gliomas( t=19.87,30.72, respectively, P<0.01). The receiver operating characteristic( ROC) curve showed that FERMT1 expression could well predict IDH mutant gliomas, and the area under the curve( AUC) were 92.7% and 94.8%, respectively. In the two cohorts, there were significant differences in FERMT1 expression in different subtypes( F=94.04,300.20, P < 0.01), with the highest expression level in proneural subtype. The expression of FERMT1 was higher in the methylation group of O6 methylguanine methyltransferase( MGMT) promoter, and the difference was statistically significant( t=6.65,13.41, respectively, P<0.01). The patients with high expression of FERMT1 had dramatically shorter overall survival than low-expression counterparts in CGGA and TCGA RNAseq databases( P<0.01). The results of single factor and multivariate Cox regression analysis showed that FERMT1 expression and pathological grade were independent risk factors influencing prognosis of glioblastoma patients (RR=0.718, 95%CI:0.517-0.996,P=0.047;RR=2.519, 95%CI: 1.763-3.599,P < 0.001). GO enrichment analysis showed that the genes negative related with FERMT1 expression were enriched in "cell-cell adhesion", "extracellular matrix organization", "inflammatory response", "Leukocyte migration", "chemotaxis" and other biological process. KEGG pathway enrichment analysis showed that genes negative related with FERMT1 were enriched in "cytoskeletal regulation", "focal adhesion", "ECM-receptor interaction" and other pathways. Conclusions FERMT1 can be used as a potential indicator to predict the prognosis of glioma patients, and might provide a new perspective for the research and individual therapy of glioma.

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刘玉清 李阳芳 李敬军 韩建立. Fermitin家族成员1在脑胶质瘤中的表达及其临床意义[J].神经疾病与精神卫生,2021,21(5):
DOI :10.3969/j. issn.1009-6574.2021.05.006.

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  • 在线发布日期: 2021-06-02