异柠檬酸脱氢酶1突变的原发性胶质母细胞瘤差异表达基因的生物学功能分析

Biological function analysis of differentially expressed genes of primary glioblastomas of isocitrate dehydrogenase 1 mutation

目的探讨异柠檬酸脱氢酶1（IDH1）突变的原发性胶质母细胞瘤患者差异表达基因的生物学功能。方法肿瘤标本来自中国脑胶质瘤数据库中2005年1月至2009年12月接受手术切除并随后接受放疗和烷化剂化疗的原发性胶质母细胞瘤患者69例。提取肿瘤组织RNA后进行全基因组微阵列芯片分析；提取组织DNA后进行焦磷酸测序，检测IDH1基因突变状态。按照IDH1基因有无点突变将组织样本分为IDH1突变型和IDH1野生型2组。使用BRB Array Tools对样本的RNA表达谱数据进行分析，得到2组间的差异表达基因。利用组学分析软件OmicsBean对2组的差异表达基因进行生物学功能注释和蛋白互作分子网络分析。结果IDH1突变型与IDH1野生型2组样本中共有525个基因表达的差异有统计学意义，其中在IDH1突变型原发性胶质母细胞瘤中表达水平上调的148个基因主要反映了IDH1突变后能量代谢和蛋白质代谢的变化（如三羧酸循环及多种氨基酸代谢）。而表达水平下调的377个基因主要涉及细胞粘连、细胞外基质与受体的相互作用等生物学过程。结论IDH1突变引起了胶质瘤中能量代谢、蛋白质代谢及一些癌症相关基因表达水平等生物学过程的变化。

Objective To investigate the biological function of differentially expressed genes of primary glioblastomas of isocitrate dehydrogenase 1 （ IDH1 ） mutation. Methods A total of 69 patients with primary glioblastoma from Chinese Glioma Genome Atlas who received surgical resection and then received radiotherapy and alkylating chemotherapy between January 2005 and December 2009 were collected. After the extraction of tissue RNA, the whole genome microarray analysis was performed ; after the extraction of tissue DNA, pyrosequencing was performed in order to detect the status of IDH1 gene mutation. The tissue samples were divided into either an IDH1 gene mutation type or an IDH1 wild type according to whether there was a point mutation or not. The RNA expression profile data of the samples were analyzed by using the BRB Array Tools. The differentially expressed genes were obtained between the 2 groups. Omies analysis software OmicsBean was used to conduct the biological function annotation and protein-protein interaction network analysis for differentially expressed genes of mutant wild-type IDH1 in two groups of cases. Results In the 2 groups of samples of the IDH1 gene mutation type and the IDH1 wild type, there were significant differences in a total of 525 gene expressions. The 148 genes up-regulated in the expression level in the IDH1 gene mutation type primary glioblastomas mainly reflected the alterations of energy metabolism and protein metabolism after IDH1 mutalion （ such as tricarhoxylic acid cycle and multiple amino acid metabolism） , whereas the 377 genes down-regulated in the expression level were mainly involved in the cell adhesion, the interaction of extracellular matrix and receptors and other biological processes. Conclusion IDH1 mutation caused the changes in biological processes including energy metabolism, protein metabolism, and the expression levels of some cancer-related genes in gliomas.