基于中国人群脑胶质瘤分子分型的转录组特征及其临床意义

Transcriptomic characterization and clinical significance of molecular classes of gliomas in Chinese cohorts

目的探讨基于中国人群的脑胶质瘤分子分型的转录组特征及其临床意义。方法回顾性分析中国脑胶质瘤基因图谱(CGGA)数据库中932例全级别脑胶质瘤患者的转录组数据和临床资料。将其分为异柠檬酸脱氢酶(IDH,包括IDH1和IDH2)突变且染色体1p/19q共缺失(Mut_Co)型(182例)、IDH突变且染色体1p/19q非共缺失(Mut_nCo)型(315例)及IDH野生(WT)型(435例)3种分子分型。比较3种脑胶质瘤分子分型患者的诊断年龄、性别、组织病理学类型、美国癌症基因组图谱计划(TCGA)脑胶质瘤分型、脑胶质瘤CpG岛甲基化表型(G-CIMP)分型及肿瘤纯度的差异;探索3种脑胶质瘤分子分型的转录组学特征;分析3种脑胶质瘤分子分型参与的生物学通路以及癌症标志评分的差异。对具有转录组数据和完整随访数据的885例患者进行生存分析,绘制Kaplan-Meier曲线,比较3种脑胶质瘤分子分型患者生存期的差异。结果与Mut_Co型和Mut_nCo型比较,WT型患者中,诊断年龄≥43岁、世界卫生组织(WHO)肿瘤分级为Ⅳ级、组织病理学为胶质母细胞瘤、TCGA分型中的经典型、G-CIMP分型中的非G-CIMP型所占比率均高,肿瘤纯度最低,差异均有统计学意义(均P<0.001)。与Mut_Co和Mut_nCo型比较,WT型脑胶质瘤的内部侵袭和局部侵袭得分均高,细胞周期处于DNA合成期(S期)的比例高,差异均有统计学意义(均P<0.001);在WT型中,转录因子PAX3高表达,p53信号通路低表达。京都基因与基因组百科全书(KEGG)通路功能富集分析显示,Mut_Co和Mut_nCo型参与的生物学通路较广泛,主要参与刺激神经组织的配体受体的相互作用、长期的抑郁等生物学通路;广泛参与刺猬蛋白信号、WNTβCATENIN信号等癌症标志;WT型主要参与p53信号通路、黏着斑及凋亡等生物学通路及癌症标志。log-rank检验结果显示,Mut_Co型患者的生存期最长(大部分存活),Mut_nCo型次之(中位生存期为1258 d),WT型生存期最短(中位生存期为415 d),差异有统计学意义(P<0.001)。结论基于中国人群的3种脑胶质瘤分子分型具有不同的临床特征,且与TCGA分型及G-CIMP相关;不同分型具有特异的转录组学特征、参与特定的生物学通路及其癌症标志。不同分子分型的脑胶质瘤患者的预后不同。

Objective To investigate the transcriptome characteristics and clinical significance of molecular classes of gliomas based on Chinese cohorts.Methods The clinical information and transcriptome sequencing data of 932 patients with gliomas were retrospectively analyzed in the Chinese Glioma Genome Atlas(CGGA)daatabase.The patients were divided into isocitrate dehydrogenase(IDH,include IDH1 and IDH2)mutation with chromosomal 1p/19q co-deletion(Mut_Co)type(182 cases),IDH mutation with chromosomal 1p/19q co-deletion(Mut_nCo)type(315 cases)and IDH wild(WT)type(435 cases).The age of diagnosis,gender,histopathological type,TCGA(The Cancer Genome Atlas)subtype,CpG island methylation phenotype(G-CIMP)and tumor purity were compared among patients with three molecular classes of gliomas.We explored the transcriptome characteristics of three molecular types of gliomas,the biological pathways involved and their differences in cancer marker scores.A total of 885 patients with transcriptomic data and complete follow-up data were included for survival analysis and Kaplan-Meier curves were drawn to compare the difference in median survival of patients with three molecular classes of gliomas.Results Compared with Mut_Co and Mut_nCo,the proportion of WT patients with diagnosis age≥43 years,WHO gradeⅣ,glioblastoma,TCGA classical type and G-CIMP type was higher,and the tumor purity was the lowest,the differences were statistically significant(all P<0.001).Compared with Mut_Co and Mut_nCo,the intra-and local-invasion scores of WT glioma were higher,and the proportion of cell cycle in DNA synthesis phase(S phase)was higher,with statistical significance(all P<0.001).In WT type,the transcription factor PAX3 was highly expressed and the p53 signaling pathway was lowly expressed.Pathway functional enrichment analysis of Kyoto Encyclopedia of Genes and Genomes(KEGG)showed that Mut_Co and Mut_nCo types were widely involved in the interaction of ligand receptors stimulating neural tissue and long-term depression,which were also widely involved in Hedgehog protein signal,WNTβCATENIN signal and other cancer markers;WT type was mainly involved in p53 signaling pathway,adhesion plaque,apoptosis and other biological pathways and cancer hallmarkers.The log-rank test showed that the median survival time of Mut_Co patients was the longest(most of them survived),followed by Mut_nCo(1258 d),and WT with the shortest survival time(415 d),and the difference was statistically significant(P<0.001).Conclusion The three molecularly classified gliomas based on the Chinese cohorts are associated with different clinical features,different prognosis of patients,specific transcriptomic features,and involve specific biological pathways and cancer hallmarkers.