Supplemental File 2.xlsx from Glioblastoma multiforme: a multi-omics analysis of driver genes and tumour heterogeneity

Glioblastoma (GBM) is the most aggressive and common brain cancer in adults with the lowest life expectancy. The current neuro-oncology practice has incorporated genes involved in key molecular events that drive GBM tumorigenesis as biomarkers to guide diagnosis and design treatment. This study summarizes findings describing the significant heterogeneity of GBM at the transcriptional and genomic levels, emphasizing 18 driver genes with clinical relevance. A pattern was identified fitting the stem cell model for GBM ontogenesis, with an upregulation profile for <i>MGMT</i> and downregulation for <i>ATRX, H3F3A, TP53</i> and <i>EGFR</i> in the mesenchymal subtype. We also detected overexpression of <i>EGFR, NES, VIM</i> and <i>TP53</i> in the classical subtype and of <i>MKi67</i> and <i>OLIG2</i> genes in the proneural subtype. Furthermore, we found a combination of the four biomarkers <i>EGFR, NES, OLIG2</i> and <i>VIM</i> with a remarkable differential expression pattern which confers them a strong potential to determine the GBM molecular subtype. A unique distribution of somatic mutations was found for the young and adult population, particularly for genes related to DNA repair and chromatin remodelling, highlighting <i>ATRX, MGMT</i> and <i>IDH1.</i> Our results also revealed that highly lesioned genes undergo differential regulation with particular biological pathways for young patients. This multi-omic analysis will help delineate future strategies related to the use of these molecular markers for clinical decision-making in the medical routine.

胶质母细胞瘤（Glioblastoma, GBM）是成人中最具侵袭性且最常见的脑恶性肿瘤，患者生存期最短。当前神经肿瘤学临床实践已将参与驱动胶质母细胞瘤发生的关键分子事件的基因作为生物标志物，用于指导诊断与治疗方案设计。本研究总结了在转录组与基因组层面揭示胶质母细胞瘤显著异质性的相关研究成果，重点聚焦18个具有临床相关性的驱动基因。本研究发现了契合胶质母细胞瘤发生干细胞模型的表达模式：在间充质亚型中，MGMT基因呈上调表达，而ATRX、H3F3A、TP53与EGFR基因则呈下调表达。本研究同时检测到：在经典亚型中，EGFR、NES、VIM与TP53基因存在过表达；在原神经亚型中，则存在MKI67与OLIG2基因的过表达。此外，本研究发现EGFR、NES、OLIG2与VIM这四种生物标志物的组合具有显著的差异表达模式，使其具备极强的胶质母细胞瘤分子亚型鉴定潜力。研究还发现青年与成年人群的体细胞突变分布存在独特特征，尤其在DNA修复与染色质重塑相关基因中尤为突出，其中ATRX、MGMT与IDH1基因尤为值得关注。本研究结果同时显示，青年患者体内发生高频损伤的基因存在差异化调控，并伴随特定的生物学通路异常。本多组学分析将有助于明确未来临床实践中利用这些分子标志物进行临床决策的相关策略。