Glioblastoma (GBM) is the most aggressive nervous system cancer. Understanding its molecular pathogenesis is crucial to improving diagnosis and treatment. Integrated analysis of genomic, proteomic, post-translational modification and metabolomic data on 99 treatment-naive GBMs provides insights to GBM biology. We identify key phosphorylation events (e.g., phosphorylated PTPN11 and PLCG1) as potential switches mediating oncogenic pathway activation, as well as potential targets for EGFR-, TP53-, and RB1-altered tumors. Immune subtypes with distinct immune cell types are discovered using bulk omics methodologies, validated by snRNA-seq, and correlated with specific expression and histone acetylation patterns. Histone H2B acetylation in classical-like and immune-low GBM is driven largely by BRDs, CREBBP, and EP300. Integrated metabolomic and proteomic data identify specific lipid distributions across subtypes and distinct global metabolic changes in IDH-mutated tumors. This work highlights biological relationships that could contribute to stratification of GBM patients for more effective treatment.

胶质母细胞瘤 (GBM) 是最具侵袭性的神经系统癌症。了解其分子发病机制对于改进诊断和治疗至关重要。对 99 种未经治疗的 GBM 的基因组、蛋白质组、翻译后修饰和代谢组数据的综合分析为 GBM 生物学提供了见解。我们将关键的磷酸化事件（例如，磷酸化的 PTPN11 和 PLCG1）确定为介导致癌途径激活的潜在开关，以及 EGFR-、TP53-和RB1的潜在靶标-改变的肿瘤。使用批量组学方法发现具有不同免疫细胞类型的免疫亚型，经 snRNA-seq 验证，并与特定表达和组蛋白乙酰化模式相关。经典样和免疫低 GBM 中的组蛋白 H2B 乙酰化主要由 BRD、CREBBP 和 EP300 驱动。综合代谢组学和蛋白质组学数据确定了跨亚型的特定脂质分布和IDH突变肿瘤中不同的全局代谢变化。这项工作强调了可能有助于对 GBM 患者进行分层以获得更有效治疗的生物学关系。