Princess Margaret Cancer Centre, MacFeeters Hamilton Neuro-Oncology Program, University Health Network and University of Toronto, Toronto, ON, Canada.
Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada.
Acta Neuropathol. 2024 Apr 7;147(1):68. doi: 10.1007/s00401-024-02713-1.
Mutations in the pivotal metabolic isocitrate dehydrogenase (IDH) enzymes are recognized to drive the molecular footprint of diffuse gliomas, and patients with IDH mutant gliomas have overall favorable outcomes compared to patients with IDH wild-type tumors. However, survival still varies widely among patients with IDH mutated tumors. Here, we aimed to characterize molecular signatures that explain the range of IDH mutant gliomas. By integrating matched epigenome-wide methylome, transcriptome, and global metabolome data in 154 patients with gliomas, we identified a group of IDH mutant gliomas with globally altered metabolism that resembled IDH wild-type tumors. IDH-mutant gliomas with altered metabolism have significantly shorter overall survival from their IDH mutant counterparts that is not fully accounted for by recognized molecular prognostic markers of CDKN2A/B loss and glioma CpG Island Methylator Phenotype (GCIMP) status. IDH-mutant tumors with dysregulated metabolism harbored distinct epigenetic alterations that converged to drive proliferative and stem-like transcriptional profiles, providing a window to target novel dependencies in gliomas.
IDH 关键代谢酶的突变被认为是推动弥漫性神经胶质瘤分子特征的主要因素，与 IDH 野生型肿瘤患者相比，IDH 突变型神经胶质瘤患者的总体预后较好。然而，IDH 突变型肿瘤患者的生存仍然存在很大差异。在这里，我们旨在描述能够解释 IDH 突变型神经胶质瘤范围的分子特征。通过整合 154 例胶质瘤患者匹配的全基因组甲基化组、转录组和全局代谢组数据，我们鉴定出一组具有全局代谢改变的 IDH 突变型神经胶质瘤，其代谢改变与 IDH 野生型肿瘤相似。与 IDH 野生型肿瘤相比，具有代谢改变的 IDH 突变型神经胶质瘤的总生存期明显缩短，但这不能完全用 CDKN2A/B 缺失和胶质瘤 CpG 岛甲基化表型 (GCIMP) 状态等公认的分子预后标志物来解释。代谢失调的 IDH 突变型肿瘤存在明显的表观遗传改变，这些改变汇聚在一起，驱动增殖和干细胞样转录谱，为靶向神经胶质瘤的新靶点提供了一个窗口。
