Abstract 5068: Spatial architecture and epigenetic programs in IDH-mutant and wildtype glioma

Abstract Gliomas account for over 80% of primary malignant brain tumors. Among the most aggressive of these is IDH-wildtype high-grade glioma (HGG), known as glioblastoma, which is resistant to treatment and carries a median survival of 15 months. Genomic and transcriptomic characterization of HGG demonstrate strong inter- and intra-tumor heterogeneity. Distinct from IDH-mutant glioma which notably exhibit diffuse infiltrative histology with hypermethylated molecular phenotype, IDH-wildtype HGG circumferentially organize around a necrotic core with aggressive tumor expansion and macrovascular proliferation. Both IDH mutation status and tumor grade are significant prognostic factors. While IDH inhibitors have had success in IDH-mutant low-grade glioma (LGG), prognosis remains poor for HGG regardless of IDH status. Hence, a comprehensive multi-omic and spatial dataset spanning IDH status and tumor grades is crucial to further delineate similarity and heterogeneity along the disease course. In this study, we present a cohort of 85 specimens from 68 patients with high- and low-grade glioma, as well as comparisons with metastases and normal brain. To comprehensively investigate the epigenetic programs and spatial architecture of glioma driven by IDH status and tumor grade, we performed multiome single-nucleus sequencing, Xenium spatial in-situ gene expression assay, whole exome sequencing and pathological reviews. Concurrent snATAC and snRNA, in the same cell, identified differential epigenetic programs and downstream transcriptional changes. Global ATAC and RNA similarity shows IDH-mutant tumors, regardless of grade, are most closely related to oligodendroglial precursor cells (OPCs) whereas IDH-wildtype tumors show similarity to neurons, astrocytes and OPCs. To understand the spatial context differences between these tumors, we performed Xenium in-situ gene expression assays on 9 IDH-wildtype and 8 IDH-mutant HGG samples. We observe not only an increased density of OPCs in IDH-mutant HGG, but also a distinct tumor niche organized around OPCs that is more frequently observed in IDH-mutant tumors. This niche demonstrated upregulation of neurogenesis pathways and reduced hypoxia signature compared to tumor cells spatially discontiguous from OPC communities. Taken together, multimodal assessment of single-cell epigenetics, transcriptomic trajectory, and spatial organization provide further insight on glioma pathogenesis. Citation Format: Jingxian Liu, Song Cao, Wagma Caravan, Xiangwei Fang, Preet Lal, Andrew Houston, Yuting Zhao, Faria Anjum Simin, Michael C. Jin, Jennifer Ponce, Robert Fulton, Michael Heinz, Yang Li, Sonika Dahiya, Dimitrios Mathios, Tao Liu, Albert H. Kim, Milan G. Chheda, Li Ding. Spatial architecture and epigenetic programs in IDH-mutant and wildtype glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5068.