Abstract B039: Multi-regional surgical sampling reveals tumor origins and early developmental pathways in glioblastoma, IDH-mutant glioma, and meningioma

Abstract Brain tumors may start long before diagnosis, but the earliest genetic event and the first mutant “normal” cell remain unclear. We used multi-regional surgical sampling plus single-cell/spatial genomics and mouse models to map early initiation steps in glioblastoma (GBM), IDH-mutant glioma, and meningioma. We collected matched tumor and non-tumor tissues from patients. For GBM, we profiled tumors and matched non-tumor regions, including the tumor-free subventricular zone (SVZ) and peritumoral cortex, using single-nucleus RNA sequencing (snRNA-seq) with copy-number inference (13 tumors, 10 SVZ, 2 controls). For IDH-mutant glioma, we collected tumor, tumor-free SVZ, peritumoral cortex (n=18), and blood, and performed deep sequencing, droplet digital PCR (ddPCR), and spatial mapping. For meningioma, we analyzed paired meningioma tumors and pathologically tumor-free dura (n=22) using whole-exome sequencing (WES), amplicon sequencing, long-read sequencing, clonal and mutational-signature analyses, and single-nucleus DNA sequencing (snDNA-seq). In parallel, we tested SVZ-specific tumorigenicity in a mouse GBM model and built an oligodendrocyte progenitor cell (OPC) –targeted Idh1 (R132H) CRISPR model with Trp53/Atrx/Nf1. GBM: Putative mouse originating cell candidate (mGBM-OCs) formed spheres, showed neuro/glial differentiation, and were highly invasive, but tumorigenicity was niche dependent: cortex implantation produced no tumors (0/20), whereas SVZ implantation produced tumors (11/29). In patients, SVZ neural stem cell–like, astrocyte-like, and OPC-like subsets showed low-level early copy-number signals consistent with chromosome 7 gain and/or chromosome 10 loss, suggesting these subsets as putative human GBM-OCs. IDH-mutant glioma: Tumor-free SVZ showed no shared mutations with tumor. Low-level IDH1 (R132H) was detected in peritumoral normal cortex in 11/18 patients (61. 1%) and localized mainly to OPC and astrocyte-precursor–like cells, supporting peritumoral cortical glial progenitor lineages as the first mutant cells. In mice, adding Idh1 (R132H) increased tumor incidence (OPC-ITAN 18/29, 62. 1% vs OPC-TAN 3/7, 42. 9%) and worsened survival. Meningioma: Driver alterations were detected in tumor-free dura in 18/22 patients (82%) at very low variant allele fractions, including NF2 and non-NF2 drivers (TRAF7/KLF4/AKT1-related) ; remaining cases were supported by long-read detection of structural drivers. Dura patterns were inconsistent with tumor microinvasion and supported clonal evolution from dural developmental mosaicism. snDNA-seq identified NF2-mutant cells with chromosome 22q loss in both dura and tumor, indicating prenatal biallelic NF2 inactivation. Shared clonal mutations were enriched for SBS1/5, whereas tumor-private subclonal mutations were enriched for SBS15, consistent with later postnatal steps. These data reveal tumor-type–specific initiation programs and support origin-based therapeutic strategies targeting origin-like cells and their niches, beyond tumor-mass–focused treatment. Generative AI was used only for English-language editing. Citation Format: Hyeong-Chol Oh, Jung Won Park, Young-soo Chung, Ran Joo Choi, Hye Joung Cho, Se-Young Jo, Eunchae Yeo, Jihwan Yoo, Tae Hoon Roh, Jong Hee Chang, Joo Ho Lee, Hoon Kim, Jeong Ho Lee, Sangwoo Kim, Seok-Gu Kang. Multi-regional surgical sampling reveals tumor origins and early developmental pathways in glioblastoma, IDH-mutant glioma, and meningioma abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86 (6Suppl): Abstract nr B039.