CNSC-88. DIFFERENCES IN REGIONAL DEVELOPMENTAL ORIGINS OF GLIOBLASTOMAS REVEALED BY INTEGRATED MOLECULAR PROFILING

Abstract BACKGROUND High-grade IDH-wildtype gliomas are among the most aggressive primary brain tumors, exhibiting extensive molecular heterogeneity. Although previous studies have shown that tumor location can correlate with molecular subtype, it remains unclear whether anatomical location reflects distinct developmental origins. This study aimed to determine whether high-grade IDH-wildtype gliomas exhibit location-dependent molecular profiles indicative of divergent developmental programs. METHODS This retrospective study analyzed 5,945 high-grade IDH-wildtype gliomas using de-identified mutational and transcriptomic data from a multi-institutional registry. Tumor locations, determined by Caris Life Sciences pathologists, were categorized as cortical or deep/dorsal midline. Mutation frequencies, co-mutations, and gene expression differences were assessed using chi-squared and Mann-Whitney U tests. RESULTS Cortical tumor patients were older than those with deep/dorsal midline tumors (60.8 vs. 45.8 years) and more often male (59.3% vs. 55.2%). Cortical tumors showed higher mutation rates compared to Deep/dorsal midline of TERT promoter (53.3% vs. 20.5%, p<0.001), PTEN (34.1% vs. 13.4%, p<0.001), and EGFR (17.1% vs. 9.5%, p<0.001) mutations, with elevated expression of FOXG1 (6.1 vs. 2.4, p<0.001), MOXD1 (4.0 vs. 2.5, p<0.001), and MEOX2 (2.9 vs. 1.2, p<0.001). Deep/dorsal midline tumors compared to cortical tumors were enriched for mutations in H3F3A (22.3% vs. 0.8%, p<0.001), ATRX (17.5% vs. 2.4%, p<0.001), FGFR1 (10.1% vs. 0.5%, p<0.001), and NF1 (27.0% vs. 15.5%, p<0.001), with increased SOX10 (5.2 vs. 3.5, p<0.001), SMOC1 (4.8 vs. 2.9, p<0.001), and PPAPDC1A (4.3 vs. 2.9, p<0.001) expression. TERT–PTEN co-mutations were significantly more frequent in cortical tumors (21.4% vs. 3.9%, p<0.01); ATRX-associated patterns were specific to deep/dorsal midline tumors. Overall survival was slightly shorter in the cortical group (15.4 vs. 18.2 months), though PFS data were unavailable. CONCLUSIONS High-grade IDH-wildtype gliomas stratify into cortical NSC-like and deep/dorsal midline OPC-like subtypes. These results support a dual cell-of-origin model and highlight developmental compartmentalization as a driver of glioma heterogeneity.