Differences in regional developmental origins of glioblastomas revealed by integrated molecular profiling.

BACKGROUND

High-grade IDH-wildtype gliomas are aggressive tumors with marked molecular heterogeneity. This study assessed whether tumor location reflects distinct developmental origins.

METHODS

We retrospectively analyzed 5,945 high-grade IDH-wildtype gliomas using de-identified mutational and transcriptomic data. Tumors were grouped as cortical (e.g., frontal, temporal) or deep/dorsal midline (e.g., brainstem, spinal cord). Mutation frequencies, co-mutations, and gene expression profiles were compared.

RESULTS

Cortical tumors were enriched for TERT promoter (53.3%), PTEN (34.1%), and EGFR (17.1%) mutations and showed elevated FOXG1, MOXD1, and MEOX2 expression. Deep/dorsal midline tumors had higher rates of H3F3A (22.3%), ATRX (17.5%), FGFR1 (10.1%), and NF1 (27.0%) mutations with increased SOX10, SMOC1, and PPAPDC1A expression. Co-mutation patterns further distinguished subgroups.

CONCLUSIONS

High-grade IDH-wildtype gliomas stratify into cortical NSC-like and deep/dorsal midline OPC-like subtypes, supporting a dual cell-of-origin model and highlighting developmental compartmentalization as a contributor to glioma heterogeneity.