Journal of neuro-oncology · 2026
Differences in regional developmental origins of glioblastomas revealed by integrated molecular profiling.
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Gensler Ryan, Ahmed A Karim, Alfonzo Horowitz Melanie, Khalifeh Jawad M, Li Marvin, Sadeghipour Negar, Abdulrahim Mostafa, Glantz Mike, Aulakh Sonikpreet, Nicolaides Theodore, Lucas Calixto-Hope G, Yegnasubramanian Srinivasan, Rincon-Torroella Jordina, Bettegowda Chetan
Аннотация
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.