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Background <p>High-grade IDH-wildtype gliomas are aggressive tumors with marked molecular heterogeneity. This study assessed whether tumor location reflects distinct developmental origins.</p> Methods <p>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.</p> Results <p>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.</p> Conclusions <p>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.</p>

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

  • 期刊论文

  • 发表日期：

    2026年1月19日

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  • Ryan Gensler,
  • A. Karim Ahmed,
  • Melanie Alfonzo Horowitz,
  • Jawad M. Khalifeh,
  • Marvin Li,
  • Negar Sadeghipour,
  • Mostafa Abdulrahim,
  • Mike Glantz,
  • Sonikpreet Aulakh,
  • Theodore Nicolaides,
  • Calixto-Hope G. Lucas Jr.,
  • Srinivasan Yegnasubramanian,
  • Jordina Rincon-Torroella,
  • Chetan Bettegowda

摘要

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.