Glioblastoma, Brain metastasis,MRI Brain The doctor pointed out the location of the brain tumor on the computer screen.
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Despite extensive research into the genomic anomalies of glioblastoma (GBM) over the past decade, the five-year survival rate remains under five percent. To address this, researchers led by a team of proteogenomic experts from Washington University studied high-grade gliomas—which includes both IDH-wildtype GBM and IDH-mutant grade 4 astrocytoma—using various molecular data. Their approach incorporated proteomic, metabolomic, lipidomic, and post-translational modifications (PTMs) with existing genomic and transcriptomic data. The team’s goal was to uncover the multi-scale regulatory interactions that drive tumor development and evolution and identify regulatory networks that influence the behavior of high-grade gliomas. Their results are published in Cancer Cell.

Since the initial characterization of the GBM genome by The Cancer Genome Atlas in 2008, the scientific community has devoted significant effort to probing genomic and transcriptomic data for new therapeutic targets that will improve clinical outcomes. In 2021, the collective efforts of researchers, including the authors of this study, led to the availability of proteogenomic analysis of adult GBM and pediatric brain tumors through the Clinical Proteomic Tumor Analysis Consortium (CPTAC).

In this study, we have extended our prior to an independent cohort of 200 patients and added a limited set of paired primary-recurrent tumors from the same patient to provide an initial glimpse of proteogenomic changes associated with progression,” the authors write.

In this analysis, the team used 14 different proteogenomic and metabolomic platforms to analyze 228 tumor samples (212 GBM and 16 grade 4 IDH-mutant astrocytoma), including 28 recurrent tumors, alongside 18 normal brain samples and 14 brain metastases for comparison.

Their analysis revealed diverse upstream alterations converging on common downstream events at the proteomic and metabolomic levels.


  • Metabolome and glycoproteome data reveal driver interactions and recurrence markers
  • Alterations in TERTpPTEN, or TERTp/EGFRproduce similar molecular features
  • PTPN11 signaling links EGFR, PDGFR, and IDH1 to downstream effectors
  • A low hypoxia signature and reduced AMPKA activities are found in IDH-mutant high-grade gliomas

Notably, they discovered that a set of 13 driver genes is highly altered in gliomas. As an example, recurrent genetic alterations and phosphorylation events on PTPN11 highlighted its crucial role in signaling across high-grade gliomas.

This study also included one standout feature: 25 sets of primary and recurrent tumor samples from the same patients, allowing the team to study how high-grade gliomas evolve over time after post-treatment recurrence.

“By studying a set of 25 primary and recurrent tumors at the single-cell level, we aimed to better understand how tumors evolve over time and in response to treatment with a goal towards improving therapeutic strategies,” the authors write.  They found that tumors transition towards a more mesenchymal state and decreased expression of genes related to the cell cycle and mismatch repair gene expression.

“Our investigation adds mechanistic detail to previous observations, identifying changes in transcription factor expression that may drive the transition to a more neuronal state, alongside the expression of a neuronal-like glycosylation pattern,” the authors conclude. Driver gene mutations between paired primary and recurrent tumors showed heterogeneous evolution patterns. “These findings emphasize the array of genetic and post-translational differences between primary and recurrent tumors, suggesting that targeting protein interactions, PTMs, and metabolites may be effective against recurrence.”

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