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Metabologenomic characterization uncovers a clinically aggressive IDH mutant glioma subtype

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Abstract

Mutations in the pivotal metabolic isocitrate dehydrogenase (IDH) enzymes are recognized to drive the molecular footprint of diffuse gliomas, and patients with IDH mutant gliomas have overall favorable outcomes compared to patients with IDH wild-type tumors. However, survival still varies widely among patients with IDH mutated tumors. Here, we aimed to characterize molecular signatures that explain the range of IDH mutant gliomas. By integrating matched epigenome-wide methylome, transcriptome, and global metabolome data in 154 patients with gliomas, we identified a group of IDH mutant gliomas with globally altered metabolism that resembled IDH wild-type tumors. IDH-mutant gliomas with altered metabolism have significantly shorter overall survival from their IDH mutant counterparts that is not fully accounted for by recognized molecular prognostic markers of CDKN2A/B loss and glioma CpG Island Methylator Phenotype (GCIMP) status. IDH-mutant tumors with dysregulated metabolism harbored distinct epigenetic alterations that converged to drive proliferative and stem-like transcriptional profiles, providing a window to target novel dependencies in gliomas.

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Data availability

Raw methylation (idat files) from Universiy Health Network (UHN) for the IDH-Mutant Gliomas have been deposited to the European Genome-Phenome Archive with the dataset identifier of EGAS00001006961 (https://wwwdev.ebi.ac.uk/ega/studies/EGAS00001006961). The Cancer Genome Atlas (TCGA) dataset is open access. Additional idats for the IDH wild type cohort, RNAseq data and metabolomic data from this study can be made available upon request to our corresponding author (gelareh.zadeh@uhn.ca).

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Author information

Author notes

  1. Farshad Nassiri and Andrew Ajisebutu have equally contributed to this work.

  2. Vikas Patil and Yasin Mamatjan are have equally contributed to this work as second authors.

Authors and Affiliations

  1. Princess Margaret Cancer Centre, MacFeeters Hamilton Neuro-Oncology Program, University Health Network and University of Toronto, Toronto, ON, Canada

    Farshad Nassiri, Andrew Ajisebutu, Vikas Patil, Yasin Mamatjan, Jeff Liu, Justin Z. Wang, Mathew R. Voisin, Romina Nejad, Sheila Mansouri, Shirin Karimi, Kenneth Aldape & Gelareh Zadeh

  2. Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada

    Farshad Nassiri, Justin Z. Wang, Mathew R. Voisin & Gelareh Zadeh

  3. Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada

    Ankur Chakravarthy, Eric Chen & Daniel D. De Carvalho

  4. Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada

    Daniel D. De Carvalho

  5. Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

    Kenneth Aldape

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  1. Farshad Nassiri
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Nassiri, F., Ajisebutu, A., Patil, V. et al. Metabologenomic characterization uncovers a clinically aggressive IDH mutant glioma subtype. Acta Neuropathol 147, 68 (2024). https://doi.org/10.1007/s00401-024-02713-1

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