A prognostic neural epigenetic signature in high-grade glioma

Drexler R, Khatri R, Sauvigny T, Mohme M, Maire CL, Ryba A, Zghaibeh Y, Dührsen L, Salviano-Silva A, Lamszus K, Westphal M, Gempt J, Wefers AK, Neumann JE, Bode H, Hausmann F, Huber TB, Bonn S, Jütten K, Delev D, Weber KJ, Harter PN, Onken J, Vajkoczy P, Capper D, Wiestler B, Weller M, Snijder B, Buck A, Weiss T, Göller PC, Sahm F, Menstel JA, Zimmer DN, Keough MB, Ni L, Monje M, Silverbush D, Hovestadt V, Suvà ML, Krishna S, Hervey-Jumper SL, Schüller U, Heiland DH, Hänzelmann S, Ricklefs FL (2024)

Publication Language: English

Publication Type: Journal article

Publication year: 2024

Journal

Nature Medicine Nature Publishing Group

Book Volume: 30

Pages Range: 1622-1635

Journal Issue: 6

DOI: 10.1038/s41591-024-02969-w

Abstract

Neural–tumor interactions drive glioma growth as evidenced in preclinical models, but clinical validation is limited. We present an epigenetically defined neural signature of glioblastoma that independently predicts patients’ survival. We use reference signatures of neural cells to deconvolve tumor DNA and classify samples into low- or high-neural tumors. High-neural glioblastomas exhibit hypomethylated CpG sites and upregulation of genes associated with synaptic integration. Single-cell transcriptomic analysis reveals a high abundance of malignant stemcell-like cells in high-neural glioblastoma, primarily of the neural lineage. These cells are further classified as neural-progenitor-cell-like, astrocyte-like and oligodendrocyte-progenitor-like, alongside oligodendrocytes and excitatory neurons. In line with these findings, high-neural glioblastoma cells engender neuron-to-glioma synapse formation in vitro and in vivo and show an unfavorable survival after xenografting. In patients, a high-neural signature is associated with decreased overall and progression-free survival. High-neural tumors also exhibit increased functional connectivity in magnetencephalography and resting-state magnet resonance imaging and can be detected via DNA analytes and brain-derived neurotrophic factor in patients’ plasma. The prognostic importance of the neural signature was further validated in patients diagnosed with diffuse midline glioma. Our study presents an epigenetically defined malignant neural signature in high-grade gliomas that is prognostically relevant. High-neural gliomas likely require a maximized surgical resection approach for improved outcomes.

Authors with CRIS profile

Dieter Henrik Heiland Department of Neurosurgery

Additional Organisation(s)

FAU Profilzentrum Licht.Materie.Quantentechnologien (FAU LMQ)

Involved external institutions

Universitätsklinikum Hamburg-Eppendorf (UKE) DE Germany (DE) Kinderkrebs-Zentrum Hamburg gGmbH DE Germany (DE) Universitätsklinikum Aachen (UKA) DE Germany (DE) Universitätsklinikum Frankfurt am Main (KGU) DE Germany (DE) Charité - Universitätsmedizin Berlin DE Germany (DE) Klinikum rechts der Isar DE Germany (DE) Universitätsspital Zürich (USZ) CH Switzerland (CH) Eidgenössische Technische Hochschule Zürich (ETHZ) / Swiss Federal Institute of Technology in Zurich CH Switzerland (CH) Hopp-Kindertumorzentrum Heidelberg - KiTZ DE Germany (DE) Universitätsklinikum Freiburg DE Germany (DE) Stanford University US United States (USA) (US) Perelman School of Medicine University of Pennsylvania US United States (USA) (US) Eli and Edythe L. Broad Institute of MIT and Harvard US United States (USA) (US) University of California San Francisco (UCSF) US United States (USA) (US)

How to cite

APA:

Drexler, R., Khatri, R., Sauvigny, T., Mohme, M., Maire, C.L., Ryba, A.,... Ricklefs, F.L. (2024). A prognostic neural epigenetic signature in high-grade glioma. Nature Medicine, 30(6), 1622-1635. https://doi.org/10.1038/s41591-024-02969-w

MLA:

Drexler, Richard, et al. "A prognostic neural epigenetic signature in high-grade glioma." Nature Medicine 30.6 (2024): 1622-1635.

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