학술논문

A prognostic neural epigenetic signature in high-grade glioma.
Document Type
Academic Journal
Author
Drexler R; Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Department of Neurology, Stanford University, Stanford, CA, USA.; Khatri R; Institute of Medical Systems Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Center for Biomedical AI, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Sauvigny T; Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Mohme M; Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Maire CL; Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Ryba A; Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Zghaibeh Y; Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Dührsen L; Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Salviano-Silva A; Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Lamszus K; Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Westphal M; Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Gempt J; Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Wefers AK; Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Neumann JE; Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Center for Molecular Neurobiology Hamburg (ZMNH), University Hospital Hamburg Eppendorf, Hamburg, Germany.; Bode H; Research Institute Children's Cancer Center Hamburg, Hamburg, Germany.; Hausmann F; Institute of Medical Systems Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Center for Biomedical AI, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Huber TB; III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Hamburg Center for Kidney Health (HCKH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Bonn S; Institute of Medical Systems Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Center for Biomedical AI, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Jütten K; Department of Neurosurgery, University Hospital Aachen, Aachen, Germany.; Delev D; Department of Neurosurgery, University Hospital Aachen, Aachen, Germany.; Department of Neurosurgery, University Clinic Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany.; Weber KJ; Neurological Institute (Edinger Institute), University Hospital Frankfurt, Frankfurt am Main, Germany.; German Cancer Consortium (DKTK), Heidelberg, Germany and German Cancer Research Center (DKFZ), Heidelberg, Germany.; Frankfurt Cancer Institute (FCI), Frankfurt am Main, Germany.; University Cancer Center (UCT) Frankfurt, Frankfurt am Main, Germany.; Harter PN; Neurological Institute (Edinger Institute), University Hospital Frankfurt, Frankfurt am Main, Germany.; Institute of Neuropathology, Faculty of Medicine, LMU Munich, Munich, Germany.; Onken J; Department of Neurosurgery, Charité - Universitätsmedizin Berlin, Berlin, Germany.; Vajkoczy P; Department of Neurosurgery, Charité - Universitätsmedizin Berlin, Berlin, Germany.; Capper D; Department of Neuropathology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.; Wiestler B; Department of Neuroradiology, Klinikum rechts der Isar, School of Medicine, Technical University Munich, Munich, Germany.; Weller M; Department of Neurology, Clinical Neuroscience Center, University Hospital Zurich, Zurich, Switzerland.; Department of Neurology, University of Zürich, Zurich, Switzerland.; Snijder B; Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland.; Buck A; Department of Neurology, Clinical Neuroscience Center, University Hospital Zurich, Zurich, Switzerland.; Department of Neurology, University of Zürich, Zurich, Switzerland.; Weiss T; Department of Neurology, Clinical Neuroscience Center, University Hospital Zurich, Zurich, Switzerland.; Department of Neurology, University of Zürich, Zurich, Switzerland.; Göller PC; Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.; Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany.; Sahm F; Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.; Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany.; Menstel JA; Department of Neurosurgery, Medical Center University of Freiburg, Freiburg, Germany.; Zimmer DN; Department of Neurosurgery, Medical Center University of Freiburg, Freiburg, Germany.; Keough MB; Department of Neurology, Stanford University, Stanford, CA, USA.; Ni L; Department of Neurology, Stanford University, Stanford, CA, USA.; Monje M; Department of Neurology, Stanford University, Stanford, CA, USA.; Silverbush D; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Hovestadt V; Broad Institute of Harvard and MIT, Cambridge, MA, USA.; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Suvà ML; Broad Institute of Harvard and MIT, Cambridge, MA, USA.; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.; Krishna S; Department of Neurological Surgery, University of California, San Francisco, CA, USA.; Hervey-Jumper SL; Department of Neurological Surgery, University of California, San Francisco, CA, USA.; Schüller U; Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Research Institute Children's Cancer Center Hamburg, Hamburg, Germany.; Department of Pediatric Hematology and Oncology, Research Institute Children's Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Heiland DH; Department of Neurosurgery, University Clinic Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany.; Department of Neurosurgery, Medical Center University of Freiburg, Freiburg, Germany.; Translational Neurosurgery, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany.; Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.; German Cancer Consortium (DKTK), Partner Site Freiburg, Freiburg, Germany.; Hänzelmann S; Institute of Medical Systems Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Center for Biomedical AI, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Hamburg Center for Kidney Health (HCKH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Ricklefs FL; Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. f.ricklefs@uke.de.
Source
Publisher: Nature Publishing Company Country of Publication: United States NLM ID: 9502015 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1546-170X (Electronic) Linking ISSN: 10788956 NLM ISO Abbreviation: Nat Med Subsets: MEDLINE
Subject
Language
English
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.
(© 2024. The Author(s).)