A prognostic neural epigenetic signature in high-grade glioma
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A prognostic neural epigenetic signature in high-grade glioma. / Drexler, Richard; Khatri, Robin; Sauvigny, Thomas; Mohme, Malte; Maire, Cecile L; Ryba, Alice; Zghaibeh, Yahya; Dührsen, Lasse; Salviano-Silva, Amanda; Lamszus, Katrin; Westphal, Manfred; Gempt, Jens; Wefers, Annika K; Neumann, Julia E; Bode, Helena; Hausmann, Fabian; Huber, Tobias B; Bonn, Stefan; Jütten, Kerstin; Delev, Daniel; Weber, Katharina J; Harter, Patrick N; Onken, Julia; Vajkoczy, Peter; Capper, David; Wiestler, Benedikt; Weller, Michael; Snijder, Berend; Buck, Alicia; Weiss, Tobias; Göller, Pauline C; Sahm, Felix; Menstel, Joelle Aline; Zimmer, David Niklas; Keough, Michael B; Ni, Lijun; Monje, Michelle; Silverbush, Dana; Hovestadt, Volker; Suvà, Mario L; Krishna, Saritha; Hervey-Jumper, Shawn L; Schüller, Ulrich; Heiland, Dieter H; Hänzelmann, Sonja; Ricklefs, Franz L.
In: NAT MED, Vol. 30, No. 6, 06.2024, p. 1622-1635.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - A prognostic neural epigenetic signature in high-grade glioma
AU - Drexler, Richard
AU - Khatri, Robin
AU - Sauvigny, Thomas
AU - Mohme, Malte
AU - Maire, Cecile L
AU - Ryba, Alice
AU - Zghaibeh, Yahya
AU - Dührsen, Lasse
AU - Salviano-Silva, Amanda
AU - Lamszus, Katrin
AU - Westphal, Manfred
AU - Gempt, Jens
AU - Wefers, Annika K
AU - Neumann, Julia E
AU - Bode, Helena
AU - Hausmann, Fabian
AU - Huber, Tobias B
AU - Bonn, Stefan
AU - Jütten, Kerstin
AU - Delev, Daniel
AU - Weber, Katharina J
AU - Harter, Patrick N
AU - Onken, Julia
AU - Vajkoczy, Peter
AU - Capper, David
AU - Wiestler, Benedikt
AU - Weller, Michael
AU - Snijder, Berend
AU - Buck, Alicia
AU - Weiss, Tobias
AU - Göller, Pauline C
AU - Sahm, Felix
AU - Menstel, Joelle Aline
AU - Zimmer, David Niklas
AU - Keough, Michael B
AU - Ni, Lijun
AU - Monje, Michelle
AU - Silverbush, Dana
AU - Hovestadt, Volker
AU - Suvà, Mario L
AU - Krishna, Saritha
AU - Hervey-Jumper, Shawn L
AU - Schüller, Ulrich
AU - Heiland, Dieter H
AU - Hänzelmann, Sonja
AU - Ricklefs, Franz L
N1 - © 2024. The Author(s).
PY - 2024/6
Y1 - 2024/6
N2 - 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.
AB - 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.
U2 - 10.1038/s41591-024-02969-w
DO - 10.1038/s41591-024-02969-w
M3 - SCORING: Journal article
C2 - 38760585
VL - 30
SP - 1622
EP - 1635
JO - NAT MED
JF - NAT MED
SN - 1078-8956
IS - 6
ER -
