Explore the vast range of titles available.

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. A neural epigenetic signature detectable via plasma analyses is prognostic in patients with glioblastoma, resembling an oligodendrocyte-progenitor- and neuronal-progenitor-cell-like state and showing increased neuro-to-glioma synapse formation.

Glioblastomas are known for their immunosuppressive tumor microenvironment, which may explain the failure of most clinical trials in the past decade. Recent studies have emphasized the significance of stratifying glioblastoma patients to predict better therapeutic responses and survival outcomes. This study aims to investigate the prognostic relevance of peripheral immune cell counts sampled prior to surgery, with a special focus on methylation‐based subclassification. Peripheral blood was sampled in patients with newly diagnosed (n = 176) and recurrent (n = 41) glioblastoma at the time of surgery and analyzed for neutrophils, monocytes, leukocytes, platelets, neutrophil–lymphocyte ratio, lymphocyte–monocyte ratio, and platelet–lymphocyte ratio. Peripheral immune cell counts were correlated with patients' survival after combined radiochemotherapy. In addition, 850 k genome‐wide DNA methylation was assessed on tissue for defining tumor subclasses and performing cell‐type deconvolution. In newly diagnosed glioblastoma, patients with higher peripheral neutrophil counts had an unfavorable overall survival (OS) (p = 0.01, median overall‐survival (mOS) 17.0 vs. 10.0 months). At the time of first recurrence, a significant decrease of peripheral immune cell counts was observed, and elevated monocyte (p = 0.03), neutrophil (p = 0.04), and platelet (p = 0.01) counts were associated with poorer survival outcomes. DNA methylation subclass‐stratified analysis revealed a significant survival influence of neutrophils (p = 0.007) and lymphocytes (p = 0.04) in the mesenchymal (MES) subclass. Integrating deconvolution of matched tumor tissue showed that platelets and monocytes were correlated with a more differentiated, tumor‐progressive cell state, and peripheral immune cell counts were most accurately reflected in tissue of the MES subclass. This study illustrates a restricted prognostic significance of peripheral immune cell counts in newly diagnosed glioblastoma and a constrained representation in matched tumor tissue, but it demonstrates a more pertinent situation at the time of recurrence and after DNA methylation‐based stratification. This study illustrates the prognostic relevance of epigenetic molecular profiling and the peripheral immune cell counts in newly diagnosed and matched recurrent glioblastoma patients.

Neural-tumor interactions drive glioma growth as evidenced in preclinical models, but clinical validation is nascent. We present an epigenetically defined neural signature of glioblastoma that independently affects 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 high abundance of stem cell-like malignant cells classified as oligodendrocyte precursor and neural precursor cell-like in high-neural glioblastoma. High-neural glioblastoma cells engender neuron-to-glioma synapse formation and and show an unfavorable survival after xenografting. In patients, a high-neural signature associates with decreased survival as well as increased functional connectivity and can be detected via DNA analytes and brain-derived neurotrophic factor in plasma. Our study presents an epigenetically defined malignant neural signature in high-grade gliomas that is prognostically relevant.