A prognostic human brain network for diffuse midline glioma

Diffuse midline glioma (DMG) are near-universally lethal tumours of the paediatric central nervous system. In animal models, DMG form brain-wide, integrated networks through neuron-to-glioma synapses and glioma-to-glioma gap junctional coupling. This extensive connectivity robustly promotes the growth and invasion of DMG and other glial malignancies through paracrine mechanisms and direct neuron-to-glioma synapses. The organisation and clinical implications of these connections in the living human brain, however, remain to be elucidated. Here, we develop tumour network mapping to compute the brain-wide connectivity profile of DMG. In doing so, we define a conserved brain network across pontine and thalamic DMG associated with patient short-term survival (DMG network). Tumour functional connectivity with the DMG network was independently predictive of overall survival across two external validation cohorts and tumour growth mapped to DMG network-specific trajectories. Single-nucleus RNA-sequencing confirmed diverse synaptic gene enrichment in high-connectivity DMG. Peak neurometabolic changes across development spatiotemporally aligned with the peak age incidence of DMG. Strikingly, incidental surgical resection of thalamic DMG tissue with high DMG network connectivity conferred a significant survival advantage. Collectively, these data define a conserved and prognostically important brain network in children with DMG, consistent with the hypothesis that DMG exploit otherwise healthy brain circuits to promote tumour growth.

• Type: RNASeq
• Archiver: European Genome-phenome Archive (EGA)