A prognostic human brain network for diffuse midline glioma
Diffuse midline gliomas (DMGs) are near-universally lethal tumours of the childhood central nervous system1,2. In animal models, DMGs form brain-wide integrated networks through neuron-to-glioma synapses3–6 and glioma-to-glioma gap junctional coupling3. This extensive connectivity robustly promotes the growth and invasion of DMG3–9 and other glial malignancies10–12 through paracrine mechanisms and direct neuron-to-glioma synapses. However, the organization and clinical implications of these connections in the living human brain remain to be elucidated. Here, we develop tumour network mapping to compute the brain-wide connectivity profile of DMG, defining 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 patient overall survival across two external validation cohorts. Tumour growth mapped to DMG network-specific trajectories and peak in-network neurometabolic changes across development spatiotemporally aligned with the peak age incidence of DMG. Analyses of single-nucleus RNA sequencing data confirmed diverse synaptic gene enrichment in high-connectivity DMG. Strikingly, incidental surgical resection of high-connectivity thalamic DMG tissue 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 DMGs exploit otherwise healthy brain circuits to promote tumour growth. Tumour network mapping of diffuse midline glioma (DMG) defines a conserved and prognostically important brain network in children with DMG, consistent with the hypothesis that DMGs exploit otherwise healthy brain circuits to promote tumour growth.