CNSC-04. 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, DMGs form brain-wide, synaptically integrated neuron-glioma networks, connectivity of which regulates tumour growth. The organisation and clinical implications of these connections in the living human brain do, however, remain to be elucidated. Here, we leverage multimodal, real-world clinical data from 125 children with primary DMG (discovery dataset) and paediatric connectomic data (n = 1000 children) to compute the brain-wide connectivity profile of DMG using lesion network mapping. In doing so, we define a unified brain network across pontine and thalamic DMG associated with patient short-term survival which exhibits strong connectivity to the brainstem, cerebellum, limbic system, motor cortex, and insular cortex (the DMG network; PFWE<0.01). Tumour connectivity with the DMG network was independently predictive of patient overall survival in an external, multicentre validation cohort of 125 children with primary DMG (AUROC 0.95). Moreover, incidental surgical resection of thalamic DMG tissue with high connectivity to the DMG network conferred a significant survival advantage (P=0.02; median overall survival 9.2 vs. 30.5 months). Interrogation of tumour growth patterns demonstrated a directional tropism to connectivity peaks in the DMG network (Spearman’s ρ = 0.543; PFWE=0.028). Orthogonal characterisation of the DMG network using multi-tracer positron emission tomography data identified peak, in-network neurometabolic changes spatiotemporally aligned with the peak age incidence of DMG (R2=0.41) as well as dominant chemoarchitectural patterns of serotonergic, cholinergic, and noradrenergic signalling (R2adj=0.62). Finally, DMG with higher network-to-tumour connectivity exhibited epigenetic enrichment of programs promoting neurogenesis, synaptic integration, and neural stemness (PFDR<0.05). Collectively, these data provide real-world evidence for neural activity modulating DMG growth in humans, as previously described only in animal models, and are consistent with the hypothesis that DMG exploit otherwise healthy brain circuits to establish an environment that promotes tumour growth across multiple connectomic, neuromodulatory, and neurometabolic scales.