A PROGNOSTIC HUMAN BRAIN NETWORK FOR DIFFUSE MIDLINE GLIOMA

Abstract AIMS 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 DMG growth and inva- sion through paracrine mechanisms and direct, neuron-to-glioma synapses. The organisation and clinical im- plications of these connections in the living human brain, however, remain to be elucidated. METHODS 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. RESULTS Pontine and thalamic DMG map to a uniﬁed brain network associated with patient short-term survival and deﬁned by connectivity with the brainstem, cerebellum, limbic system, motor cortex, and insular cortex (DMG network; PFWE&lt;0.01). Tumour connectivity with the DMG network was independently predictive of patient over- all survival in an external, multicentre validation cohort of 125 children with 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). Tumour growth pat- terns demonstrated directional tropism to DMG network connectivity peaks (Spearman’s ρ=0.54; PFWE=0.03). Orthogonal DMG network characterisation using multi-tracer positron emission tomography 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 pro- grammes promoting neurogenesis, neural stemness, and synaptic integration. CONCLUSION 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.

A PROGNOSTIC HUMAN BRAIN NETWORK FOR DIFFUSE MIDLINE GLIOMA

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