Sidpra, Jai; (2025) Molecular and connectomic determinants of patient prognosis in paediatric high-grade glioma. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Paediatric-type high grade gliomas are near-universally lethal tumours of the central nervous system. In animal models, high-grade gliomas 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 glial malignancies through paracrine mechanisms and direct, neuron-to-glioma synapses. The organisation and clinical implications of these connections in the living human brain, how- ever, remain to be elucidated. Here, we first describe the clinical characteristics, molecular profiles, and survival trajectories of 569 children with high-grade glioma. Diffuse midline glioma (DMG) data from this cohort were extracted and integrated with paediatric connectomic data, using lesion network mapping to compute the brain-wide connectivity profile of DMG. These analyses defined a unified brain network across pontine and thalamic DMG (the DMG network), connectivity with which was independently and inversely predictive of patient short-term survival across multiple clinical datasets. Moreover, incidental surgical resection of thalamic DMG tissue with high connectivity to the DMG network conferred a signif- icant survival advantage. Interrogation of tumour growth patterns demonstrated a directional tropism to DMG network connectivity peaks. Orthogonal characterisation of the DMG network using multi-tracer positron emission tomography data identified peak, in-network neurometabolic changes spatiotempo- rally aligned with the peak age incidence of DMG as well as dominant chemoarchitectural patterns of serotonergic, cholinergic, and noradrenergic signalling. Finally, DMG with higher network-to-tumour connectivity exhibited epigenetic enrichment of programmes promoting neurogenesis, synaptic integra- tion, and neural stemness. Collectively, the data presented in this thesis provide real-world evidence for DMG growth along brain circuit trajectories, as previously described only in animal models, and are consistent with the hypothesis that DMG exploit otherwise healthy brain circuits to establish an environ- ment that promotes tumour growth across multiple connectomic, neuromodulatory, and neurometabolic scales

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