A prognostic human brain network for diffuse midline glioma
Abstract
Abstract Diffuse midline gliomas (DMGs) are near-universally lethal tumours of the childhood central nervous system 1,2 . In animal models, DMGs form brain-wide integrated networks through neuron-to-glioma synapses 3–6 and glioma-to-glioma gap junctional coupling 3 . This extensive connectivity robustly promotes the growth and invasion of DMG 3–9 and other glial malignancies 10–12 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.
Article Details
Authors (51)
Jai Sidpra
Valentina Lind
Alexander L. Cohen
Frederic L. W. V. J. Schaper
Thomas J. Stone
Yura Grabovska
Asthik Biswas
Sniya Sudhakar
Francisco Sepulveda
Bruno S. Peres
Greta Veronese
Cristina Alemán-Charlet
Olumide Ogunbiyi
Kiarash Shamardani
Jiaqi Zhao
Alberto Castro Palacin
Gillian Miller
Raffaella S. Opipari
Enrico De Vita
Deborah Ridout
Suely F. Ferraciolli
Leandro T. Lucato
Jernej Avsenik
Eleonora Piccirilli
Andrés Morales-La Madrid
Jordi Muchart
Maura E. Ryan
Rajan Patel
Parthiv Haldipur
Ciaran S. Hill
Marie T. Krüger
Ludvic Zrinzo
Noor ul Owase Jeelani
Juan Pedro Martinez-Barbera
Andrew M. Donson
Kathleen Dorris
Paul S. Morgan
Alan Mackay
Humsa S. Venkatesh
Andreas Horn
Sabine Mueller
Adam L. Green
David M. Mirsky
Harith Akram
Chris Jones
Kristian Aquilina
Kshitij Mankad
Michelle Monje
Thomas S. Jacques
Michael D. Fox
Darren R. Hargrave