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Lookup NU author(s): Dr Marina Danilenko, Dr Claire Keeling, Dr Stephen Crosier, Dr Martina Finetti, Dr Daniel Williamson, Raf Hussain, Dr Jonathan Coxhead, Dr Peixun Zhou, Dr Rebecca Hill, Dr Debbie Hicks, Professor Vikki Rand, Dr Ed Schwalbe, Professor Simon BaileyORCiD, Professor Steven CliffordORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2022, The Author(s).We reconstructed the natural history and temporal evolution of the most common childhood brain malignancy, medulloblastoma, by single-cell whole-genome sequencing (sc-WGS) of tumours representing its major molecular sub-classes and clinical risk groups. Favourable-risk disease sub-types assessed (MBWNT and infant desmoplastic/nodular MBSHH) typically comprised a single clone with no evidence of further evolution. In contrast, highest risk sub-classes (MYC-amplified MBGroup3 and TP53-mutated MBSHH) were most clonally diverse and displayed gradual evolutionary trajectories. Clinically adopted biomarkers (e.g. chromosome 6/17 aberrations; CTNNB1/TP53 mutations) were typically early-clonal/initiating events, exploitable as targets for early-disease detection; in analyses of spatially distinct tumour regions, a single biopsy was sufficient to assess their status. Importantly, sc-WGS revealed novel events which arise later and/or sub-clonally and more commonly display spatial diversity; their clinical significance and role in disease evolution post-diagnosis now require establishment. These findings reveal diverse modes of tumour initiation and evolution in the major medulloblastoma sub-classes, with pathogenic relevance and clinical potential.
Author(s): Danilenko M, Zaka M, Keeling C, Crosier S, Lyman S, Finetti M, Williamson D, Hussain R, Coxhead J, Zhou P, Hill RM, Hicks D, Rand V, Joshi A, Schwalbe EC, Bailey S, Clifford SC
Publication type: Article
Publication status: Published
Journal: Acta Neuropathologica
Year: 2022
Volume: 144
Pages: 565–578
Online publication date: 13/07/2022
Acceptance date: 29/06/2022
Date deposited: 19/06/2023
ISSN (print): 0001-6322
ISSN (electronic): 1432-0533
Publisher: Springer Science and Business Media Deutschland GmbH
URL: https://doi.org/10.1007/s00401-022-02464-x
DOI: 10.1007/s00401-022-02464-x
PubMed id: 35831448
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