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Single-cell DNA sequencing identifies risk-associated clonal complexity and evolutionary trajectories in childhood medulloblastoma development

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 Bailey, Professor Steven Clifford

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Abstract

© 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.


Publication metadata

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

Pages: epub ahead of print

Online publication date: 13/07/2022

Acceptance date: 29/06/2022

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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