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Medulloblastoma group 3 and 4 tumors comprise a clinically and biologically significant expression continuum reflecting human cerebellar development

Lookup NU author(s): Dr Daniel Williamson, Dr Ed Schwalbe, Dr Debbie Hicks, Dr Janet Lindsey, Dr Stephen Crosier, Dr Stacey RichardsonORCiD, Dr Jack GoddardORCiD, Dr Rebecca Hill, Jemma Castle, Dr Yura Grabovska, James HackingORCiD, Professor Simon BaileyORCiD, Professor Steven CliffordORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2022 The Author(s)Medulloblastoma is currently subclassified into distinct DNA methylation subgroups/subtypes with particular clinico-molecular features. Using RNA sequencing (RNA-seq) in large, well-annotated cohorts of medulloblastoma, we show that transcriptionally group 3 and group 4 medulloblastomas exist as intermediates on a bipolar continuum between archetypal group 3 and group 4 entities. Continuum position is prognostic, reflecting a propensity for specific DNA copy-number changes, and specific switches in isoform/enhancer usage and RNA editing. Examining single-cell RNA-seq (scRNA-seq) profiles, we show that intratumoral transcriptional heterogeneity along the continuum is limited in a subtype-dependent manner. By integrating with a human scRNA-seq reference atlas, we show that this continuum is mirrored by an equivalent continuum of transcriptional cell types in early fetal cerebellar development. We identify distinct developmental niches for all four major subgroups and link each to a common developmental antecedent. Our findings show a transcriptional continuum arising from oncogenic disruption of highly specific fetal cerebellar cell types, linked to almost every aspect of group 3/group 4 molecular biology and clinico-pathology.

Publication metadata

Author(s): Williamson D, Schwalbe EC, Hicks D, Aldinger KA, Lindsey JC, Crosier S, Richardson S, Goddard J, Hill RM, Castle J, Grabovska Y, Hacking J, Pizer B, Wharton SB, Jacques TS, Joshi A, Bailey S, Clifford SC

Publication type: Article

Publication status: Published

Journal: Cell Reports

Year: 2022

Volume: 40

Issue: 5

Online publication date: 03/08/2022

Acceptance date: 13/07/2022

Date deposited: 30/06/2023

ISSN (electronic): 2211-1247

Publisher: Elsevier B.V.

URL: https://doi.org/10.1016/j.celrep.2022.111162

DOI: 10.1016/j.celrep.2022.111162

PubMed id: 35926460

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