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