Medulloblastoma group 3 and 4 tumors comprise a clinically and biologically significant expression continuum reflecting human cerebellar development.
CP: cancer
development
genomics
medulloblastoma
pediatrics
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
02 08 2022
02 08 2022
Historique:
received:
26
07
2021
revised:
26
05
2022
accepted:
13
07
2022
entrez:
4
8
2022
pubmed:
5
8
2022
medline:
9
8
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35926460
pii: S2211-1247(22)00971-8
doi: 10.1016/j.celrep.2022.111162
pmc: PMC9638015
pii:
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
111162Subventions
Organisme : NCATS NIH HHS
ID : KL2 TR001854
Pays : United States
Organisme : Cancer Research UK
ID : C8464/A23391
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/V001647/1
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C8464/A13457
Pays : United Kingdom
Informations de copyright
Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.
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