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

Daniel Williamson, Ed Schwalbe, Debbie Hicks, Kimberly A. Aldinger, Janet C. Lindsey, Stephen Crosier, Stacey Richardson, Jack Goddard, Rebecca M. Hill, Jemma Castle, Yura Grabovska, James Hacking, Barry Pizer, Stephen B. Wharton, Thomas S. Jacques, Abhijit Joshi, Simon Bailey, Steven C. Clifford

Research output: Contribution to journalArticlepeer-review

Abstract

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. [Abstract copyright: Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.]
Original languageEnglish
Article number111162
Number of pages26
JournalCell Reports
Volume40
Issue number5
DOIs
Publication statusPublished - 2 Aug 2022

Fingerprint

Dive into the research topics of 'Medulloblastoma group 3 and 4 tumors comprise a clinically and biologically significant expression continuum reflecting human cerebellar development'. Together they form a unique fingerprint.

Cite this