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

Williamson, Daniel, Schwalbe, Ed, Hicks, Debbie, Aldinger, Kimberly A., Lindsey, Janet C., Crosier, Stephen, Richardson, Stacey, Goddard, Jack, Hill, Rebecca M., Castle, Jemma, Grabovska, Yura, Hacking, James, Pizer, Barry, Wharton, Stephen B., Jacques, Thomas S., Joshi, Abhijit, Bailey, Simon and Clifford, Steven C. (2022) Medulloblastoma group 3 and 4 tumors comprise a clinically and biologically significant expression continuum reflecting human cerebellar development. Cell Reports, 40 (5). p. 111162. ISSN 2211-1247

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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.

Item Type: Article
Additional Information: Funding information: This work was supported by Cancer Research UK (C8464/A13457 and C8464/A23391), the Tom Graham Trust/CCLG, LoveOliver, Star for Harris and the INSTINCT network, co-funded by The Brain Tumor Charity, Great Ormond Street Children’s Charity, and Children with Cancer UK (grant no. 16/193). T.S.J. is grateful for additional funding from the Olivia Hodson Cancer Fund, Cancer Research UK, and the National Institute of Health Research. All of the research conducted at Great Ormond Street Hospital NHS Foundation Trust and UCL Great Ormond Street Institute of Child Health is made possible by the NIHR Great Ormond Street Hospital Biomedical Research Center. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.
Uncontrolled Keywords: DNA Methylation - genetics, Medulloblastoma - genetics - pathology, genomics, Humans, CP: cancer, development, medulloblastoma, pediatrics, Cerebellar Neoplasms - genetics - pathology
Subjects: C400 Genetics
Department: Faculties > Health and Life Sciences > Applied Sciences
Depositing User: Elena Carlaw
Date Deposited: 18 Aug 2022 14:02
Last Modified: 18 Aug 2022 14:15

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