@article{c86dd8bf63054c02828fba5f0596f58c,
title = "Medulloblastoma group 3 and 4 tumors comprise a clinically and biologically significant expression continuum reflecting human cerebellar development",
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 {\textcopyright} 2022 The Author(s). Published by Elsevier Inc. All rights reserved.]",
keywords = "DNA Methylation - genetics, Medulloblastoma - genetics - pathology, genomics, Humans, CP: cancer, development, medulloblastoma, pediatrics, Cerebellar Neoplasms - genetics - pathology",
author = "Daniel Williamson and Ed Schwalbe and Debbie Hicks and Aldinger, {Kimberly A.} and Lindsey, {Janet C.} and Stephen Crosier and Stacey Richardson and Jack Goddard and Hill, {Rebecca M.} and Jemma Castle and Yura Grabovska and James Hacking and Barry Pizer and Wharton, {Stephen B.} and Jacques, {Thomas S.} and Abhijit Joshi and Simon Bailey and Clifford, {Steven C.}",
note = "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{\textquoteright}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.",
year = "2022",
month = aug,
day = "2",
doi = "10.1016/j.celrep.2022.111162",
language = "English",
volume = "40",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "5",
}
