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Unified rhombic lip origins of group 3 and group 4 medulloblastoma

Smith, KS; Bihannic, L; Gudenas, BL; Haldipur, P; Tao, R; Gao, Q; Li, Y; ... Northcott, PA; + view all (2022) Unified rhombic lip origins of group 3 and group 4 medulloblastoma. Nature , 609 (7929) pp. 1012-1020. 10.1038/s41586-022-05208-9. Green open access

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Abstract

Medulloblastoma, a malignant childhood cerebellar tumour, segregates molecularly into biologically distinct subgroups, suggesting that a personalized approach to therapy would be beneficial1. Mouse modelling and cross-species genomics have provided increasing evidence of discrete, subgroup-specific developmental origins2. However, the anatomical and cellular complexity of developing human tissues3—particularly within the rhombic lip germinal zone, which produces all glutamatergic neuronal lineages before internalization into the cerebellar nodulus—makes it difficult to validate previous inferences that were derived from studies in mice. Here we use multi-omics to resolve the origins of medulloblastoma subgroups in the developing human cerebellum. Molecular signatures encoded within a human rhombic-lip-derived lineage trajectory aligned with photoreceptor and unipolar brush cell expression profiles that are maintained in group 3 and group 4 medulloblastoma, suggesting a convergent basis. A systematic diagnostic-imaging review of a prospective institutional cohort localized the putative anatomical origins of group 3 and group 4 tumours to the nodulus. Our results connect the molecular and phenotypic features of clinically challenging medulloblastoma subgroups to their unified beginnings in the rhombic lip in the early stages of human development.

Type: Article
Title: Unified rhombic lip origins of group 3 and group 4 medulloblastoma
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41586-022-05208-9
Publisher version: https://doi.org/10.1038/s41586-022-05208-9
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions.
Keywords: Animals, Cell Lineage, Cerebellar Neoplasms, Cerebellum, Humans, Medulloblastoma, Metencephalon, Mice, Neurons, Prospective Studies
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Neurosciences Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10201645
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