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Unified rhombic lip origins of group 3 and group 4 medulloblastoma

Lookup NU author(s): Dr Parthiv Haldipur, Lynne Overman

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Abstract

© 2022, The Author(s), under exclusive licence to Springer Nature Limited. 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.

Publication metadata

Author(s): Smith KS, Bihannic L, Gudenas BL, Haldipur P, Tao R, Gao Q, Li Y, Aldinger KA, Iskusnykh IY, Chizhikov VV, Scoggins M, Zhang S, Edwards A, Deng M, Glass IA, Overman LM, Millman J, Sjoboen AH, Hadley J, Golser J, Mankad K, Sheppard H, Onar-Thomas A, Gajjar A, Robinson GW, Hovestadt V, Orr BA, Patay Z, Millen KJ, Northcott PA

Publication type: Article

Publication status: Published

Journal: Nature

Year: 2022

Volume: 609

Pages: 1012-1020

Print publication date: 29/09/2022

Online publication date: 21/09/2022

Acceptance date: 08/08/2022

ISSN (print): 0028-0836

ISSN (electronic): 1476-4687

Publisher: Springer Nature

URL: https://doi.org/10.1038/s41586-022-05208-9

DOI: 10.1038/s41586-022-05208-9

PubMed id: 36131015

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