Unified rhombic lip origins of group 3 and group 4 medulloblastoma

Kyle S. Smith, Laure Bihannic, Brian L. Gudenas, Parthiv Haldipur, Ran Tao, Qingsong Gao, Yiran Li, Kimberly A. Aldinger, Igor Y. Iskusnykh, Victor V. Chizhikov, Matthew Scoggins, Silu Zhang, Angela Edwards, Mei Deng, Ian A. Glass, Lynne M. Overman, Jake Millman, Alexandria H. Sjoboen, Jennifer Hadley, Joseph Golser, Kshitij Mankad, Heather Sheppard, Arzu Onar-Thomas, Amar Gajjar, Giles W. Robinson, Volker Hovestadt, Brent A. Orr, Zoltán Patay, Kathleen J. Millen and Paul A. Northcott ()
Additional contact information
Kyle S. Smith: St Jude Children’s Research Hospital
Laure Bihannic: St Jude Children’s Research Hospital
Brian L. Gudenas: St Jude Children’s Research Hospital
Parthiv Haldipur: Seattle Children’s Research Institute
Ran Tao: St Jude Children’s Research Hospital
Qingsong Gao: St Jude Children’s Research Hospital
Yiran Li: St Jude Children’s Research Hospital
Kimberly A. Aldinger: Seattle Children’s Research Institute
Igor Y. Iskusnykh: University of Tennessee
Victor V. Chizhikov: University of Tennessee
Matthew Scoggins: St Jude Children’s Research Hospital
Silu Zhang: St Jude Children’s Research Hospital
Angela Edwards: St Jude Children’s Research Hospital
Mei Deng: University of Washington
Ian A. Glass: University of Washington
Lynne M. Overman: Newcastle University
Jake Millman: Seattle Children’s Research Institute
Alexandria H. Sjoboen: Seattle Children’s Research Institute
Jennifer Hadley: St Jude Children’s Research Hospital
Joseph Golser: Seattle Children’s Research Institute
Kshitij Mankad: Great Ormond Street Hospital for Children
Heather Sheppard: St Jude Children’s Research Hospital
Arzu Onar-Thomas: St Jude Children’s Research Hospital
Amar Gajjar: St Jude Children’s Research Hospital
Giles W. Robinson: St Jude Children’s Research Hospital
Volker Hovestadt: Dana Farber Cancer Institute
Brent A. Orr: St Jude Children’s Research Hospital
Zoltán Patay: St Jude Children’s Research Hospital
Kathleen J. Millen: Seattle Children’s Research Institute
Paul A. Northcott: St Jude Children’s Research Hospital

Nature, 2022, vol. 609, issue 7929, 1012-1020

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41586-022-05208-9

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