biostudies-literatureSmith KSNICHD NIH HHSNCATS NIH HHSMedical Research CouncilNCI NIH HHSNINDS NIH HHSThe Brain Tumour CharityWellcome Trust1012-1020https://www.ebi.ac.uk/biostudies/studies/S-EPMC9748853biostudies-literatureUnknown609(7929)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.NatureUnified rhombic lip origins of group 3 and group 4 medulloblastoma.PMC9748853GN-000518R01 NS122902R01 NS093009R01 CA232143R37 NS095733R01 CA270785KL2 TR001854P50 HD103524P30 CA021765MR/R006237/1R01 NS095733R24 HD000836P01 CA096832R50 CA211481Millman JMankad KIskusnykh IYDeng MZhang SSmith KSBihannic LEdwards AHaldipur PScoggins MAldinger KAGajjar AOverman LMHovestadt VMillen KJNorthcott PAHadley JOnar-Thomas ARobinson GWGudenas BLSjoboen AHGao QGolser JChizhikov VVLi YSheppard HTao ROrr BAPatay ZGlass IAfalseUnified rhombic lip origins of group 3 and group 4 medulloblastoma.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.2022-01-01T00:00:00Z2022 Sep2026-05-29T02:17:08.578Z2025-02-19T02:21:56.942ZS-EPMC97488533613101510.1038/s41586-022-05208-9