Medulloblastoma, a malignant childhood cerebellar tumor, molecularly segregates into biologically distinct subgroups warranting personalized therapy(1). Murine modeling and cross-species genomics have provided mounting evidence of discrete, subgroup-specific developmental origins(2). However, human-specific anatomic and cellular complexity(3), particularly within the rhombic lip germinal zone that produces all glutamatergic neuronal lineages prior to internalization into the cerebellar nodulus, complicates prior murine-derived inferences. Here, we utilized multi-omics to resolve medulloblastoma subgroup origins 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 maintained in Group 3 and Group 4 medulloblastoma, implicating convergent basis. Systematic diagnostic imaging review of a prospective institutional cohort localized the putative anatomic origins of Group 3 and Group 4 tumors to the nodulus. Our results connect molecular and phenotypic features of clinically challenging medulloblastoma subgroups to their unified beginnings in the early human rhombic lip.
