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.

髓母细胞瘤是一种恶性儿童小脑肿瘤，在分子上分为生物学上不同的亚群，这表明个性化的治疗方法将是有益的¹。小鼠建模和跨物种基因组学提供了越来越多的离散的、特定于亚群的发育起源的证据²。然而，人体组织发育的解剖学和细胞学复杂性³- 特别是在菱形唇生发区内，它在内化到小脑结节之前产生所有谷氨酸能神经元谱系 - 使得很难验证先前从小鼠研究中得出的推论。在这里，我们使用多组学来解决发育中的人类小脑中成神经管细胞瘤亚群的起源。在人类菱形唇衍生谱系轨迹中编码的分子特征与第 3 组和第 4 组髓母细胞瘤中维持的光感受器和单极刷细胞表达谱一致，表明存在趋同基础。一项对前瞻性机构队列的系统诊断成像审查将第 3 组和第 4 组肿瘤的假定解剖学起源定位于结节。