Subtypes of medulloblastoma have distinct developmental origins

Medulloblastoma encompasses a collection of clinically and molecularly diverse tumour subtypes that together comprise the most common malignant childhood brain tumour^1-4. These tumours are thought to arise within the cerebellum, with approximately 25% originating from granule neuron precursor cells (GNPCs) after aberrant activation of the Sonic Hedgehog pathway (hereafter, SHHsubtype)^3-8. The pathologicalprocesses that drive heterogeneity among the other medulloblastoma subtypes are not known, hindering the development ofmuch needed newtherapies.Here we provide evidence that a discrete subtype of medulloblastoma that contains activating mutations in the WNT pathway effector CTNNB1 (hereafter, WNT subtype)^1,3,4 arises outside the cerebellum from cells of the dorsal brainstem. We found that genes marking human WNTsubtype medulloblastomas are more frequently expressed in the lower rhombic lip (LRL) and embryonic dorsal brainstem than in the upper rhombic lip (URL) and developing cerebellum. Magnetic resonance imaging (MRI) and intra-operative reports showed that human WNT-subtype tumours infiltrate the dorsal brainstem, whereas SHH-subtype tumours are located within the cerebellar hemispheres. Activating mutations in Ctnnb1 had little impact on progenitor cell populations in the cerebellum, but caused the abnormal accumulation of cells on the embryonic dorsal brainstem which included aberrantly proliferating Zicl⁺ precursor cells. These lesions persisted in all mutant adult mice; moreover, in 15% of cases in which Tp53 was concurrently deleted, they progressed to form medulloblastomas that recapitulated the anatomy and gene expression profiles of humanWNT-subtypemedulloblastoma.Weprovide the first evidence, to our knowledge, that subtypes of medulloblastoma have distinct cellular origins.Our data provide an explanation for the marked molecular and clinical differences between SHHand WNT-subtype medulloblastomas and have profound implications for future research and treatment of this important childhood cancer.