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The pathological processes that drive heterogeneity among the other medulloblastoma subtypes are not known, hindering the development of much needed new therapies. Here we provide evidence that a discrete subtype of medulloblastoma that contains activating mutations in the WNT pathway effector CTNNB1 (hereafter, WNT subtype) arises outside the cerebellum from cells of the dorsal brainstem. We found that genes marking human WNT-subtype 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 Zic1(+) 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 human WNT-subtype medulloblastoma. We provide 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 SHH- and WNT-subtype medulloblastomas and have profound implications for future research and treatment of this important childhood cancer.","is_dataset_classified":null,"base_score":6.732210706467206,"endowment":6.732210706467206,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"21150899","pmcid":"PMC3059767","openalex_id":"https://openalex.org/W1971412744","authors":[],"funders":[{"funder_name":"NINDS NIH HHS","grant_id":"R01 NS037956","title":null},{"funder_name":"NCI NIH HHS","grant_id":"P01 CA096832","title":null},{"funder_name":"NCI NIH HHS","grant_id":"R01CA129541","title":null},{"funder_name":"NCI NIH HHS","grant_id":"P30 CA021765","title":null},{"funder_name":"NCI NIH HHS","grant_id":"01CA96832","title":null},{"funder_name":"National Institutes of Health","grant_id":"5P01CA096832-07","title":"Normal &Neoplastic Growth in the Brain"},{"funder_name":"National Institutes of Health","grant_id":"3P30CA021765-41S2","title":"Cancer Center Support Grant (CCSG)"},{"funder_name":"National Institutes of Health","grant_id":"1R01CA129541-01","title":"An investigation of radial glia as the source of ependymoma stem cells"},{"funder_name":"National Institutes of Health","grant_id":"5P30CA021765-12","title":"CANCER CENTER SUPPORT GRANT"}],"total_grants":9,"fwci":24.8976,"citation_percentile":0.99793716,"influential_citations":0,"citation_trend":[{"year":2012,"count":87},{"year":2013,"count":61},{"year":2014,"count":58},{"year":2015,"count":60},{"year":2016,"count":59},{"year":2017,"count":45},{"year":2018,"count":60},{"year":2019,"count":59},{"year":2020,"count":66},{"year":2021,"count":53},{"year":2022,"count":44},{"year":2023,"count":43},{"year":2024,"count":29},{"year":2025,"count":38},{"year":2026,"count":20}],"oa_status":"green","license":"Springer TDM","oa_locations":[{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/3059767","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/3059767","host_type":"repository"},{"url":"http://www.nature.com/articles/nature09587.pdf","host_type":"publisher"},{"url":"http://www.nature.com/articles/nature09587","host_type":"publisher"},{"url":"https://doi.org/10.1038/nature09587","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/21150899","host_type":"repository"},{"url":"https://www.nature.com/articles/nature09587","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC3059767","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC3059767?pdf=render","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/pmc3059767?pdf=render","host_type":""},{"url":"http://dx.doi.org/10.1038/nature09587","host_type":""},{"url":"https://dx.doi.org/10.1038/nature09587","host_type":""},{"url":"https://doi.org/https://doi.org/10.1038/nature09587","host_type":""}],"fields_of_study":["Hedgehog Signaling Pathway Studies","Epigenetics and DNA Methylation","Teratomas and Epidermoid Cysts","0301 basic medicine","0303 health sciences","03 medical and health sciences"],"mesh_terms":["Animals","Brain Stem","Cerebellar Neoplasms","Disease Models, Animal","Humans","Medulloblastoma","Mice, Transgenic","Mutation","Gene Expression Regulation, Neoplastic","Gene Expression Profiling","beta Catenin","Mice"],"keywords":["Medulloblastoma","Sonic hedgehog","Biology","Hedgehog","Wnt signaling pathway","Cerebellum","Hedgehog signaling pathway","Neuroscience","Brainstem","PTCH1","Cancer research","Signal transduction","Genetics","Gene Expression Profiling","Mice, Transgenic","Article","Gene Expression Regulation, Neoplastic","Disease Models, Animal","Mice","Mutation","Animals","Humans","Cerebellar Neoplasms","beta Catenin","Brain Stem"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. 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