title: Evasion of cell senescence in SHH medulloblastoma.
abstract: The mechanisms leading to brain tumor formation are poorly understood. Using Ptch1+/-mice as a medulloblastoma model, sequential mutations were found to shape tumor evolution. Initially, medulloblastoma preneoplastic lesions display loss of heterozygosity of the Ptch1 wild-type allele, an event associated with cell senescence in preneoplasia. Subsequently, p53 mutations lead to senescence evasion and progression from preneoplasia to medulloblastoma. These findings are consistent with a model where high levels of Hedgehog signaling caused by the loss of the tumor suppressor Ptch1 lead to oncogene-induced senescence and drive p53 mutations. Thus, cell senescence is an important characteristic of a subset of SHH medulloblastoma and might explain the acquisition of somatic TP53 mutations in human medulloblastoma. This mode of medulloblastoma formation contrasts with the one characterizing Li-Fraumeni patients with medulloblastoma, where TP53 germ-line mutations cause chromothriptic genomic instability and lead to mutations in Hedgehog signaling genes, which drive medulloblastoma growth. Here we discuss in detail these 2 alternative mechanisms leading to medulloblastoma tumorigenesis.
authors.affiliation: a Molecular Biology of Neural Development , Institut de Recherches Cliniques de Montréal (IRCM) , Montreal , Quebec , Canada.|b Integrated Program in Neuroscience , McGill University , Montreal , Quebec , Canada.
authors.forename: Lukas
authors.initials: L
authors.lastname: Tamayo-Orrego
authors.affiliation: a Molecular Biology of Neural Development , Institut de Recherches Cliniques de Montréal (IRCM) , Montreal , Quebec , Canada.|b Integrated Program in Neuroscience , McGill University , Montreal , Quebec , Canada.
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Swikert
authors.affiliation: a Molecular Biology of Neural Development , Institut de Recherches Cliniques de Montréal (IRCM) , Montreal , Quebec , Canada.|b Integrated Program in Neuroscience , McGill University , Montreal , Quebec , Canada.|c Department of Medicine , University of Montreal , Montreal , Quebec , Canada.|d Division of Experimental Medicine , Department of Medicine, Department of Anatomy and Cell Biology, Department of Biology , McGill University , Quebec , Canada.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Charron
mesh_terms: D000818:Animals; D016922:Cellular Senescence; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D008527:Medulloblastoma / Q000235:genetics / Q000473:pathology*; D009154:Mutation / Q000235:genetics; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D053823:Hedgehog Proteins; D016159:Tumor Suppressor Protein p53
keywords: Medulloblastoma; p53; Ptch1; TP53; cell senescence; preneoplasia; sonic hedgehog