title: Evasion of Cell Senescence Leads to Medulloblastoma Progression.
abstract: How brain tumors progress from precancerous lesions to advanced cancers is not well understood. Using Ptch1(+/-) mice to study medulloblastoma progression, we found that Ptch1 loss of heterozygosity (LOH) is an early event that is associated with high levels of cell senescence in preneoplasia. In contrast, advanced tumors have evaded senescence. Remarkably, we discovered that the majority of advanced medulloblastomas display either spontaneous, somatic p53 mutations or Cdkn2a locus inactivation. Consistent with senescence evasion, these p53 mutations are always subsequent to Ptch1 LOH. Introduction of a p53 mutation prevents senescence, accelerates tumor formation, and increases medulloblastoma incidence. Altogether, our results show that evasion of senescence associated with Ptch1 LOH allows progression to advanced tumors.
authors.affiliation: Molecular Biology of Neural Development, Institut de Recherches Cliniques de Montréal, 110 Pine Avenue West, Montreal, QC H2W 1R7, Canada; Integrated Program in Neuroscience, McGill University, Montreal, QC H3A 2K6, Canada.
authors.forename: Lukas
authors.initials: L
authors.lastname: Tamayo-Orrego
authors.affiliation: Molecular Biology of Neural Development, Institut de Recherches Cliniques de Montréal, 110 Pine Avenue West, Montreal, QC H2W 1R7, Canada; Department of Medicine, University of Montreal, Montreal, QC H3T 1J4, Canada.
authors.forename: Chia-Lun
authors.initials: CL
authors.lastname: Wu
authors.affiliation: Molecular Biology of Neural Development, Institut de Recherches Cliniques de Montréal, 110 Pine Avenue West, Montreal, QC H2W 1R7, Canada; Department of Medicine, University of Montreal, Montreal, QC H3T 1J4, Canada.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Bouchard
authors.affiliation: Molecular Biology of Neural Development, Institut de Recherches Cliniques de Montréal, 110 Pine Avenue West, Montreal, QC H2W 1R7, Canada.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Khedher
authors.affiliation: Molecular Biology of Neural Development, Institut de Recherches Cliniques de Montréal, 110 Pine Avenue West, Montreal, QC H2W 1R7, Canada; Integrated Program in Neuroscience, McGill University, Montreal, QC H3A 2K6, Canada.
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Swikert
authors.affiliation: Research Group "Non-coding RNAs in Pediatric Cancers," German Cancer Consortium, University Hospital Düsseldorf, Department of Pediatric Oncology, Hematology, and Clinical Immunology, 40225 Düsseldorf, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Remke
authors.affiliation: Division of Neurosurgery and The Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada.
authors.forename: Patryk
authors.initials: P
authors.lastname: Skowron
authors.affiliation: Division of Neurosurgery and The Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.affiliation: Molecular Biology of Neural Development, Institut de Recherches Cliniques de Montréal, 110 Pine Avenue West, Montreal, QC H2W 1R7, Canada; Integrated Program in Neuroscience, McGill University, Montreal, QC H3A 2K6, Canada; Department of Medicine, University of Montreal, Montreal, QC H3T 1J4, Canada; Division of Experimental Medicine, Department of Medicine, Department of Anatomy and Cell Biology, Department of Biology, McGill University, Montreal, QC H3A 2B2, Canada. Electronic address: frederic.charron@ircm.qc.ca.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Charron
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D016922:Cellular Senescence; D002531:Cerebellum / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D018450:Disease Progression; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D019656:Loss of Heterozygosity; D008527:Medulloblastoma / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D020125:Mutation, Missense; D000072081:Patched-1 Receptor / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D014466:Ultraviolet Rays
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D053823:Hedgehog Proteins; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; C509239:SHH protein, human; D016159:Tumor Suppressor Protein p53
keywords: cerebellum; medulloblastoma; p16ink4a; p53; preneoplasia; ptch1; sonic hedgehog