title: Combined MYC and P53 defects emerge at medulloblastoma relapse and define rapidly progressive, therapeutically targetable disease.
abstract: We undertook a comprehensive clinical and biological investigation of serial medulloblastoma biopsies obtained at diagnosis and relapse. Combined MYC family amplifications and P53 pathway defects commonly emerged at relapse, and all patients in this group died of rapidly progressive disease postrelapse. To study this interaction, we investigated a transgenic model of MYCN-driven medulloblastoma and found spontaneous development of Trp53 inactivating mutations. Abrogation of p53 function in this model produced aggressive tumors that mimicked characteristics of relapsed human tumors with combined P53-MYC dysfunction. Restoration of p53 activity and genetic and therapeutic suppression of MYCN all reduced tumor growth and prolonged survival. Our findings identify P53-MYC interactions at medulloblastoma relapse as biomarkers of clinically aggressive disease that may be targeted therapeutically.
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE1 4LP, UK.
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Hill
authors.affiliation: Division of Clinical Studies, The Institute of Cancer Research, Sutton SM2 5NG, UK.
authors.forename: Sanne
authors.initials: S
authors.lastname: Kuijper
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE1 4LP, UK.
authors.forename: Janet C
authors.initials: JC
authors.lastname: Lindsey
authors.affiliation: Division of Clinical Studies, The Institute of Cancer Research, Sutton SM2 5NG, UK.
authors.forename: Kevin
authors.initials: K
authors.lastname: Petrie
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE1 4LP, UK.
authors.forename: Ed C
authors.initials: EC
authors.lastname: Schwalbe
authors.affiliation: Division of Clinical Studies, The Institute of Cancer Research, Sutton SM2 5NG, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Barker
authors.affiliation: Division of Radiotherapy and Imaging, The Institute of Cancer Research, Sutton SM2 5NG, UK.
authors.forename: Jessica K R
authors.initials: JK
authors.lastname: Boult
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE1 4LP, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Williamson
authors.affiliation: Division of Clinical Studies, The Institute of Cancer Research, Sutton SM2 5NG, UK.
authors.forename: Zai
authors.initials: Z
authors.lastname: Ahmad
authors.affiliation: Division of Clinical Studies, The Institute of Cancer Research, Sutton SM2 5NG, UK.
authors.forename: Albert
authors.initials: A
authors.lastname: Hallsworth
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE1 4LP, UK.
authors.forename: Sarra L
authors.initials: SL
authors.lastname: Ryan
authors.affiliation: Division of Clinical Studies, The Institute of Cancer Research, Sutton SM2 5NG, UK.
authors.forename: Evon
authors.initials: E
authors.lastname: Poon
authors.affiliation: Division of Radiotherapy and Imaging, The Institute of Cancer Research, Sutton SM2 5NG, UK.
authors.forename: Simon P
authors.initials: SP
authors.lastname: Robinson
authors.affiliation: Division of Clinical Studies, The Institute of Cancer Research, Sutton SM2 5NG, UK.
authors.forename: Ruth
authors.initials: R
authors.lastname: Ruddle
authors.affiliation: Division of Clinical Studies, The Institute of Cancer Research, Sutton SM2 5NG, UK.
authors.forename: Florence I
authors.initials: FI
authors.lastname: Raynaud
authors.affiliation: Division of Clinical Studies, The Institute of Cancer Research, Sutton SM2 5NG, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Howell
authors.affiliation: Division of Clinical Studies, The Institute of Cancer Research, Sutton SM2 5NG, UK.
authors.forename: Colin
authors.initials: C
authors.lastname: Kwok
authors.affiliation: Department of Cellular Pathology, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK.
authors.forename: Abhijit
authors.initials: A
authors.lastname: Joshi
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE1 4LP, UK.
authors.forename: Sarah Leigh
authors.initials: SL
authors.lastname: Nicholson
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE1 4LP, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Crosier
authors.affiliation: St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Ellison
authors.affiliation: Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield S10 2HQ, UK.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Wharton
authors.affiliation: Children's Brain Tumour Research Centre, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2RD, UK.
authors.forename: Keith
authors.initials: K
authors.lastname: Robson
authors.affiliation: Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK.
authors.forename: Antony
authors.initials: A
authors.lastname: Michalski
authors.affiliation: Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK.
authors.forename: Darren
authors.initials: D
authors.lastname: Hargrave
authors.affiliation: Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK; Neural Development Unit, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Jacques
authors.affiliation: Oncology Unit, Alder Hey Children's Hospital, Liverpool L12 2AP, UK.
authors.forename: Barry
authors.initials: B
authors.lastname: Pizer
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE1 4LP, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Bailey
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala 751 85, Sweden.
authors.forename: Fredrik J
authors.initials: FJ
authors.lastname: Swartling
authors.affiliation: Department of Pediatrics, UCSF Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA 94158, USA; Departments of Neurology and Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Weiss
authors.affiliation: Division of Clinical Studies, The Institute of Cancer Research, Sutton SM2 5NG, UK. Electronic address: louis.chesler@icr.ac.uk.
authors.forename: Louis
authors.initials: L
authors.lastname: Chesler
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE1 4LP, UK. Electronic address: steve.clifford@ncl.ac.uk.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Clifford
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002528:Cerebellar Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D005260:Female; D005784:Gene Amplification; D006801:Humans; D007223:Infant; D008297:Male; D008527:Medulloblastoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D000071447:N-Myc Proto-Oncogene Protein; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics*; D009374:Neoplasms, Experimental; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; C489427:MYC protein, human; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53