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Cancer Cell. 2015 Jan 12;27(1):72-84. doi: 10.1016/j.ccell.2014.11.002. Epub 2014 Dec 18.

Combined MYC and P53 defects emerge at medulloblastoma relapse and define rapidly progressive, therapeutically targetable disease.

Author information

1
Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE1 4LP, UK.
2
Division of Clinical Studies, The Institute of Cancer Research, Sutton SM2 5NG, UK.
3
Division of Radiotherapy and Imaging, The Institute of Cancer Research, Sutton SM2 5NG, UK.
4
Department of Cellular Pathology, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK.
5
St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
6
Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield S10 2HQ, UK.
7
Children's Brain Tumour Research Centre, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2RD, UK.
8
Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK.
9
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.
10
Oncology Unit, Alder Hey Children's Hospital, Liverpool L12 2AP, UK.
11
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala 751 85, Sweden.
12
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.
13
Division of Clinical Studies, The Institute of Cancer Research, Sutton SM2 5NG, UK. Electronic address: louis.chesler@icr.ac.uk.
14
Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE1 4LP, UK. Electronic address: steve.clifford@ncl.ac.uk.

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.

PMID:
25533335
PMCID:
PMC4297293
DOI:
10.1016/j.ccell.2014.11.002
[Indexed for MEDLINE]
Free PMC Article
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