Combined MYC and P53 defects emerge at medulloblastoma relapse and define rapidly progressive, therapeutically targetable disease.
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Date
2015-01-12ICR Author
Author
Hill, RM
Kuijper, S
Lindsey, JC
Petrie, K
Schwalbe, EC
Barker, K
Boult, JKR
Williamson, D
Ahmad, Z
Hallsworth, A
Ryan, SL
Poon, E
Robinson, SP
Ruddle, R
Raynaud, FI
Howell, L
Kwok, C
Joshi, A
Nicholson, SL
Crosier, S
Ellison, DW
Wharton, SB
Robson, K
Michalski, A
Hargrave, D
Jacques, TS
Pizer, B
Bailey, S
Swartling, FJ
Weiss, WA
Chesler, L
Clifford, SC
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Subject
Animals
Humans
Mice
Medulloblastoma
Cerebellar Neoplasms
Neoplasms, Experimental
Neoplasm Recurrence, Local
Proto-Oncogene Proteins c-myc
Oncogene Proteins
Nuclear Proteins
Antineoplastic Agents
Signal Transduction
Gene Amplification
Mutation
Molecular Sequence Data
Adolescent
Adult
Child
Child, Preschool
Infant
Female
Male
Tumor Suppressor Protein p53
Young Adult
N-Myc Proto-Oncogene Protein
Research team
Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
Paediatric Solid Tumour Biology and Therapeutics
Pre-Clinical MRI
Language
eng
Date accepted
2014-11-05
License start date
2015-01
Citation
Cancer cell, 2015, 27 (1), pp. 72 - 84
Publisher
CELL PRESS
Except where otherwise noted, this item's license is described
as
https://creativecommons.org/licenses/by/4.0
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