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Lookup NU author(s): Dr Rebecca Hill, Dr Janet Lindsey, Dr Ed Schwalbe, Dr Karen Barker, Dr Daniel Williamson, Sarra Ryan, Sarah Nicholson, Dr Stephen Crosier, Professor Simon BaileyORCiD, Professor Steven CliffordORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
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.
Author(s): 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
Publication type: Article
Publication status: Published
Journal: Cancer Cell
Year: 2015
Volume: 27
Issue: 1
Pages: 72-84
Print publication date: 12/01/2015
Online publication date: 18/12/2014
Acceptance date: 05/11/2014
Date deposited: 17/03/2015
ISSN (print): 1535-6108
ISSN (electronic): 1878-3686
Publisher: Cell Press
URL: http://dx.doi.org/10.1016/j.ccell.2014.11.002
DOI: 10.1016/j.ccell.2014.11.002
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