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Combined MYC and P53 Defects Emerge at Medulloblastoma Relapse and Define Rapidly Progressive, Therapeutically Targetable Disease

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 Bailey, Professor Steven Clifford

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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.


Publication metadata

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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Funding

Funder referenceFunder name
Great Ormond Street Hospital UCL Biomedical Research Centre award
JGW Patterson Foundation
National Institute for Health Research
Brain Tumour Charity
Great Ormond Street Children's Charity
16/193Children with Cancer UK
09NCL02Sparks
16/164Brain Tumour Charity
C34648/A12054Cancer Research UK
C8464/A13457Cancer Research UK
CXC002HChristopher's Smile
C1060/A10334Cancer Research UK
RTF1414Action Medical Research
SDR004XBrain Tumour Charity

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