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

Hill, Rebecca M, Kuijper, Sanne, Lindsey, Janet C, Petrie, Kevin, Schwalbe, Ed C, Barker, Karen, Boult, Jessica K R, Williamson, Daniel, Ahmad, Zai, Hallsworth, Albert, Ryan, Sarra L, Poon, Evon, Robinson, Simon P, Ruddle, Ruth, Raynaud, Florence I, Howell, Louise, Kwok, Colin, Joshi, Abhijit, Nicholson, Sarah Leigh, Crosier, Stephen, Ellison, David W, Wharton, Stephen B, Robson, Keith, Michalski, Antony, Hargrave, Darren, Jacques, Thomas S, Pizer, Barry, Bailey, Simon, Swartling, Fredrik J, Weiss, William A, Chesler, Louis and Clifford, Steven C (2015) Combined MYC and P53 defects emerge at medulloblastoma relapse and define rapidly progressive, therapeutically targetable disease. Cancer cell, 27 (1). pp. 72-84. ISSN 1878-3686

Item Type: Article

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.

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More Information

Depositing User: Kevin Petrie

Identifiers

Item ID: 12437
Identification Number: https://doi.org/10.1016/j.ccell.2014.11.002
ISSN: 1878-3686
URI: http://sure.sunderland.ac.uk/id/eprint/12437
Official URL: https://www.cell.com/cancer-cell/fulltext/S1535-61...

Users with ORCIDS

ORCID for Kevin Petrie: ORCID iD orcid.org/0000-0002-9805-9152

Catalogue record

Date Deposited: 18 Aug 2020 18:12
Last Modified: 30 Sep 2020 10:48

Contributors

Author: Kevin Petrie ORCID iD
Author: Rebecca M Hill
Author: Sanne Kuijper
Author: Janet C Lindsey
Author: Ed C Schwalbe
Author: Karen Barker
Author: Jessica K R Boult
Author: Daniel Williamson
Author: Zai Ahmad
Author: Albert Hallsworth
Author: Sarra L Ryan
Author: Evon Poon
Author: Simon P Robinson
Author: Ruth Ruddle
Author: Florence I Raynaud
Author: Louise Howell
Author: Colin Kwok
Author: Abhijit Joshi
Author: Sarah Leigh Nicholson
Author: Stephen Crosier
Author: David W Ellison
Author: Stephen B Wharton
Author: Keith Robson
Author: Antony Michalski
Author: Darren Hargrave
Author: Thomas S Jacques
Author: Barry Pizer
Author: Simon Bailey
Author: Fredrik J Swartling
Author: William A Weiss
Author: Louis Chesler
Author: Steven C Clifford

University Divisions

Faculty of Health Sciences and Wellbeing > School of Medicine

Subjects

Sciences > Biomedical Sciences
Sciences > Health Sciences

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