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Sunderland Repository records the research produced by the University of Sunderland including practice-based research and theses.

Abstract MB-013: MYC and TP53 defects interact at medulloblastoma relapse to define rapidly progressive disease and can be targeted therapeutically.

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, 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 (2014) Abstract MB-013: MYC and TP53 defects interact at medulloblastoma relapse to define rapidly progressive disease and can be targeted therapeutically. Neuro-Oncology, 16 (Sup 1). i74-i74. ISSN 1522-8517

Item Type: Article


Relapse following multi-modal therapy is the most adverse event in medul- loblastoma. Currently .90% of relapsing patients die, accounting for ~10% of childhood cancer deaths. Medulloblastoma is heterogeneous at diagnosis, comprising four molecular subgroups with distinct clinicopathological and molecular features. The relevance of these features at relapse is unknown, making characterisation, modelling and targeted therapy of relapse biology essential to improve outcomes. We undertook a comprehensive investigation of the molecular and clinicopathological features of 29 relapsed medulloblastomas and paired tumour samples taken at diagnosis, including the assessment of features with established significance at diagnosis (e.g. TP53 pathway status, MYC/MYCN amplification and molecular subgroup status). Molecular subgroup was unchanged, however evidence of alteration of all other features examined was found at relapse, with the majority of changes (30/44) representing acquired high-risk events. Most notably, MYC gene family amplifications and TP53 pathway defects commonly emerged in combination at relapse following conventional multimodal treatment (P 1⁄4 0.02, 7/ 22, 32%) and predicted rapid progression to death (P 1⁄4 0.016). Spontaneous development of Trp53 inactivating mutations was similarly common in a transgenic model of MYCN driven medulloblastoma (GTML;Glt1-tTA/ TRE-MYCN-Luc). Direct modelling of this interaction in GTML/Trp53KI/KI mice enhanced medulloblastoma formation (100%, 43/43 vs. 6%, 3/50 in GTML; P , 0.0001), mimicked clinicopathological characteristics of TP53-MYC relapsed human tumours, and validated the role of TP53 in potentiating the growth of MYCN-driven medulloblastoma. Therapeutic inhibition of Aurora-A kinase using MLN8237 in these tumours, and in derived neurospheres in vitro, promoted degradation of MYCN, reduced tumour growth and prolonged survival. In summary, medulloblastomas display altered molecular, pathological and clinical features at relapse and the emergence of combined TP53-MYC gene family defects is common following conventional therapy. Their association with rapid demise, and their validation as driving and therapeutically exploitable events in a novel mouse model, strongly support routine biopsy at relapse to drive future therapeutic strategies.

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Uncontrolled Keywords: chemotherapy, regimen, child, medulloblastoma, diagnosis, neoplasms
Depositing User: Kevin Petrie


Item ID: 15827
ISSN: 1522-8517
Official URL:

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ORCID for Kevin Petrie: ORCID iD

Catalogue record

Date Deposited: 22 Mar 2023 15:51
Last Modified: 22 Mar 2023 15:51


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: 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


Sciences > Biomedical Sciences

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