Close menu


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

Abstract LB-201: 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, Schwalbe, Ed C., Barker, Karen, Boult, Jessica, Williamson, Daniel, Ahmad, Zai, Hallsworth, Albert, Ryan, Sarra, Poon, Evon, Robinson, Simon, Ruddle, Ruth, Raynaud, Florence, Howell, Louise, Kwok, Colin, Joshi, Abhijit, Nicholson, Sarah, Crosier, Stephen, Wharton, Stephen, Jacques, Tom, Robson, Keith, Michalski, Antony, Hargrave, Darren, Pizer, Barry, Bailey, Simon, Swartling, Fredrik J., Petrie, Kevin, Weiss, William A., Chesler, Louis and Clifford, Steve (2014) Abstract LB-201: MYC and TP53 defects interact at medulloblastoma relapse to define rapidly progressive disease and can be targeted therapeutically. Cancer Research, 74 (19_Sup). LB-201. ISSN 0008-5472

Item Type: Article


Disease recurrence following multi-modal therapy is the single most adverse event in medulloblastoma (MB). Currently >90% of relapsing patients die, accounting for ∼10% of childhood cancer deaths. MB is heterogeneous at diagnosis, comprising four molecular subgroups with distinct clinicopathological and molecular features and outcomes. The relevance of these features at relapse is unknown, making characterisation, modelling and targeted therapy of relapse biology essential to improve outcomes. However, relapsed MBs are not routinely biopsied in clinical practice.
We undertook a first comprehensive investigation of the molecular, clinical and pathological features of 29 relapsed MBs and paired tumour samples taken at diagnosis, including the assessment of features with established significance at diagnosis (e.g. chromosome 17 and TP53 pathway status, MYC family (MYC, MYCN) gene amplification, polyploidy, CTNNB1 mutation and molecular subgroup status). Molecular subgroup was concordant at diagnosis and relapse, however evidence of alteration of all other features examined was found in relapsed tumours, with the majority of changes (30/44) representing acquired high-risk events. Most notably, MYC family gene amplifications and TP53 pathway defects commonly emerged in combination at relapse following conventional multimodal treatment (P=0.02, 7/22, 32%) and predicted rapid progression to death (P=0.016).
These observations suggested aberrant activation of MYC family genes synergizes with TP53 inactivation in the genesis of biologically aggressive MB. To investigate any such relationship, we examined Trp53 status in our transgenic mouse model of spontaneously-arising MYCN-driven MB (GTML; Glt1-tTA/TRE-MYCN-Luc). Somatic Trp53 mutations were found in 83% of tumors (n=10/12). Direct modelling of this interaction in GTML/Trp53KI/KI mice dramatically enhanced MB formation with 100% penetrance (43/43, median survival 47 days) in GTML/Trp53KI/KI versus 6% (3/50) in GTML; P<0.0001), faithfully mimicked clinicopathological characteristics of TP53-MYC family gene-associated relapsed human tumors, and validated the essential role of TP53 in potentiating the growth of MYCN-driven MB. Finally, therapeutic inhibition of Aurora-A kinase using MLN8237 in these tumours, and in derived neurospheres in vitro, promoted degradation of MYCN, reduced tumor growth and prolonged survival.
In summary, while subgroup status remains stable, MBs display altered molecular, pathological and clinical features at relapse, and the emergence of combined TP53-MYC family gene defects is common following conventional therapy. Their association with rapid demise, coupled with their biological validation as driving and therapeutically exploitable events in a novel mouse MB model, strongly support further investigation and routine biopsy of relapse disease to drive future individualised therapeutic strategies.

Full text not available from this repository.

More Information

Depositing User: Kevin Petrie


Item ID: 15811
Identification Number:
ISSN: 0008-5472
Official URL:

Users with ORCIDS

ORCID for Kevin Petrie: ORCID iD

Catalogue record

Date Deposited: 22 Mar 2023 14:27
Last Modified: 22 Mar 2023 14:27


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

University Divisions

Faculty of Health Sciences and Wellbeing > School of Medicine


Sciences > Biomedical Sciences

Actions (login required)

View Item View Item