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

Rebecca Hill, Sanne Kuijper, Janet Lindsey, Kevin Petrie, Ed Schwalbe, Karen Barker, Jessica Boult, Daniel Williamson, Zai Ahmad, Albert Hallsworth, Sarra Ryan, Evon Poon, Simon Robinson, Ruth Ruddle, Florence Raynaud, Louise Howell, Colin Kwok, Abhijit Joshi, Sarah Leigh Nicholson, Stephen CrosierDavid Ellison, Stephen Wharton, Keith Robson, Antony Michalski, Darren Hargrave, Thomas Jacques, Barry Pizer, Simon Bailey, Fredrik J. Swartling, William Weiss, Louis Chesler, Steven Clifford*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

170 Citations (Scopus)
20 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)72-84
Number of pages13
JournalCancer Cell
Volume27
Issue number1
DOIs
Publication statusPublished - 12 Jan 2015
Externally publishedYes

Fingerprint

Dive into the research topics of 'Combined MYC and P53 Defects Emerge at Medulloblastoma Relapse and Define Rapidly Progressive, Therapeutically Targetable Disease'. Together they form a unique fingerprint.

Cite this