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Cell Press, Cancer Cell, 1(27), p. 72-84, 2015

DOI: 10.1016/j.ccell.2014.11.002

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

Journal article published in 2015 by Rebecca M. Hill, Sanne Kuijper, Janet C. Lindsey, Kevin Petrie, Ed C. Schwalbe, Karen Barker, Jessica K. R. Boult, Daniel Williamson, Zai Ahmad, Albert Hallsworth, Sarra L. Ryan, Evon Poon, Simon P. Robinson, Ruth Ruddle, Florence I. Raynaud and other authors.
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This paper is available in a repository.

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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.