Hill, R. M., Kuijper, S., Lindsey, J. C., Petrie, K., Schwalbe, E. C., Barker, K., Boult, J. K. R., Williamson, D., Ahmad, Z., Hallsworth, A., Ryan, S. L., Poon, E., Robinson, S. P., Ruddle, R., Raynaud, F. I., Howell, L., Kwok, C., Joshi, A., Nicholson, S. L., Crosier, S., Ellison, D. W., Wharton, S. B., Robson, K., Michalski, A., Hargrave, D., Jacques, T. S., Pizer, B., Bailey, S., Swartling, F. J., Weiss, W. A., Chesler, L., Clifford, S. 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 1535-6108

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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.

Item Type:	Article
Authors (ICR Faculty only):	Robinson, Simon and Raynaud, Florence and Chesler, Louis
All Authors:	Hill, R. M., Kuijper, S., Lindsey, J. C., Petrie, K., Schwalbe, E. C., Barker, K., Boult, J. K. R., Williamson, D., Ahmad, Z., Hallsworth, A., Ryan, S. L., Poon, E., Robinson, S. P., Ruddle, R., Raynaud, F. I., Howell, L., Kwok, C., Joshi, A., Nicholson, S. L., Crosier, S., Ellison, D. W., Wharton, S. B., Robson, K., Michalski, A., Hargrave, D., Jacques, T. S., Pizer, B., Bailey, S., Swartling, F. J., Weiss, W. A., Chesler, L., Clifford, S. C.
Additional Information:	ISI Document Delivery No.: AY9ZS Times Cited: 0 Cited Reference Count: 48 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 Clifford, Steven C. Cancer Research UK [C34648/A12054, C8464/A13457, C1060/A10334]; Action Medical Research [RTF1414]; Sparks [09NCL02]; Brain Tumour Charity [SDR004X, 16/164]; JGW Patterson Foundation; Christopher's Smile [CXC002H]; Brain Tumour Charity; Great Ormond Street Children's Charity; Children with Cancer UK [16/193]; National Institute for Health Research; Great Ormond Street Hospital UCL Biomedical Research Centre award This study was supported by grants from Cancer Research UK (grants C34648/A12054, C8464/A13457, and C1060/A10334), Action Medical Research (RTF1414), Sparks (09NCL02), The Brain Tumour Charity (grants SDR004X and 16/164), the JGW Patterson Foundation, and Christopher's Smile (CXC002H) and was undertaken as part of the INSTINCT network, co-funded by The Brain Tumour Charity, Great Ormond Street Children's Charity, and Children with Cancer UK (grant 16/193). T.S.J. is supported by the National Institute for Health Research and a Great Ormond Street Hospital UCL Biomedical Research Centre award. F.I.R. and R.R. are employees of the Institute of Cancer Research and are involved in the development of aurora kinase inhibitors. 0 CELL PRESS CAMBRIDGE CANCER CELL
Uncontrolled Keywords:	CENTRAL-NERVOUS-SYSTEM CHILDHOOD MEDULLOBLASTOMA ANAPLASTIC MEDULLOBLASTOMA OUTCOME PREDICTION CHILDRENS-CANCER TP53 MUTATION N-MYC SUBGROUPS NEUROBLASTOMA AMPLIFICATION
Research teams:	ICR divisions > Cancer Therapeutics > Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group) ICR divisions > Radiotherapy and Imaging > Magnetic Resonance ICR divisions > Clinical Studies > Paediatric Solid Tumour Biology and Therapeutics ICR divisions > Cancer Therapeutics > Paediatric Solid Tumour Biology and Therapeutics ICR divisions > Molecular Pathology > Paediatric Solid Tumour Biology and Therapeutics
Depositing User:	Barry Jenkins
Date Deposited:	13 Feb 2015 16:25
Last Modified:	13 Feb 2015 16:26
URI:	http://publications.icr.ac.uk/id/eprint/13899

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