Combined MYC and P53 defects emerge at medulloblastoma relapse and define rapidly progressive, therapeutically targetable disease

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; Louise Howell; Colin Kwok; Abhijit Joshi; Sarah Leigh Nicholson; Stephen Crosier; David W Ellison; Stephen B Wharton; Keith Robson; Antony Michalski; Darren Hargrave; Thomas S Jacques; Barry Pizer; Simon Bailey; Fredrik J Swartling; William A Weiss; Louis Chesler; Steven C Clifford

doi:10.1016/j.ccell.2014.11.002

Combined MYC and P53 defects emerge at medulloblastoma relapse and define rapidly progressive, therapeutically targetable disease

Cancer Cell. 2015 Jan 12;27(1):72-84. doi: 10.1016/j.ccell.2014.11.002. Epub 2014 Dec 18.

Authors

Rebecca M Hill¹, Sanne Kuijper², Janet C Lindsey¹, Kevin Petrie², Ed C Schwalbe¹, Karen Barker², Jessica K R Boult³, Daniel Williamson¹, Zai Ahmad², Albert Hallsworth², Sarra L Ryan¹, Evon Poon², Simon P Robinson³, Ruth Ruddle², Florence I Raynaud², Louise Howell², Colin Kwok², Abhijit Joshi⁴, Sarah Leigh Nicholson¹, Stephen Crosier¹, David W Ellison⁵, Stephen B Wharton⁶, Keith Robson⁷, Antony Michalski⁸, Darren Hargrave⁸, Thomas S Jacques⁹, Barry Pizer¹⁰, Simon Bailey¹, Fredrik J Swartling¹¹, William A Weiss¹², Louis Chesler¹³, Steven C Clifford¹⁴

Affiliations

¹ Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE1 4LP, UK.
² Division of Clinical Studies, The Institute of Cancer Research, Sutton SM2 5NG, UK.
³ Division of Radiotherapy and Imaging, The Institute of Cancer Research, Sutton SM2 5NG, UK.
⁴ Department of Cellular Pathology, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK.
⁵ St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
⁶ Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield S10 2HQ, UK.
⁷ Children's Brain Tumour Research Centre, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2RD, UK.
⁸ Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK.
⁹ Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK; Neural Development Unit, UCL Institute of Child Health, London WC1N 1EH, UK.
¹⁰ Oncology Unit, Alder Hey Children's Hospital, Liverpool L12 2AP, UK.
¹¹ Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala 751 85, Sweden.
¹² Department of Pediatrics, UCSF Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA 94158, USA; Departments of Neurology and Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
¹³ Division of Clinical Studies, The Institute of Cancer Research, Sutton SM2 5NG, UK. Electronic address: [email protected].
¹⁴ Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE1 4LP, UK. Electronic address: [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Animals
Antineoplastic Agents / therapeutic use
Cerebellar Neoplasms / drug therapy
Cerebellar Neoplasms / genetics*
Cerebellar Neoplasms / pathology
Child
Child, Preschool
Female
Gene Amplification
Humans
Infant
Male
Medulloblastoma / drug therapy
Medulloblastoma / genetics*
Medulloblastoma / pathology
Mice
Molecular Sequence Data
Mutation
N-Myc Proto-Oncogene Protein
Neoplasm Recurrence, Local / drug therapy
Neoplasm Recurrence, Local / genetics*
Neoplasms, Experimental
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Oncogene Proteins / genetics
Oncogene Proteins / metabolism
Proto-Oncogene Proteins c-myc / genetics*
Proto-Oncogene Proteins c-myc / metabolism
Signal Transduction
Tumor Suppressor Protein p53 / genetics*
Tumor Suppressor Protein p53 / metabolism
Young Adult

Substances

Antineoplastic Agents
MYC protein, human
MYCN protein, human
N-Myc Proto-Oncogene Protein
Nuclear Proteins
Oncogene Proteins
Proto-Oncogene Proteins c-myc
TP53 protein, human
Tumor Suppressor Protein p53

Associated data

GEO/GSE62618
GEO/GSE62625

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding