Combined MYC and P53 defects emerge at medulloblastoma relapse and define rapidly progressive, therapeutically targetable disease
Open accessAbstract
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.
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The incubation period of this model is in accordance with most other autochthonous models of medulloblastoma or adult glioma and may represent a fundamental aspect of brain cancer modeling in mice.
“However, this incubation period is in accordance with most, if not all, other autochthonous models of medulloblastoma or adult glioma and may represent a fundamental aspect of brain cancer modeling in mice (Alcantara Llaguno et al., 2009; Hill et al., 2015).”
From H3.3K27M Cooperates with Trp53 Loss and PDGFRA Gain in Mouse Embryonic Neural Progenitor Cells to Induce Invasive High-Grade Gliomas (2017) · cites this paper as Hill et al., 2015
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References 50 · Cited by 210
- 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.
- Affiliations
- Newcastle University (GB)
- Institute of Cancer Research (GB)
- Royal Victoria Infirmary (GB)
- St. Jude Children's Research Hospital (US)
- University of Sheffield (GB)
- University of Nottingham (GB)
- Great Ormond Street Hospital (GB)
- Alder Hey Children's Hospital (GB)
- Uppsala University (SE)
- University of California, San Francisco (US)
- Corresponding author
- Chesler, Louis
- Clifford, Steven C.
- ORCID
- Hill, Rebecca M.
- Lindsey, Janet C.
- Petrie, Kevin
- Schwalbe, Ed C.
- Barker, Karen
- Boult, Jessica K.R.
- Williamson, Daniel
- Ryan, Sarra L.
- Poon, Evon
- Robinson, Simon P.
- Ruddle, Ruth
- Raynaud, Florence I.
- Howell, Louise
- Kwok, Colin
- Ellison, David W.
- Wharton, Stephen B.
- Michalski, Antony
- Hargrave, Darren
- Jacques, Thomas S.
- Pizer, Barry
- Bailey, Simon
- Swartling, Fredrik J.
- Weiss, William A.
- Chesler, Louis
- Clifford, Steven C.
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2015-01
- Volume
- 27
- Issue
- 1
- Pages
- 72-84
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC4297293
- OpenAlex
- W2098776492
- Cited by
- 210
- References
- 50
- Citations by year
- 2026: 13 · 2025: 12 · 2024: 17 · 2023: 20 · 2022: 14 · 2021: 27 · 2020: 13 · 2019: 25 · 2018: 20 · 2017: 22 · 2016: 18 · 2015: 9
- FWCI
- 8.19
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Cancer Cell (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Northumbria Research Link (Northumbria University) (acceptedVersion)
- Sunderland Repository (University of Sunderland) (acceptedVersion)
- KTH Publication Database DiVA (KTH Royal Institute of Technology) (submittedVersion, other-oa)
- Stirling Online Research Repository (University of Stirling) (submittedVersion, cc-by)
- UCL Discovery (University College London) (submittedVersion)
- Newcastle University ePrints (Newcastle Univesity) (cc-by)
- Funders
- Action Medical Research
- Cancer Research UK (C1060/A10334, 13457, 11566, C8464/A13457, 18779, 18339, C34648/A12054, 18777, 16464)
- National Institute for Health and Care Research (CL-2014-01-502)
- Sparks (09NCL02, 09RMH01)
- Brain Tumour Charity (16/193, 16/164)
- Topics
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- medulloblastoma, tumor recurrence, MYCN amplification, MYC family genes, p53 inactivation, transgenic mouse model, prognostic factors, targeted therapy, tumor progression
- MeSH terms
- N-Myc Proto-Oncogene Protein, Adolescent, Adult, Animals, Antineoplastic Agents, Cerebellar Neoplasms, Child, Child, Preschool, Female, Gene Amplification, Humans, Infant, Male, Medulloblastoma, Molecular Sequence Data, Mutation, Neoplasm Recurrence, Local, Neoplasms, Experimental, Nuclear Proteins, Signal Transduction, Oncogene Proteins, Tumor Suppressor Protein p53, Proto-Oncogene Proteins c-myc, Mice, Young Adult
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