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| Status |
Public on Apr 23, 2015 |
| Title |
Combined MYC and TP53 defects emerge at medulloblastoma relapse and define rapidly progressive, therapeutically targetable disease [gene expression] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
We undertook a comprehensive clinical and biological investigation of serial medulloblastoma biopsies obtained at diagnosis and relapse. Combined MYC gene family amplifications and P53 pathway defects commonly emerged at relapse, and all patients in this molecular group died of rapidly progressive disease post-relapse. To study this genetic interaction, we investigated a transgenic model of MYCN-driven medulloblastoma and found spontaneous development of Trp53 inactivating mutations. Abrogation of Trp53 function in this model produced aggressive tumors that mimicked the characteristics of relapsed human tumors with combined P53–MYC dysfunction. Restoration of p53 activity, genetic and therapeutic suppression of MYCN all reduced tumor growth and prolonged survival. Our findings identify P53–MYC interactions which emerge at medulloblastoma relapse as biomarkers of clinically aggressive disease that may be targeted therapeutically.
There are currently no effective therapies for children with relapsed medulloblastoma. While clinical and biological features of the disease at diagnosis are increasingly well understood, biopsy is rarely performed at relapse and few biological data are available to guide more effective treatments. Here, we show that medulloblastomas develop altered biology at relapse which is predictive of disease course and cannot be detected at diagnosis. We have discovered the emergence of P53–MYC interactions at relapse, as biomarkers of clinically aggressive relapsed disease, which can be modelled and targeted therapeutically in genetically-engineered mice. These data provide clear precedent for the incorporation of biopsy at relapse into routine clinical practice, to direct palliative care and the development of improved treatment strategies.
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| Overall design |
mouse model expression profiles from various mouse Medulloblastoma models MYCN/MYC overexpressing with/without p53 Mutations were compared to human MB expression profiles using Non-negative Matrix Factorization projection in order to sub-type the mouse models
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| Contributor(s) |
Williamson D |
| Citation(s) |
25533335 |
| Submission date |
Oct 22, 2014 |
| Last update date |
Jun 14, 2018 |
| Contact name |
Ed Schwalbe |
| E-mail(s) |
ed.schwalbe@northumbria.ac.uk
|
| Organization name |
Northumbria University
|
| Department |
Applied Sciences
|
| Street address |
Ellison Place
|
| City |
Newcastle upon Tyne |
| ZIP/Postal code |
NE1 8ST |
| Country |
United Kingdom |
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| Platforms (1) |
| GPL6885 |
Illumina MouseRef-8 v2.0 expression beadchip |
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| Samples (48)
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| This SubSeries is part of SuperSeries: |
| GSE62626 |
Combined MYC and TP53 defects emerge at medulloblastoma relapse and define rapidly progressive, therapeutically targetable disease |
|
| Relations |
| BioProject |
PRJNA264566 |
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