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| Status |
Public on Feb 01, 2016 |
| Title |
Progression from low- to high-grade astrocytoma is characterized by transcriptomal heterogeneity and genomic number copy alterations (part 3) |
| Organism |
Mus musculus |
| Experiment type |
Genome variation profiling by genome tiling array
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| Summary |
We used genetically-engineered mice (GEM) to target constitutive RTK effector pathway (KrasG12D and/or Pten deletion) mutations in G1/S checkpoint-defective adult mouse astrocytes. Genetic lineage tracing showed that these mutations potentiated tumor initiation in cortical, diencephalic, brainstem, and olfactory bulb astrocytes, producing low-grade astrocytomas (LGA). LGA lacked copy number abnormalities (CNA), but showed oncogenic driver- and astrocyte location-specific transcriptome profiles, suggesting that both driver mutations and cellular origin contribute to LGA genomic heterogeneity. Progression to high-grade astrocytomas (HGA) occurred stochastically, in part through location-specific acquisition of CNA. HGA transcriptomes were heterogeneous and consisted of three subtypes that were also evident in GEM HGA with different oncogenic drivers and cellular origins. HGA subtypes expressing immune/invasion, proliferation, and neuronal genes mimicked human mesenchymal, proneural, and neural GBM, respectively. HGA subtypes also expressed distinct neural lineage signatures and were correlated with astrocyte location, but not oncogenic driver mutations. These results suggest that oncogenic drivers influence LGA subtype and that regional astrocyte identity and progression-acquired CNA contribute strongly to HGA transcriptomal heterogeneity. Defining tumor-initiating and progression-acquired mutations and the cells in which they occur would facilitate molecular classification and development of molecularly targeted strategies to manage GBM.
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| Overall design |
CGH microarray analysis was completed for 10 low-grade astrocytoma (LGA) dissected from neurollogically asymptomatic mice at least a year after induction. LGA showed few and infrequent CNA.
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| Contributor(s) |
Vitucci M, Miller CR |
| Citation(s) |
28398584 |
| |
| Submission date |
Jul 26, 2013 |
| Last update date |
Jun 15, 2017 |
| Contact name |
Ryan Miller |
| E-mail(s) |
miller@med.unc.edu
|
| Phone |
919-966-4333
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| Organization name |
University of North Carolina
|
| Department |
Pathology
|
| Street address |
6109B NRB CB 7250
|
| City |
Chapel HIll |
| State/province |
North Carolina |
| ZIP/Postal code |
27599 |
| Country |
USA |
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| Platforms (1) |
| GPL15076 |
Agilent-014695 Mouse Genome CGH Microarray 244A (G4415A)(Probe Name version) |
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| Samples (10)
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| This SubSeries is part of SuperSeries: |
| GSE49269 |
Progression from low- to high-grade astrocytoma is characterized by transcriptomal heterogeneity and genomic number copy alterations |
|
| Relations |
| BioProject |
PRJNA213444 |
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