Progression from low- to high-grade astrocytoma is characterized by transcriptomal heterogeneity and genomic number copy alterations
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE49269 | GEO | 2016/02/01
SECONDARY ACCESSION(S): PRJNA213442
REPOSITORIES: GEO
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2016-02-01 | GSE49267 | GEO
Project description: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.
2016-02-01 | GSE49266 | GEO
Project description: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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Project description:Progression from low- to high-grade astrocytoma is characterized by transcriptomal heterogeneity and genomic number copy alterations
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