Progression from low- to high-grade astrocytoma is characterized by transcriptomal heterogeneity and genomic number copy alterations
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ABSTRACT:
PROVIDER: PRJNA213442 | ENA |
REPOSITORIES: ENA
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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: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: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:Survival in the majority of high grade astrocytoma (HGA) patients is very poor, with only a rare population of long-term survivors. A better understanding of the biological factors associated with long-term survival in HGA would aid development of more effective therapy and prognostication. We used microarray gene expression profiling of 26 patient surgical samples with known clinical outcomes to discover novel prognostic markers.
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Project description:Copy number analysis of 21 paediatric low-grade astrocytomas identified a discrete copy number gain of 1.9Mb in chromosome band 7q34. The gain was present in 12/14 cerebellar pilocytic astrocytomas. Subsequent analysis of tumour cDNA indentified a novel gene fusion between KIAA1549 and BRAF in these tumours. Copy number analysis of 21 paediatric low-grade astrocytomas using the Affymetrix GeneChip Human Mapping 250K Nsp Array. This study comprised 14 pilocytic astrocytomas, 4 diffuse astrocytomas, one pilomyxoid astrocytoma, one pilomyxoid glioma and one pleomorphic xanthoastrocytoma. Tumours were compared to the mean of two normal male DNA controls.
2010-04-09 | E-GEOD-14960 | biostudies-arrayexpress
Project description:Survival in the majority of high grade astrocytoma (HGA) patients is very poor, with only a rare population of long-term survivors. A better understanding of the biological factors associated with long-term survival in HGA would aid development of more effective therapy and prognostication. We used microarray gene expression profiling of 26 patient surgical samples with known clinical outcomes to discover novel prognostic markers. Gene expression profiles were generated from surgical tumor samples using Affymetrix HG-U133plus2 chips. All genes were correlated with survival as a continuous variable in order to identify ontologys associated with risk of recurrence.
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Project description:Mutations in the PTEN, TP53 and RB1 pathways are obligate events in the pathogenesis of human glioblastomas, the highest grade of astrocytoma. To investigate synergy between these tumor suppressors in mice, we induced various combinations of compound deletions conditionally in astrocytes and neural precursors in the mature brain. The resulting highly penetrant astrocytomas showed a spectrum of histopathological variation reminiscent of human tumors, and ranged from grade III to grade IV (glioblastoma). Secondary somatic mutations varied depending on the combination of initiating deletions and were relevant to human disease. Receptor tyrosine kinase amplifications were frequent in tumors initiated by combined conditional deletion of Pten and Tp53, but not when Rb, Pten and Tp53 were simultaneously deleted. Multiple mutations within PI3K and Rb pathways were acquired, however, Mapk activation was not consistently detected in astrocytomas. Gene expression profiling revealed striking similarities to previously described human astrocytoma subclasses. A subset of astrocytomas initiated outside of proliferative niches in the adult brain.
2011-03-23 | GSE22927 | GEO
Project description:Primary astrocytomas of high histopathological grade (HG-astrocytomas) are largely restricted to older patients and are almost invariably fatal despite multimodal therapy. Here, we show that the young brain has an endogenous defense mechanisms against HG-astrocytomas. Neural precursor cells (NPCs) migrate to HG-astrocytomas, reduce glioma expansion and prolong survival by releasing a group of fatty-acid ethanolamides that have agonistic activity on the vanilloid receptor (transient receptor potential vanilloid subfamily member-1; TRPV1). TRPV1 expression is much higher in HG-astrocytomas than in the tumor-free brain and TRPV1 stimulation triggers tumor cell-death via the activating transcription factor-3 (ATF3) controlled branch of the ER-stress pathway. The anti-tumourigenic response of NPCs is lost with aging. NPC-mediated tumor suppression can be mimicked in the old brain by systemic administration of the synthetic vanilloid Arvanil, indicating that TRPV1 agonists hold potential as new HG-astrocytoma therapeutics. The goal of this microarray study was understand how neural stem / precursor cell (NPC) induced high grade astrocytoma cell-death is controlled by changes in gene expression. We investigated the gene-expression pattern in mouse high grade astrocytoma GL261 cells after incubation with NPC non-conditioned medium (controls) or NPC-conditioned medium by microarrays and found that endoplasmic reticulum stress genes like the activating transcription factor-3 (ATF3) were robustly up-regulated in NPC-conditioned medium treated mouse high grade astrocytoma cells, compared to controls. Comparison of two experimental groups (conditioned medium treated versus non-conditioned medium treated) in three dye swap experiments (6 arrays used in total).
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