Illumina Infinium 450K array data for Diffuse Intrinsic Pontine Glioma
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Pawel Buczkowicz
PROVIDER: E-GEOD-50022 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:Diffuse Intrinsic Pontine Glioma (DIPG) is a fatal brain cancer that arises in the brainstem of children with no effective treatment and near 100% fatality. The failure of most therapies can be attributed to the delicate location of these tumors and choosing therapies based on assumptions that DIPGs are molecularly similar to adult disease. Recent studies have unraveled the unique genetic make-up of this brain cancer with nearly 80% harboring a K27M-H3.3 or K27M-H3.1 mutation. However, DIPGs are still thought of as one disease with limited understanding of the genetic drivers of these tumors. To understand what drives DIPGs we integrated whole-genome-sequencing with methylation, expression and copy-number profiling, discovering that DIPGs are three molecularly distinct subgroups (H3-K27M, Silent, MYCN) and uncovering a novel recurrent activating mutation in the activin receptor ACVR1, in 20% of DIPGs. Mutations in ACVR1 were constitutively activating, leading to SMAD phosphorylation and increased expression of downstream activin signaling targets ID1 and ID2. Our results highlight distinct molecular subgroups and novel therapeutic targets for this incurable pediatric cancer. Illumina HT-12 arrays were performed according to the manufacturer's directions on RNA extracted from FFPE biopsy and autopsy brain tissue from DIPG patients. Gene expression profiling on Illumina HT-12 arrays was performed for 35 paediatric DIPG samples and 10 normal brain samples
2014-03-31 | E-GEOD-50021 | biostudies-arrayexpress
Project description:Diffuse Intrinsic Pontine Glioma (DIPG) is a fatal brain cancer that arises in the brainstem of children with no effective treatment and near 100% fatality. The failure of most therapies can be attributed to the delicate location of these tumors and choosing therapies based on assumptions that DIPGs are molecularly similar to adult disease. Recent studies have unraveled the unique genetic make-up of this brain cancer with nearly 80% harboring a K27M-H3.3 or K27M-H3.1 mutation. However, DIPGs are still thought of as one disease with limited understanding of the genetic drivers of these tumors. To understand what drives DIPGs we integrated whole-genome-sequencing with methylation, expression and copy-number profiling, discovering that DIPGs are three molecularly distinct subgroups (H3-K27M, Silent, MYCN) and uncovering a novel recurrent activating mutation in the activin receptor ACVR1, in 20% of DIPGs. Mutations in ACVR1 were constitutively activating, leading to SMAD phosphorylation and increased expression of downstream activin signaling targets ID1 and ID2. Our results highlight distinct molecular subgroups and novel therapeutic targets for this incurable pediatric cancer. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from snap frozen biopsy and autopsy brain tissue from DIPG patients. Copy number analysis on Affymetrix 6.0 SNP arrays was performed for 45 paediatric DIPG samples, 27 matched normal brain samples, and HapMap samples.
2014-03-31 | E-GEOD-50024 | biostudies-arrayexpress
Project description:Diffuse Intrinsic Pontine Glioma (DIPG) is a fatal brain cancer that arises in the brainstem of children with no effective treatment and near 100% fatality. The failure of most therapies can be attributed to the delicate location of these tumors and choosing therapies based on assumptions that DIPGs are molecularly similar to adult disease. Recent studies have unraveled the unique genetic make-up of this brain cancer with nearly 80% harboring a K27M-H3.3 or K27M-H3.1 mutation. However, DIPGs are still thought of as one disease with limited understanding of the genetic drivers of these tumors. To understand what drives DIPGs we integrated whole-genome-sequencing with methylation, expression and copy-number profiling, discovering that DIPGs are three molecularly distinct subgroups (H3-K27M, Silent, MYCN) and uncovering a novel recurrent activating mutation in the activin receptor ACVR1, in 20% of DIPGs. Mutations in ACVR1 were constitutively activating, leading to SMAD phosphorylation and increased expression of downstream activin signaling targets ID1 and ID2. Our results highlight distinct molecular subgroups and novel therapeutic targets for this incurable pediatric cancer.
2014-03-31 | GSE50022 | GEO
Project description:Diffuse Intrinsic Pontine Glioma (DIPG) is a fatal brain cancer that arises in the brainstem of children with no effective treatment and near 100% fatality. The failure of most therapies can be attributed to the delicate location of these tumors and choosing therapies based on assumptions that DIPGs are molecularly similar to adult disease. Recent studies have unraveled the unique genetic make-up of this brain cancer with nearly 80% harboring a K27M-H3.3 or K27M-H3.1 mutation. However, DIPGs are still thought of as one disease with limited understanding of the genetic drivers of these tumors. To understand what drives DIPGs we integrated whole-genome-sequencing with methylation, expression and copy-number profiling, discovering that DIPGs are three molecularly distinct subgroups (H3-K27M, Silent, MYCN) and uncovering a novel recurrent activating mutation in the activin receptor ACVR1, in 20% of DIPGs. Mutations in ACVR1 were constitutively activating, leading to SMAD phosphorylation and increased expression of downstream activin signaling targets ID1 and ID2. Our results highlight distinct molecular subgroups and novel therapeutic targets for this incurable pediatric cancer.
2014-03-31 | GSE50021 | GEO
Project description:Diffuse Intrinsic Pontine Glioma (DIPG) is a fatal brain cancer that arises in the brainstem of children with no effective treatment and near 100% fatality. The failure of most therapies can be attributed to the delicate location of these tumors and choosing therapies based on assumptions that DIPGs are molecularly similar to adult disease. Recent studies have unraveled the unique genetic make-up of this brain cancer with nearly 80% harboring a K27M-H3.3 or K27M-H3.1 mutation. However, DIPGs are still thought of as one disease with limited understanding of the genetic drivers of these tumors. To understand what drives DIPGs we integrated whole-genome-sequencing with methylation, expression and copy-number profiling, discovering that DIPGs are three molecularly distinct subgroups (H3-K27M, Silent, MYCN) and uncovering a novel recurrent activating mutation in the activin receptor ACVR1, in 20% of DIPGs. Mutations in ACVR1 were constitutively activating, leading to SMAD phosphorylation and increased expression of downstream activin signaling targets ID1 and ID2. Our results highlight distinct molecular subgroups and novel therapeutic targets for this incurable pediatric cancer.
2014-03-31 | GSE50024 | GEO
Project description:Diffuse intrinsic pontine glioma (DIPG) is an incurable pediatric brain tumor, resulting in the death of 200-300 children each year in the United States. Recently it was discovered that approximately 25% of all DIPG cases harbor activating mutations in ACVR1, a gene that encodes Activin A receptor (ALK2), a receptor in the bone morphogenetic protein (BMP) pathway, and that DIPGs with ALK2 mutations commonly harbor an H3.1K27M mutation. Herein, we used the RCAS/TVA retroviral system to study the effects of ACVR1 mutations and H3.1K27M on DIPG pathogenesis. In vitro expression of R206H ACVR1 with and without H3.1K27M in nestin-expressing brainstem progenitors resulted in upregulation of mesenchymal markers and gene set enrichment analysis (GSEA) revealed Stat3 pathway activation. Neonatal expression of ACVR1 R206H or G328V in combination with H3.1K27M and p53 deletion in nestin-expressing brainstem progenitors induced glioma-like lesions expressing mesenchymal markers with Stat3 activation but was not sufficient for full gliomagenesis. In combination with platelet-derived growth factor A (PDGFA) signaling, ACVR1 R206H and H3.1K27M significantly decreased survival and increased tumor incidence. We demonstrate that targeting the BMP signaling pathway may be an effective therapeutic strategy to treat ACVR1 R206H mutant DIPGs. Exogenous Noggin expression at tumor initiation significantly increased tumor latency and treatment of ACVR1 R206H mutant murine DIPGs with LDN212854, an ACVR1 inhibitor, significantly prolonged their survival. We confirm relevance of our model to the human disease as human DIPG models with ACVR1 mutations were also sensitive to treatment with LDN212854 in vitro. Altogether, our studies demonstrate that ACVR1 R206H and H3.1K27M promote tumor initiation, accelerate gliomagenesis, promote a mesenchymal profile in part due to Stat3 activation, and identify LDN212854 as a promising compound to treat children with DIPG.
2019-01-25 | GSE125627 | GEO
Project description:Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are the most lethal of all childhood cancers. Palliative radiotherapy is the only proven life-prolonging treatment, with patient survival 9-11 months. ONC201 shows preclinical and emerging clinical efficacy in DIPG. Currently, little is known about the mechanisms of sensitivity/resistance of DIPGs to ONC201, or whether recurring genomic features influence response. Using a systems-biological approach, we show ONC201 elicits potent agonism of the mitochondrial protease, CLPP, driving proteolysis of electron transport chain (ETC) and tricarboxylic acid (TCA) cycle proteins. DIPGs harboring TP53-mutations show reduced sensitivity to ONC201. Molecular mechanisms identify metabolic adaptation and resistance to ONC201 regulated by redox-activated PI3K/Akt signaling, counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib, in both wt-TP53 and TP53-mutant DIPGs. The discoveries described within, coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib inform the DIPG/DMG phase II combination clinical trial NCT05009992.
2023-05-25 | PXD036245 | Pride
Project description:Diffuse intrinsic pontine glioma (DIPG) is an aggressive childhood tumor of the brainstem with currently no curative treatment available. The vast majority of DIPGs carry a mutation in histone H3 leading to a lysine 27-to-methionine exchange (H3K27M). The H3K27M mutation has been shown to inhibit EZH2, the catalytic subunit of the polycomb repressive complex 2, which presumably leads to global reduction of H3K27 trimethylation and upregulation of tumor-driving genes. However, the exact pathomechanism and cellular context remain elusive. Recent single cell transcriptome data suggested the DIPG cell of origin to be of oligodendroglial lineage, whereas in vivo studies demonstrated neural stem or progenitor cells (NPCs, NSCs) to be susceptible for malignant transformation upon H3K27M expression. Here, we used targeted human induced pluripotent stem cells (iPSCs) carrying an inducible H3.3-K27M allele in the endogenous H3F3A locus together with specific differentiation methods to study the effects of the mutation in disease-relevant cell identities of the neural lineage. Phenotypic, transcriptomic, and chromatin immunoprecipitation sequencing (ChIP-seq) analyses revealed a distinct role of H3.3-K27M for deregulating bivalent promoter-associated developmental genes producing diverse outcomes in different cell types. While being fatal for iPSCs, H3.3-K27M increased proliferation in NSCs and to a lesser extent in oligodendroglial progenitor cells (OPCs) but not in astroglial-restricted precursors. Importantly, we demonstrated that only NSCs but not OPCs gave rise to tumors upon induction of the H3.3-K27M and TP53 inactivation in an orthotopic xenograft model faithfully recapitulating human DIPGs. Thus, we provide evidence that indeed only NSCs can develop H3.3-K27M-driven DIPG-like tumors but that the mutation actively drives acquisition of oligodendroglial characteristics, thus explaining the different observations of cell identity. Identification of the originating cell type may help to determine specific vulnerabilities of this tumor for developing targeted therapies.
2021-02-09 | GSE133153 | GEO
Project description:Diffuse intrinsic pontine glioma (DIPG) is an aggressive childhood tumor of the brainstem with currently no curative treatment available. The vast majority of DIPGs carry a mutation in histone H3 leading to a lysine 27-to-methionine exchange (H3K27M). The H3K27M mutation has been shown to inhibit EZH2, the catalytic subunit of the polycomb repressive complex 2, which presumably leads to global reduction of H3K27 trimethylation and upregulation of tumor-driving genes. However, the exact pathomechanism and cellular context remain elusive. Recent single cell transcriptome data suggested the DIPG cell of origin to be of oligodendroglial lineage, whereas in vivo studies demonstrated neural stem or progenitor cells (NPCs, NSCs) to be susceptible for malignant transformation upon H3K27M expression. Here, we used targeted human induced pluripotent stem cells (iPSCs) carrying an inducible H3.3-K27M allele in the endogenous H3F3A locus together with specific differentiation methods to study the effects of the mutation in disease-relevant cell identities of the neural lineage. Phenotypic, transcriptomic, and chromatin immunoprecipitation sequencing (ChIP-seq) analyses revealed a distinct role of H3.3-K27M for deregulating bivalent promoter-associated developmental genes producing diverse outcomes in different cell types. While being fatal for iPSCs, H3.3-K27M increased proliferation in NSCs and to a lesser extent in oligodendroglial progenitor cells (OPCs) but not in astroglial-restricted precursors. Importantly, we demonstrated that only NSCs but not OPCs gave rise to tumors upon induction of the H3.3-K27M and TP53 inactivation in an orthotopic xenograft model faithfully recapitulating human DIPGs. Thus, we provide evidence that indeed only NSCs can develop H3.3-K27M-driven DIPG-like tumors but that the mutation actively drives acquisition of oligodendroglial characteristics, thus explaining the different observations of cell identity. Identification of the originating cell type may help to determine specific vulnerabilities of this tumor for developing targeted therapies.
2021-02-09 | GSE132605 | GEO
Project description:Purpose: More than 90% of children with diffuse intrinsic pontine glioma (DIPG) die within 2 years of diagnosis. There is a dire need to identify therapeutic targets, however lack of patient material for research has limited progress. We evaluated a large cohort of diffuse intrinsic pontine gliomas (DIPGs) to identify recurrent genomic abnormalities and gene expression signatures underlying DIPG. Patients and Methods: We used single nucleotide polymorphism arrays to evaluate genomic copy number imbalances in 43 DIPGs from 40 patients and in 8 low-grade exophytic brainstem gliomas. Gene expression arrays were used to evaluate expression signatures from 27 DIPGs, 6 low-grade exophytic brainstem gliomas and 66 low-grade gliomas arising outside the brainstem. Results: Frequencies of specific large-scale and focal imbalances varied significantly between DIPGs and pediatric glioblastomas outside the brainstem. Focal amplifications of genes within the receptor tyrosine kinase-Ras-PI3-kinase signaling pathway were found in 47% of DIPG, with PDGFRA and MET showing the highest frequency. 30% of DIPG contained focal amplifications of cell-cycle regulatory genes controlling RB phosphorylation, and 21% had concurrent amplification of genes from both pathways. Some tumors showed heterogeneity in amplification patterns. DIPGs showed distinct gene expression signatures relating to developmental processes compared to pediatric glioblastomas arising outside the brainstem, while expression signatures of low-grade exophytic brainstem gliomas were similar to low-grade gliomas outside the brainstem. Copy number analaysis: 43 DIPG samples, 8 Low Grade Gliomas using SNP6.0. Available matched normals are also profiled with SNP6.0. Expression analysis: 29 DIPG samples, 6 Low grade samples Please contact Suzanne Baker at Suzanne.Baker@stjude.org for CEL files and genotype calls.
2011-09-20 | E-GEOD-26576 | biostudies-arrayexpress