A non-coding single nucleotide polymorphism at 8q24 drives IDH1-mutant glioma formation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA852543 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14280041_1.fastq.gz | Fastqsanger.gz | |||
| SRR14280041_2.fastq.gz | Fastqsanger.gz | |||
| SRR14280042_1.fastq.gz | Fastqsanger.gz | |||
| SRR14280042_2.fastq.gz | Fastqsanger.gz | |||
| SRR14280043_1.fastq.gz | Fastqsanger.gz |
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Project description:Establishing causal links between inherited polymorphisms and cancer risk is challenging. Here, we focus on the single nucleotide polymorphism rs55705857 (A>G), which confers a 6-fold increased risk of IDH-mutant low-grade glioma (LGG) and is amongst the highest genetic associations with cancer. By fine-mapping the locus, we reveal that rs55705857 itself is the causal variant and is associated with molecular pathways that drive LGG. Mechanistically, we show that rs55705857 resides within a brain-specific enhancer, where the risk allele disrupts OCT2/4 binding, allowing increased interaction with the Myc promoter and increased Myc expression. To functionally test rs55705857, we generated an IDH1R132H-driven LGG mouse model and show that mutating the highly conserved, orthologous mouse rs55705857 locus dramatically accelerated tumor development from 463 to 172 days and increased penetrance from 30% to 75%. Overall, our work generates new LGG models and reveals mechanisms of the heritable predisposition to lethal glioma in ~40% of LGG-patients.
2022-09-12 | GSE206875 | GEO
Project description:The R132H mutation in the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) is the most important prognostic factor for survival of glioma patients. This resulted in many studies investigating the effects of this mutation, including those on energy metabolism. This led to the discovery of a panel of enzymes mainly involved in glutamate anaplerosis and aerobic glycolysis that change in abundance as a result of the IDH1 mutation. To further study these changes and investigate the therapeutic value of inhibitors of IDH1 R132H-associated metabolic pathways, appropriate glioma models are required that mimic in vivo metabolism as good as possible. To investigate how metabolism is affected by in vitro cell culture, we here compared surgically obtained snap frozen glioma tissues with their corresponding primary glioma cell culture models with a previously developed targeted mass spectrometry proteomic assay. We determined the relative abundance of a panel of metabolic enzymes. Results confirmed increased glutamate use and decreased aerobic glycolysis in resected IDH1 R132H glioma tissue samples. However, these metabolic profiles were not reflected in the paired glioma culture samples. Analysis of orthotopic glioma xenograft samples with and without the IDH1 mutation revealed metabolic profiles that more closely resembled clinical counterparts. We suggest that culture conditions and tumor microenvironment play a crucial role in maintaining the in vivo metabolic situation in cell culture models. For this reason, new models that more closely resemble the in vivo microenvironment, such as 3-dimensional cell co-cultures or organotypic multicellular spheroid models, need to be developed and investigated.
2022-02-16 | PXD024019 | Pride
Project description:The R132H mutation in the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) is the most important prognostic factor for survival of glioma patients. This resulted in many studies investigating the effects of this mutation, including those on energy metabolism. This led to the discovery of a panel of enzymes mainly involved in glutamate anaplerosis and aerobic glycolysis that change in abundance as a result of the IDH1 mutation. To further study these changes and investigate the therapeutic value of inhibitors of IDH1 R132H-associated metabolic pathways, appropriate glioma models are required that mimic in vivo metabolism as good as possible. To investigate how metabolism is affected by in vitro cell culture, we here compared surgically obtained snap frozen glioma tissues with their corresponding primary glioma cell culture models with a previously developed targeted mass spectrometry proteomic assay. We determined the relative abundance of a panel of metabolic enzymes. Results confirmed increased glutamate use and decreased aerobic glycolysis in resected IDH1 R132H glioma tissue samples. However, these metabolic profiles were not reflected in the paired glioma culture samples. Analysis of orthotopic glioma xenograft samples with and without the IDH1 mutation revealed metabolic profiles that more closely resembled clinical counterparts. We suggest that culture conditions and tumor microenvironment play a crucial role in maintaining the in vivo metabolic situation in cell culture models. For this reason, new models that more closely resemble the in vivo microenvironment, such as 3-dimensional cell co-cultures or organotypic multicellular spheroid models, need to be developed and investigated.
2022-02-14 | PXD024009 | Pride
Project description:Astrocytoma, oligodendroglioma, oligoastrocytoma, and ependymoma are the main histologic subtypes of glioma. The molecular character of these subtypes has profound implications for understanding their causes and treatment. We describe the epigenetic landscape of these tumor types using novel DNA methylation profiling tools. There is a robust association of methylation profile with tumor histology and IDH1 mutation status. Furthermore, tumors with IDH1 mutation independently predict a tumor hypermethylator phenotype, histology, TP53 mutation status, patient age, and survival. Integrating tumor epigenetic and genetic alterations, this work provides a critical step toward better defining the somatic nature of glioma which will have great potential to impact clinical approaches to disease. This work provides an important step forward in classification of malignant brain tumors using DNA methylation profiling, integrating knowledge regarding IDH1 mutation in gliomas. The epigenetic homogeneity of the IDH1 mutant subclass despite histologic diversity implies that IDH1 mutation is a “driver” or functional determinant of a distinct DNA methylation phenotype, suggesting a novel role for an altered metabolic profile in the brain. This association occurs across histologic subtypes and demonstrates a clear relationship between genetic alteration and epigenetic profile. Fresh frozen tumor tissues were obtained from the University of California San Francisco (UCSF) Brain Tumor Research Center tissue bank with appropriate institutional review board approval. Tumors were diagnosed between 1990 and 2003. Tumor samples were defined as secondary GBM if the patients had prior histological diagnosis of a low-grade glioma. Tumors had previously been reviewed by UCSF neuropathologists to assign histologic subtype and grade. Normal brain tissue samples were from cancer-free patients who underwent temporal lobe resection as treatment for epilepsy at UCSF.
2010-12-20 | E-GEOD-20395 | biostudies-arrayexpress
Project description:Mutant IDH1 promotes glioma formation in vivo
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Project description:In the present study, we applied a quantitative MS-based strategy to characterize the proteome and phosphoproteome in HRAS- or IDH1-driven glioma cells. We describe the driving roles of the MEK and PI3K signaling pathways in RAS-NHA cells, and uncover oncogenic signaling in other pathways. We highlight the interplay between the signaling cascades and show that inhibition of MEK and PI3K reverses phosphorylation signaling patterns driven by oncogenic RAS overexpression. Applying a histone hybrid chemical labeling method and high-resolution MS, we identified significant histone methylation, acetylation, and butyrylation changes in IDH1mut-NHA cells. Our results suggest a global transcriptional repressive state, consistent with the down-regulation of the proteome, transcriptome, and the DNA hyper-methylated state in IDH1mut-NHA cells. We provide a unique resource of altered proteins, phosphosites, and histone PTMs in RAS and IDH1 mutant astrocytoma cell lines, providing insight into oncogenesis in glioma beyond the transcriptomic level.
2016-12-23 | PXD004945 | Pride
Project description:Astrocytoma, oligodendroglioma, oligoastrocytoma, and ependymoma are the main histologic subtypes of glioma. The molecular character of these subtypes has profound implications for understanding their causes and treatment. We describe the epigenetic landscape of these tumor types using novel DNA methylation profiling tools. There is a robust association of methylation profile with tumor histology and IDH1 mutation status. Furthermore, tumors with IDH1 mutation independently predict a tumor hypermethylator phenotype, histology, TP53 mutation status, patient age, and survival. Integrating tumor epigenetic and genetic alterations, this work provides a critical step toward better defining the somatic nature of glioma which will have great potential to impact clinical approaches to disease. This work provides an important step forward in classification of malignant brain tumors using DNA methylation profiling, integrating knowledge regarding IDH1 mutation in gliomas. The epigenetic homogeneity of the IDH1 mutant subclass despite histologic diversity implies that IDH1 mutation is a “driver” or functional determinant of a distinct DNA methylation phenotype, suggesting a novel role for an altered metabolic profile in the brain. This association occurs across histologic subtypes and demonstrates a clear relationship between genetic alteration and epigenetic profile.
2010-12-20 | GSE20395 | GEO
Project description:To examine the NRF2 activity in anaplastic glioma with mutated IDH1/2, we conducted the microarray analysis to measure the expression levels of representative NRF2 target genes, including NQO1, HMOX1, GCLM, TXNRD1, and PRDX1. 12 anaplastic gliomas with or without mutated IDH1/2.
2013-12-04 | E-GEOD-52942 | biostudies-arrayexpress
Project description:The discovery of the IDH1 R132H (IDH1 mut) mutation in low-grade glioma and the associated change in function of the IDH1 enzyme has increased the interest in glioma metabolism. In an earlier study, we found that changes in expression of genes involved in the aerobic glycolysis and the TCA-cycle are associated with IDH1 mut. Here we apply proteomics to FFPE samples of diffuse gliomas with or without IDH1 mutations, in order to map changes in protein levels associated with this mutation. We observed significant changes in the enzyme abundance associated with aerobic glycolysis, glutamate metabolism and the TCA-cycle in IDH1 mut gliomas. Specifically, the enzymes involved in the metabolism of glutamate, lactate and enzymes involved in the conversion of α-ketoglutarate were increased in IDH1 mut gliomas. In addition, the bicarbonate transporter (SLC4A4) was increased in IDH1 mut gliomas, supporting the idea that a mechanism preventing intracellular acidification is active. We also found that enzymes that convert proline, valine, leucine and isoleucine into glutamate were increased in IDH1 mut glioma. We conclude that in IDH1 mut glioma metabolism is rewired (increased input of lactate and glutamate) to preserve TCA cycle activity in IDH1 mut gliomas.
2020-03-09 | PXD016697 | Pride
Project description:The discovery of the IDH1 R132H (IDH1 mut) mutation in low-grade glioma and the associated change in function of the IDH1 enzyme has increased the interest in glioma metabolism. In an earlier study, we found that changes in expression of genes involved in the aerobic glycolysis and the TCA-cycle are associated with IDH1 mut. Here we apply proteomics to FFPE samples of diffuse gliomas with or without IDH1 mutations, in order to map changes in protein levels associated with this mutation. We observed significant changes in the enzyme abundance associated with aerobic glycolysis, glutamate metabolism and the TCA-cycle in IDH1 mut gliomas. Specifically, the enzymes involved in the metabolism of glutamate, lactate and enzymes involved in the conversion of α-ketoglutarate were increased in IDH1 mut gliomas. In addition, the bicarbonate transporter (SLC4A4) was increased in IDH1 mut gliomas, supporting the idea that a mechanism preventing intracellular acidification is active. We also found that enzymes that convert proline, valine, leucine and isoleucine into glutamate were increased in IDH1 mut glioma. We conclude that in IDH1 mut glioma metabolism is rewired (increased input of lactate and glutamate) to preserve TCA cycle activity in IDH1 mut gliomas.
2020-03-09 | PXD016698 | Pride