Tissue metabolites in diffuse glioma and their modulations by IDH1 mutation, histology and treatment
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA787304 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17173100_1.fastq.gz | Fastqsanger.gz | |||
| SRR17173100_2.fastq.gz | Fastqsanger.gz | |||
| SRR17173101_1.fastq.gz | Fastqsanger.gz | |||
| SRR17173101_2.fastq.gz | Fastqsanger.gz | |||
| SRR17173102_1.fastq.gz | Fastqsanger.gz |
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Project description:The discovery of the oncometabolite 2-hydroxyglutarate in isocitrate dehydrogenase 1-mutated (IDH1-mutated) tumor entities affirmed the role of metabolism in cancer. However, large databases with tissue metabolites that are modulated by IDH1 mutation remain an area of development. Here, we present an unprecedented and valuable resource for tissue metabolites in diffuse glioma and their modulations by IDH1 mutation, histology, and tumor treatments in 101 tissue samples from 73 diffuse glioma patients (24 astrocytoma, 17 oligodendroglioma, 32 glioblastoma), investigated by NMR-based metabolomics and supported by RNA-Seq. We discovered comparison-specific metabolites and pathways modulated by IDH1 (IDH1 mutation status cohort) and tumor entity. The Longitudinal investigation cohort provides metabolic profiles of untreated and corresponding treated glioma samples at first progression. Most interestingly, univariate and multivariate cox regressions and Kaplan-Meier analyses revealed that tissue metabolites correlate with progression-free and overall survival. Thus, this study introduces potentially novel candidate prognostic and surrogate metabolite biomarkers for future prospective clinical studies, aiming at further refining patient stratification in diffuse glioma. Furthermore, our data will facilitate the generation of so-far-unanticipated hypotheses for experimental studies to advance our molecular understanding of glioma biology.
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Project description:The discovery of the oncometabolite 2-hydroxyglutarate in isocitrate dehydrogenase (IDH)1-mutated tumor entities affirmed the role of metabolism in cancer. Yet, large databases with gene expression data and tissue metabolites that are modulated by IDH1 mutation remain an area of development.
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Project description:The discovery of the oncometabolite 2-hydroxyglutarate in isocitrate dehydrogenase 1-mutated (IDH1-mutated) tumor entities affirmed the role of metabolism in cancer. However, large databases with tissue metabolites that are modulated by IDH1 mutation remain an area of development. Here, we present an unprecedented and valuable resource for tissue metabolites in diffuse glioma and their modulations by IDH1 mutation, histology, and tumor treatments in 101 tissue samples from 73 diffuse glioma patients (24 astrocytoma, 17 oligodendroglioma, 32 glioblastoma), investigated by NMR-based metabolomics and supported by RNA-Seq. We discovered comparison-specific metabolites and pathways modulated by IDH1 (IDH1 mutation status cohort) and tumor entity. The Longitudinal investigation cohort provides metabolic profiles of untreated and corresponding treated glioma samples at first progression. Most interestingly, univariate and multivariate cox regressions and Kaplan-Meier analyses revealed that tissue metabolites correlate with progression-free and overall survival. Thus, this study introduces potentially novel candidate prognostic and surrogate metabolite biomarkers for future prospective clinical studies, aiming at further refining patient stratification in diffuse glioma. Furthermore, our data will facilitate the generation of so-far-unanticipated hypotheses for experimental studies to advance our molecular understanding of glioma biology.
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Project description:Diffuse low-grade gliomas are incurable brain tumours that often carry a mutation in the IDH1 gene. These tumours are heterogeneous and have different types of tumour cells. They can progress toward high grade gliomas. To understand the diversity of tumour cells and how they arise, we have performed single RNA seq of 8 cell lines derived from IDH1 mutant patients. Some cell lines maintained the IDH1 mutation while others lost it. We analysed these cultures when growth factors are present or absent for 4 days to promote differentiation.
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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.
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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.
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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.
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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.
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