Project description:Gene expression data generated for the purpose of correlating differentially-expressed genes between IDH1 mutant and IDH1 wild-type high grade gliomas with differential hydroxymethylcytosine profiles as determined using Illumina EPIC BeadChip platform.
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.
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.
Project description:20% of patients affected with diffuse low-grade brain tumors have high cell density foci harboring higher KI67 index and DNA alterations. These foci may represent tumor progression towards high-grade gliomas. Here we performed transcriptome analysis of those foci vs adjacent tumoral tissues dissected from formalin fixed and paraffin embedded blocks.
Project description:Bisulfite and oxidative bisulfite treated sample methylation analysis of IDH1 mutant and wild-type high grade human gliomas, to profile 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC). Genomic DNA isolated directly from fresh-frozen human high grade glioma specimens.
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.
Project description:Gliomas harboring mutations in isocitrate dehydrogenase 1/2 (IDH1/2) have the CpG island methylator phenotype (CIMP) and significantly longer patient survival time than wild-type IDH1/2 tumors. Although there are many factors underlying the differences in survival between these two tumor types, immune-related differences in cell content are potentially important contributors. In order to investigate the role of IDH mutations in immune response, we created a syngeneic pair mouse model for mutated IDH1 (mutIDH1) and wild-type IDH1 (wtIDH1) gliomas and demonstrated that muIDH1 mice showed many molecular and clinical similarities to muIDH1 human gliomas, including a 100-fold higher concentration of 2-hydroxygluratate (2-HG), longer survival time, and higher CpG methylation compared to wtIDH1. Also, we showed that IDH1 mutations caused downregulation of leukocyte chemotaxis, resulting in repression of the tumor-associated immune system. Given that significant infiltration of immune cells such as macrophages, microglia, monocytes, and neutrophils is linked to poor prognosis in many cancer types, these reduced immune infiltrates in muIDH1 glioma tumors may contribute in part to the differences in aggressiveness of the two glioma types.
Project description:We carried out the analyses of chromosome variations between low-grade and high-grade gliomas in Chinese population. We found out the differences in chromosomes, cytobands, genes, pathways and GO functions. To identify the glioma tissue-specific genomic alterations and compare the genomic variations between low-grade and high-grade gliomas.