Identification of Isocitrate Dehydrogenase 2 (IDH2) Mutation in Carotid Body Paraganglioma.
Ontology highlight
ABSTRACT:
SUBMITTER: Lang F
PROVIDER: S-EPMC8488436 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Gliomas are common intracranial neoplasias in dogs. However, the underlying pathogenic mechanisms remain unclear. In humans, isocitrate dehydrogenase 2 (IDH2) is often mutated in gliomas. Although almost human IDH2 mutations have been identified at the Arg172 codon, few studies have reported structural, functional or mutational information for canine IDH2. In this study, we cloned the full-length canine IDH2 (cIDH2) cDNA and substituted wild type Arg174 (cIDH2 WT: corresponding to R172 of human IDH2) with Lys (cIDH2 R174K). The cIDH2 WT and R174K proteins were overexpressed in HeLa cells, and their presence was confirmed using an anti-human IDH2-WT mAb (clone: KrMab-3) and an anti-IDH2-R172K mAb (clone: KMab-1). The IDH2 activity between cIDH2 WT and cIDH2 R174K transfectants was compared by measuring the production of NADH and NADPH. NADPH production was lower for cIDH2 R174K than that for cIDH2 WT transfectants. Finally, we detected increased expression of hypoxia inducible factor-1 alpha (HIF-1?) in cIDH2 R174K transfectants. This indicates that mutations at R174 can potentially induce carcinogenesis in canine somatic cells.
| S-EPMC5797864 | biostudies-literature
Project description:The Hedgehog (Hh) pathway regulates the growth of a subset of adult gliomas and better definition of Hh-responsive subtypes could enhance the clinical utility of monitoring and targeting this pathway in patients. Somatic mutations of the isocitrate dehydrogenase (IDH) genes occur frequently in WHO grades II and III gliomas and WHO grade IV secondary glioblastomas. Hh pathway activation in WHO grades II and III gliomas suggests that it might also be operational in glioblastomas that developed from lower-grade lesions. To evaluate this possibility and to better define the molecular and histopathological glioma subtypes that are Hh-responsive, IDH genes were sequenced in adult glioma specimens assayed for an operant Hh pathway. The proportions of grades II-IV specimens with IDH mutations correlated with the proportions that expressed elevated levels of the Hh gene target PTCH1. Indices of an operational Hh pathway were measured in all primary cultures and xenografts derived from IDH-mutant glioma specimens, including IDH-mutant glioblastomas. In contrast, the Hh pathway was not operational in glioblastomas that lacked IDH mutation or history of antecedent lower-grade disease. IDH mutation is not required for an operant pathway however, as significant Hh pathway modulation was also measured in grade III gliomas with wild-type IDH sequences. These results indicate that the Hh pathway is operational in grades II and III gliomas and glioblastomas with molecular or histopathological evidence for evolvement from lower-grade gliomas. Lastly, these findings suggest that gliomas sharing this molecularly defined route of progression arise in Hh-responsive cell types.
| S-EPMC4308293 | biostudies-literature
Project description:Mitochondria play a central role in oxidative energy metabolism and age-related diseases such as cancer. Accumulation of spurious oxidative damage can cause cellular dysfunction. Antioxidant pathways that rely on NADPH are needed for the reduction of glutathione and maintenance of proper redox status. The mitochondrial matrix protein isocitrate dehydrogenase 2 (IDH2) is a major source of NADPH. Previously, we demonstrated that the NAD(+)-dependent deacetylase SIRT3 was essential for the prevention of age-related hearing loss in mice fed a calorically restricted diet. Here we provide direct biochemical and biological evidence establishing an exquisite regulatory relationship between IDH2 and SIRT3 under acute and chronic caloric restriction. The regulated site of acetylation was mapped to Lys-413, an evolutionarily invariant residue. Site-specific, genetic incorporation of N(?)-acetyllysine into position 413 of IDH2 revealed that acetylated IDH2 displays a dramatic 44-fold loss in activity. Deacetylation by SIRT3 fully restored maximum IDH2 activity. The ability of SIRT3 to protect cells from oxidative stress was dependent on IDH2, and the deacetylated mimic, IDH2(K413R) variant was able to protect Sirt3(-/-) mouse embryonic fibroblasts from oxidative stress through increased reduced glutathione levels. Together these results uncover a previously unknown mechanism by which SIRT3 regulates IDH2 under dietary restriction. Recent findings demonstrate that IDH2 activities are a major factor in cancer, and as such, these results implicate SIRT3 as a potential regulator of IDH2-dependent functions in cancer cell metabolism.
| S-EPMC3340192 | biostudies-literature
Project description:BackgroundLymphovascular invasion (LVI) is a prerequisite step in breast cancer (BC) metastasis. We have previously identified wild-type isocitrate dehydrogenase 2 (IDH2) as a key putative driver of LVI. Thus, we explored the prognostic significance of IDH2 at transcriptome and protein expression levels in pre-invasive and invasive disease.MethodsUtlising tissue microarrays from a large well annotated BC cohort including ductal carcinoma in situ and invasive breast cancer (IBC), IDH2 was assessed at the transcriptomic and proteomic level. The associations between clinicopathological factors including LVI status, prognosis and the expression of IDH2 were evaluated.ResultsIn pure DCIS and IBC, high IDH2 protein expression was associated with features of aggressiveness including high nuclear grade, larger size, comedo necrosis and hormonal receptor negativity and LVI, higher grade, larger tumour size, high NPI, HER2 positivity, and hormonal receptor negativity, respectively. High expression of IDH2 either in mRNA or in protein levels was associated with poor patient's outcome in both DCIS and IBC. Multivariate analysis revealed that IDH2 protein expression was an independent risk factor for shorter BC specific-survival.ConclusionFurther functional studies to decipher the role of IDH2 and its mechanism of action as a driver of BC progression and LVI are warranted.
| S-EPMC6985218 | biostudies-literature
Project description:Cancers of origin in the gallbladder and bile ducts are rarely curable with current modalities of cancer treatment. Our clinical application of broad-based mutational profiling for patients diagnosed with a gastrointestinal malignancy has led to the novel discovery of mutations in the gene encoding isocitrate dehydrogenase 1 (IDH1) in tumors from a subset of patients with cholangiocarcinoma. A total of 287 tumors from gastrointestinal cancer patients (biliary tract, colorectal, gastroesophageal, liver, pancreatic, and small intestine carcinoma) were tested during routine clinical evaluation for 130 site-specific mutations within 15 cancer genes. Mutations were identified within a number of genes, including KRAS (35%), TP53 (22%), PIK3CA (10%), BRAF (7%), APC (6%), NRAS (3%), AKT1 (1%), CTNNB1 (1%), and PTEN (1%). Although mutations in the metabolic enzyme IDH1 were rare in the other common gastrointestinal malignancies in this series (2%), they were found in three tumors (25%) of an initial series of 12 biliary tract carcinomas. To better define IDH1 and IDH2 mutational status, an additional 75 gallbladder and bile duct cancers were examined. Combining these cohorts of biliary cancers, mutations in IDH1 and IDH2 were found only in cholangiocarcinomas of intrahepatic origin (nine of 40, 23%) and in none of the 22 extrahepatic cholangiocarcinomas and none of the 25 gallbladder carcinomas. In an analysis of frozen tissue specimens, IDH1 mutation was associated with highly elevated tissue levels of the enzymatic product 2-hydroxyglutarate. Thus, IDH1 mutation is a molecular feature of cholangiocarcinomas of intrahepatic origin. These findings define a specific metabolic abnormality in this largely incurable type of gastrointestinal cancer and present a potentially new target for therapy.
| S-EPMC3267826 | biostudies-other
Project description:Our study attempted to identify hub genes related to isocitrate dehydrogenase (IDH) mutation in glioma and develop a prognostic model for IDH-mutant glioma patients. In a first step, ten hub genes significantly associated with the IDH status were identified by weighted gene coexpression analysis (WGCNA). The functional enrichment analysis demonstrated that the most enriched terms of these hub genes were cadherin binding and glutathione metabolism. Three of these hub genes were significantly linked with the survival of glioma patients. 328 samples of IDH-mutant glioma were separated into two datasets: a training set (N?=?228) and a test set (N?=?100). Based on the training set, we identified two IDH-mutant subtypes with significantly different pathological features by using consensus clustering. A 31 gene-signature was identified by the least absolute shrinkage and selection operator (LASSO) algorithm and used for establishing a differential prognostic model for IDH-mutant patients. In addition, the test set was employed for validating the prognostic model, and the model was proven to be of high value in classifying prognostic information of samples. The functional annotation revealed that the genes related to the model were mainly enriched in nuclear division, DNA replication, and cell cycle. Collectively, this study provided novel insights into the molecular mechanism of IDH mutation in glioma, and constructed a prognostic model which can be effective for predicting prognosis of glioma patients with IDH-mutation, which might promote the development of IDH target agents in glioma therapies and contribute to accurate prognostication and management in IDH-mutant glioma patients.
| S-EPMC7720094 | biostudies-literature
Project description:Wild type mitochondrial isocitrate dehydrogenase (IDH2) was previously reported to produce oncometabolite 2-hydroxyglutarate (2HG). Besides, mitochondrial deacetylase SIRT3 has been shown to regulate the oxidative function of IDH2. However, regulation of 2HG formation by SIRT3-mediated deacetylation was not investigated yet. We aimed to study mitochondrial IDH2 function in response to acetylation and deacetylation, and focus specifically on 2HG production by IDH2. We used acetylation surrogate mutant of IDH2 K413Q and assayed enzyme kinetics of oxidative decarboxylation of isocitrate, 2HG production by the enzyme, and 2HG production in cells. The purified IDH2 K413Q exhibited lower oxidative reaction rates than IDH2 WT. 2HG production by IDH2 K413Q was largely diminished at the enzymatic and cellular level, and knockdown of SIRT3 also inhibited 2HG production by IDH2. Contrary, the expression of putative mitochondrial acetylase GCN5L likely does not target IDH2. Using mass spectroscopy, we further identified lysine residues within IDH2, which are the substrates of SIRT3. In summary, we demonstrate that 2HG levels arise from non-mutant IDH2 reductive function and decrease with increasing acetylation level. The newly identified lysine residues might apply in regulation of IDH2 function in response to metabolic perturbations occurring in cancer cells, such as glucose-free conditions.
| S-EPMC7250847 | biostudies-literature
Project description:Although much is known about molecular and chromosomal characteristics that distinguish glioma histological subtypes, DNA methylation patterns of gliomas and their association with other tumor features such as mutation of isocitrate dehydrogenase (IDH) genes have only recently begun to be investigated.DNA methylation of glioblastomas, astrocytomas, oligodendrogliomas, oligoastrocytomas, ependymomas, and pilocytic astrocytomas (n = 131) from the Brain Tumor Research Center at the University of California San Francisco, as well as nontumor brain tissues (n = 7), was assessed with the Illumina GoldenGate methylation array. Methylation data were subjected to recursively partitioned mixture modeling (RPMM) to derive methylation classes. Differential DNA methylation between tumor and nontumor was also assessed. The association between methylation class and IDH mutation (IDH1 and IDH2) was tested using univariate and multivariable analysis for tumors (n = 95) with available substrate for sequencing. Survival of glioma patients carrying mutant IDH (n = 57) was compared with patients carrying wild-type IDH (n = 38) using a multivariable Cox proportional hazards model and Kaplan-Meier analysis. All statistical tests were two-sided.We observed a statistically significant association between RPMM methylation class and glioma histological subtype (P < 2.2 × 10(-16)). Compared with nontumor brain tissues, across glioma tumor histological subtypes, the differential methylation ratios of CpG loci were statistically significantly different (permutation P < .0001). Methylation class was strongly associated with IDH mutation in gliomas (P = 3.0 × 10(-16)). Compared with glioma patients whose tumors harbored wild-type IDH, patients whose tumors harbored mutant IDH showed statistically significantly improved survival (hazard ratio of death = 0.27, 95% confidence interval = 0.10 to 0.72).The homogeneity of methylation classes for gliomas with IDH mutation, despite their histological diversity, suggests that IDH mutation is associated with a distinct DNA methylation phenotype and an altered metabolic profile in glioma.
| S-EPMC3022619 | biostudies-literature
Project description:PurposeMetabolic aberrations have been described in neoplasms with pathogenic variants (PV) in the Krebs cycle genes encoding succinate dehydrogenase (SDH), fumarate hydratase (FH) and isocitrate dehydrogenase (IDH). In turn, accumulation of oncometabolites succinate, fumarate, and 2-hydroxyglutarate can be employed to identify tumors with those PV . Additionally, such metabolic readouts may aid in genetic variant interpretation and improve diagnostics.MethodsUsing liquid chromatography-mass spectrometry, 395 pheochromocytomas and paragangliomas (PPGLs) from 391 patients were screened for metabolites to indicate Krebs cycle aberrations. Multigene panel sequencing was applied to detect driver PV in cases with indicative metabolite profiles but undetermined genetic drivers.ResultsAberrant Krebs cycle metabolomes identified rare cases of PPGLs with germline PV in FH and somatic PV in IDHx and SDHx, including the first case of a somatic IDH2 PV in PPGL. Metabolomics also reliably identified PPGLs with SDHx loss-of-function (LOF) PV. Therefore we utilized tumor metabolite profiles to further classify variants of unknown significance in SDHx, thereby enabling missense variants associated with SDHx LOF to be distinguished from benign variants.ConclusionWe propose incorporation of metabolome data into the diagnostics algorithm in PPGLs to guide genetic testing and variant interpretation and to help identify rare cases with PV in FH and IDHx.
| S-EPMC6353556 | biostudies-literature
Project description:Aim: Isocitrate dehydrogenase 1 (IDH1) is key enzyme involved in cellular metabolism and DNA repair. Mutations in IDH1 occur in up to 25% of cholangiocarcinomas. The present study aimed to explore the features of cellosaurus REB cells with mutant and wide-type IDH1. Methods: To compare the features of IDH1 knockout and mutation in cholangiocarcinoma, we firstly constructed the IDH1 knockout and IDH1 mutation cell lines. We then evaluated the viability of these cell lines using the cell count assay and MTT assay. Next, we determined cell migration and invasion using the Transwell assay. Additionally, to evaluate the effects of IDH1 on cellular metabolism, the levels of ?-ketoglutarate (?-KG) and nicotinamide adenine dinucleotide phosphate (NADPH) were determined using enzyme-linked immunosorbent assay. We then applied ChIPbase dataset to explore the genes that were regulated by IDH1. Results: High frequency of mutated IDH1 was observed in the cholangiocarcinoma and IDH1 R132C was presented in more than 80% of mutations. The results showed that IDH1 knockout decreased cell proliferation, migration and invasion, whereas the overexpression of IDH1 in IDH1 knockout cell line recovered its proliferation, migration and invasion capacities. Additionally, IDH1 mutation reduced the levels of NADPH and ?-KG. Furthermore, investigation into the underlying mechanisms revealed that IDH1 overexpression induced the expression of aldehyde dehydrogenase 1 thereby promoting cell proliferation, migration and invasion. Conclusion: IDH1 plays an important role in cholangiocarcinoma and its mutation impairs tumor progression in part by inhibition of isocitrate metabolism.
| S-EPMC7187788 | biostudies-literature