Comparative study of IDH1 mutations in gliomas by immunohistochemistry and DNA sequencing

Agarwal, Shipra; Sharma, Mehar Chand; Jha, Prerana; Pathak, Pankaj; Suri, Vaishali; Sarkar, Chitra; Chosdol, Kunzang; Suri, Ashish; Kale, Shashank Sharad; Kumar, Pankaj; Jha, Pankaj

doi:10.1093/neuonc/not015

Cited by 106 publications

(97 citation statements)

References 43 publications

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“…IDH1 was totally absent in astrocytosis (100%) and was expressed in 60% (18 / 30) The results of the present study were also different from previous study performed by Agarwal et al, 2013 [26] who assessed IDH1 mutation in 88% of diffuse astrocytoma cases. So they suggested that IDH1 occurs as an early event in glioma genesis.…”

Section: Resultscontrasting

confidence: 99%

Evaluation of the Role of Mutant Idh1, Egfr and Bcl2 Protein Expression in Distinguishing Diffuse Astrocytoma From Astrocytosis

Saba

Rashed

et al. 2014

Zagazig University Medical Journal

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Background: Gliomas are the most relevant primary brain tumors. Diffuse astrocytomas are the most common type of gliomas .The distinction of diffuse infiltrating astrocytoma from reactive astrocytosis is one of the most difficult differential diagnosis especially with small biopsies (e.g. stereotactic biopsies). Several markers were used for this differentiation such as glial fibrillary acidic protein, ki67 and p53; but each of them has problems with sensitivity and specificity. The immunohistochemical markers such as mutant isocitrate dehydrogenase 1 (IDH1), EGFR and Bcl2 may be useful in this differentiation. Aim: This study was conducted to clarify the value of IDH1, EGFR and Bcl2 protein expression in making a clear distinction between diffuse infiltrating astrocytomas and morphologically similar reactive astrocytosis. Methods: Fifty representative cases; 30 cases WHO grade II diffuse astrocytomas and 20 cases of reactive conditions were examined immunohistochemically using antibodies against mutant IDH1, EGFR and Bcl2. Results: IDH1 was positive in 60% of astrocytomas cases but it was totally absent in reactive astrocytosis. EGFR was expressed in 50% of astrocytomas; but it was not expressed in reactive astrocytosis. Bcl2 expression was detected in 56.7% of astrocytomas cases. However; it was expressed also in 75% of reactive astrocytosis cases. Conclusion: IDH1, EGFR were the most useful IHC markers in the discrimination of low grade diffuse astrocytomas WHO II from reactive astrocytosis; particularly in small biopsies. Bcl2 play no role in this differentiation

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Section: Resultscontrasting

confidence: 99%

Evaluation of the Role of Mutant Idh1, Egfr and Bcl2 Protein Expression in Distinguishing Diffuse Astrocytoma From Astrocytosis

Saba

Rashed

et al. 2014

Zagazig University Medical Journal

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“…The combination of our findings with the literature indicates high TrxR1 expression in primary IDH1 wild type glioblastoma, which is a more aggressive neoplasm, and lower TrxR1 expression with enhanced IDH mutation in secondary glioblastoma, which is a relatively less aggressive neoplasm (1,4,5,17). As indicated previously, this may be an explanation…”

Section: █ Conclusionsupporting

confidence: 86%

New clues in the malignant progression of glioblastoma: can thioredoxin system play a role?

Erdi¹,

Kaya²,

Esen³

et al. 2017

Turkish Neurosurgery

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“…In addition to R132H/R132C/R132G IDH1, several rarer IDH1 mutations in gliomas have been identified, including R132S/R132L/R132V IDH1 (5,6,41,42). In vitro kinetic assays have shown that R132S and R132L IDH1 catalyze production of D2HG at rates similar to the more common R132H and R132C IDH1 mutations (13,25).…”

Section: Generation Of Idh1 Mutants Engineered To Explore Mechanisticmentioning

confidence: 99%

Molecular mechanisms of isocitrate dehydrogenase 1 (IDH1) mutations identified in tumors: The role of size and hydrophobicity at residue 132 on catalytic efficiency

Matteo

Grunseth

Gonzalez

et al. 2017

Journal of Biological Chemistry

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Edited by John M. Denu Isocitrate dehydrogenase 1 (IDH1) catalyzes the reversible NADP؉ -dependent conversion of isocitrate (ICT) to ␣-ketoglutarate (␣KG) in the cytosol and peroxisomes. Mutations in IDH1 have been implicated in >80% of lower grade gliomas and secondary glioblastomas and primarily affect residue 132, which helps coordinate substrate binding. However, other mutations found in the active site have also been identified in tumors. IDH1 mutations typically result in a loss of catalytic activity, but many also can catalyze a new reaction, the NADPH-dependent reduction of ␣KG to D-2-hydroxyglutarate (D2HG). D2HG is a proposed oncometabolite that can competitively inhibit ␣KG-dependent enzymes. Some kinetic parameters have been reported for several IDH1 mutations, and there is evidence that mutant IDH1 enzymes vary widely in their ability to produce D2HG. We report that most IDH1 mutations identified in tumors are severely deficient in catalyzing the normal oxidation reaction, but that D2HG production efficiency varies among mutant enzymes up to ϳ640-fold. Common IDH1 mutations have moderate catalytic efficiencies for D2HG production, whereas rarer mutations exhibit either very low or very high efficiencies. We then designed a series of experimental IDH1 mutants to understand the features that support D2HG production. We show that this new catalytic activity observed in tumors is supported by mutations at residue 132 that have a smaller van der Waals volume and are more hydrophobic. We report that one mutation can support both the normal and neomorphic reactions. These studies illuminate catalytic features of mutations found in the majority of patients with lower grade gliomas.Metabolic changes in tumors have been described for nearly a century (1-3), but only relatively recently have enzymes involved in metabolic processes been established as tumor suppressors or oncoproteins. One of the more striking examples of metabolic enzymes playing a role in tumorigenesis includes isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2).3 These homodimeric enzymes are responsible for the reversible NADP ϩ -and Mg 2ϩ -dependent conversion of ICT to ␣KG (Fig. 1A) in the cytosol and peroxisomes (IDH1), or mitochondria (IDH2). IDH3 is responsible for the same reaction within the context of the TCA cycle, although the oxidative decarboxylation catalyzed by this enzyme is non-reversible and NAD ϩ -dependent. Mutations in IDH1 and IDH2 were identified in glioblastoma multiforme in a large sequencing effort (4), and soon Ͼ80% of adult grade II/III gliomas and secondary glioblastomas were found to have IDH1 mutations, commonly R132H or R132C IDH1 (5, 6) (reviewed in Refs. 7-9). Subsequently ϳ10 -20% of acute myeloid leukemias were shown to have primarily IDH2 mutations, typically R140Q or R172K IDH2 (10). Early mechanisms of tumorigenesis focused on deficient conversion of ICT to ␣KG (11), suggesting that IDH serves as a tumor suppressor, in part through altering levels of hypoxia-inducible transcription factor-1␣ (12). However,...

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Comparative study of IDH1 mutations in gliomas by immunohistochemistry and DNA sequencing

Cited by 106 publications

References 43 publications

Evaluation of the Role of Mutant Idh1, Egfr and Bcl2 Protein Expression in Distinguishing Diffuse Astrocytoma From Astrocytosis

Evaluation of the Role of Mutant Idh1, Egfr and Bcl2 Protein Expression in Distinguishing Diffuse Astrocytoma From Astrocytosis

New clues in the malignant progression of glioblastoma: can thioredoxin system play a role?

Molecular mechanisms of isocitrate dehydrogenase 1 (IDH1) mutations identified in tumors: The role of size and hydrophobicity at residue 132 on catalytic efficiency

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