Mutational analysis of IDH1 codon 132 in glioblastomas and other common cancers

Kang, Moon Gi; Kim, Min Sung; Oh, Ji Eun; Kim, Yoo Ri; Song, Sang Yong; Seo, Seong Il; Lee, Ji Youl; Yoo, Nam Jin; Lee, Sug Hyung

doi:10.1002/ijc.24379

Cited by 281 publications

(211 citation statements)

References 16 publications

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“…10,11 Lastly, immunopositivity may be useful in distinguishing diagnostically challenging diffuse gliomas from other tumor types, given that other primary central nervous system (CNS) tumors and metastatic malignancies are typically negative. 2,[12][13][14][15] The only other tumor type currently known to have a significant rate of IDH1 mutations is acute myelogenous leukemia. 16,17 Although the frequency of IDH1 mutation is well established in the most common forms of WHO grade II-IV gliomas, IDH1 mutant protein expression has not been widely examined in rare glioblastoma variants.…”

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confidence: 99%

Diagnostic implications of IDH1-R132H and OLIG2 expression patterns in rare and challenging glioblastoma variants

et al. 2013

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Recent work has demonstrated that nearly all diffuse gliomas display nuclear immunoreactivity for the bHLH transcription factor OLIG2, and the R132H mutant isocitrate dehydrogenase 1 (IDH1) protein is expressed in the majority of diffuse gliomas other than primary glioblastoma. However, these antibodies have not been widely applied to rarer glioblastoma variants, which can be diagnostically challenging when the astrocytic features are subtle. We therefore surveyed the expression patterns of OLIG2 and IDH1 in 167 non-conventional glioblastomas, including 45 small cell glioblastomas, 45 gliosarcomas, 34 glioblastomas with primitive neuroectodermal tumor-like foci (PNET-like foci), 23 with an oligodendroglial component, 11 granular cell glioblastomas, and 9 giant cell glioblastomas. OLIG2 was strongly expressed in all glioblastomas with oligodendroglial component, 98% of small cell glioblastomas, and all granular cell glioblastomas, the latter being particularly helpful in ruling out macrophage-rich lesions. In 74% of glioblastomas with PNET-like foci, OLIG2 expression was retained in the PNET-like foci, providing a useful distinction from central nervous system PNETs. The glial component of gliosarcomas was OLIG2 positive in 93% of cases, but only 14% retained focal expression in the sarcomatous component; as such this marker would not reliably distinguish these from pure sarcoma in most cases. OLIG2 was expressed in 67% of giant cell glioblastomas. IDH1 was expressed in 55% of glioblastomas with oligodendroglial component, 15% of glioblastomas with PNET-like foci, 7% of gliosarcomas, and none of the small cell, granular cell, or giant cell glioblastomas. This provides further support for the notion that most glioblastomas with oligodendroglial component are secondary, while small cell glioblastomas, granular cell glioblastomas, and giant cell glioblastomas are primary variants. Therefore, in one of the most challenging differential diagnoses, IDH1 positivity could provide strong support for glioblastoma with oligodendroglial component, while essentially excluding small cell glioblastoma. In 2008, whole genome analysis of human glioblastomas led to the discovery of recurrent mutations in the active site of isocitrate dehydrogenase 1 (IDH1) in secondary (those progressing from lower grade gliomas) rather than in primary glioblastomas. 1 This discovery was subsequently validated and expanded in larger series of human gliomas, establishing that roughly 80% of all WHO grade II-III infiltrating/diffuse gliomas (astrocytomas, oligodendrogliomas, and oligoastrocytomas) and secondary glioblastomas show mutations in IDH1 and to a lesser extent, IDH2; 2-4 these mutations correlate with enhanced patient survival, and by far the most common alteration is the R132H mutation in IDH1. 5,6 Immunohistochemistry (IHC) for expression of R132H IDH1 mutant protein 7 is increasingly performed in the routine pathologic evaluation of glioblastoma and lower grade diffuse gliomas because of its prognostic significance. In glioblastomas, im...

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Diagnostic implications of IDH1-R132H and OLIG2 expression patterns in rare and challenging glioblastoma variants

et al. 2013

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“…Deep sequencing further revealed that mutated IDH1 and IDH2 occur in a high proportion (>70%) of low‐grade (grade II–III) astrocytomas and oligodendrogliomas and secondary glioblastoma 51, 52, 88, 89. Since these initial reports, mutations in IDH1 and IDH2 have also been found in other diverse cancers including 16–17% of patients with AML,53 20% of patients with angioimmunoblastic T‐cell lymphomas,90 and more rarely in cholangiocarcinomas,91 breast carcinomas,92 acute lymphoblastic leukemias,93 prostate cancer,93 osteosarcoma,94 and others 53, 91, 92, 93, 95, 96, 97. Interestingly, and unlike IDH mutations in glioma which are almost entirely in IDH1 , AML have been shown to exhibit an approximately equal frequency of IDH1 and IDH2 mutations 53, 54…”

Section: Mutations Of Mitochondrial (And Associated) Metabolic Enzymementioning

confidence: 99%

“…It appears that the removal of the arginine, rather than the substitution of a specific residue, is the critical feature of this mutation, although the most frequent replacement observed is a histidine residue (R132H) 51, 52, 93, 98. Mutations in IDH2 in gliomas occur at a much lower frequency (0–6%) than IDH1 88 in the paralogous amino acid residue—R140—but also at R172.…”

Section: Mutations Of Mitochondrial (And Associated) Metabolic Enzymementioning

confidence: 99%

Mitochondrial metabolic remodeling in response to genetic and environmental perturbations

Hollinshead

Tennant

2016

WIREs Mechanisms of Disease

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Mitochondria are metabolic hubs within mammalian cells and demonstrate significant metabolic plasticity. In oxygenated environments with ample carbohydrate, amino acid, and lipid sources, they are able to use the tricarboxylic acid cycle for the production of anabolic metabolites and ATP. However, in conditions where oxygen becomes limiting for oxidative phosphorylation, they can rapidly signal to increase cytosolic glycolytic ATP production, while awaiting hypoxia‐induced changes in the proteome mediated by the activity of transcription factors such as hypoxia‐inducible factor 1. Hypoxia is a well‐described phenotype of most cancers, driving many aspects of malignancy. Improving our understanding of how mitochondria change their metabolism in response to this stimulus may therefore elicit the design of new selective therapies. Many of the recent advances in our understanding of mitochondrial metabolic plasticity have been acquired through investigations of cancer‐associated mutations in metabolic enzymes, including succinate dehydrogenase, fumarate hydratase, and isocitrate dehydrogenase. This review will describe how metabolic perturbations induced by hypoxia and mutations in these enzymes have informed our knowledge in the control of mitochondrial metabolism, and will examine what this may mean for the biology of the cancers in which these mutations are observed. WIREs Syst Biol Med 2016, 8:272–285. doi: 10.1002/wsbm.1334For further resources related to this article, please visit the WIREs website.

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“…A number of methods have been developed to detect IDH1 mutations including DNA sequencing (4,17), PCR-restriction fragment length polymorphism (RFLP) (18,19), PCR-single strand conformation polymorphism (SSCP) (20), pyrosequencing (21,22), and high-resolution melting curve analysis (HRM) (23,24). All of these methods have limitations in terms of sensitivity, ease of use and throughput.…”

Section: Comparison Of Immunohistochemistry Dna Sequencing and Allelmentioning

confidence: 99%

Comparison of immunohistochemistry, DNA sequencing and allele-specific PCR for the detection of IDH1 mutations in gliomas

et al. 2012

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Abstract. Previous studies have identified mutations of the isocitrate dehydrogenase 1 (IDH1) gene in more than 70% of World Health Organization (WHO) grade II and III gliomas. The most frequent mutation leads to a specific amino acid change from arginine to histidine at codon 132 (c.395G>A, p.R132H). IDH1 mutated tumors have a better prognosis than IDH1 non-mutated tumors. The aim of our study was to evaluate and compare the methods of mIDH1 R132H immunohistochemistry, allele-specific PCR and DNA sequencing for determination of IDH1 status. We performed a retrospective study of 91 patients with WHO grade II (n=43) and III (n=48) oligodendrogliomas. A fragment of exon 4 spanning the sequence encoding the catalytic domain of IDH1, including codon 132, was amplified and sequenced using standard conditions. Allele-specific amplification was performed using two forward primers with variations in their 3' nucleotides such that each was specific for the wild-type or the mutated variant, and one reverse primer. Immunohistochemistry was performed with mouse monoclonal mIDH1 R132H. DNA was extracted from FFPE sections following macrodissection. IDH1 mutations were found in 55/90 patients (61.1%) by direct sequencing. R132H mutations were found in 47/55 patients (85.4%). The results of the allele-specific PCR positively correlated with those from DNA sequencing. Other mutations (p.R132C, p.R132S and pR132G) were found by DNA sequencing in 3, 3 and 2 tumors, respectively (8/55 patients, 14.6%). mIDH1 R132H immunostaining was found in the 47 patients presenting the R132H mutation (sensitivity 47/47, 100% for this mutation). None of the tumors presenting a wild-type IDH1 gene were stained (specificity 35/35, 100%). Our results demonstrate that immunohistochemistry using the mIDH1 R132H antibody and allele-specific amplification are highly sensitive techniques to detect the most frequent mutation of the IDH1 gene.

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Mutational analysis of IDH1 codon 132 in glioblastomas and other common cancers

Cited by 281 publications

References 16 publications

Diagnostic implications of IDH1-R132H and OLIG2 expression patterns in rare and challenging glioblastoma variants

Diagnostic implications of IDH1-R132H and OLIG2 expression patterns in rare and challenging glioblastoma variants

Mitochondrial metabolic remodeling in response to genetic and environmental perturbations

Comparison of immunohistochemistry, DNA sequencing and allele-specific PCR for the detection of IDH1 mutations in gliomas

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