<i>IDH1</i>and<i>IDH2</i>Mutations in Gliomas

Yan, Hai; Parsons, D. Williams; Jin, Genglin; McLendon, Roger E.; Rasheed, B. Ahmed; Yuan, Weishi; Kos, Ivan; Batinić‐Haberle, Ines; Jones, Siân; Riggins, Gregory J.; Friedman, Henry S.; Reardon, David A.; Herndon, James E.; Kinzler, Kenneth W.; Velculescu, Victor E.; Vogelstein, Bert; Bigner, Darell D.

doi:10.1056/nejmoa0808710

Cited by 5,194 publications

(4,843 citation statements)

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“…Isocitrate dehydrogenase gene mutations, estimated to occur in 70–90% of diffuse lower grade gliomas, are strongly implicated in both tumourigenesis and prognosis 23, 24, 25. Loss of heterozygosity of 1p19q, was occurred in 60–80% of oligodendroglioma and up to 45% of oligoastrocytoma 26.…”

Section: Discussionmentioning

confidence: 99%

RUNX3 is down‐regulated in glioma by Myc‐regulated miR‐4295

Zheng

Diao

et al. 2016

J Cellular Molecular Medi

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MicroRNAs are increasingly reported as tumour suppressors that regulate gene expression after transcription. Our results demonstrated that miR‐4295 is overexpression in glioma tissues and its level is significantly correlated with clinical stage. We also found that miR‐4295 inhibited the cell G0/G1 arrest and apoptosis leading to promoted cell proliferation and activity. The murine modelling study revealed that female nude mice injected with U87/anti‐miR‐4295 exhibit subcutaneous tumours in the right groin. Compared with anti‐NC, the tumour volume was significantly decreased in anti‐miR‐4295 treatment group. Furthermore, we confirmed miR‐4295 mediates the expression of RUNX3 by targeting its 3′untranslation region. In addition, N‐myc protein also could bind to the promoter of pri‐miR‐4295 and inhibit the expression of RUNX3 in glioma cells. These results validate a pathogenetic role of a miR‐4295 in gliomas and establish a potentially regulatory and signalling pathway involving N‐myc/miR‐4295/RUNX3 in gliomas.

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Section: Discussionmentioning

confidence: 99%

RUNX3 is down‐regulated in glioma by Myc‐regulated miR‐4295

Zheng

Diao

et al. 2016

J Cellular Molecular Medi

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“…Isocitrate dehydrogenase 1 and 2 (IDH1/2) mutations are recognized as definitive diagnostic molecular biomarkers of secondary GBM and are more prognostically valuable than the history of tumor onset 3. Correspondingly, wild‐type IDH1/2 genotypes are considered robust biomarkers of primary GBM (<5%) 4, 5.…”

Section: Introductionmentioning

confidence: 99%

The TERT promoter mutation status and MGMT promoter methylation status, combined with dichotomized MRI‐derived and clinical features, predict adult primary glioblastoma survival

et al. 2018

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PurposeThis study aimed to integrate the TERT promoter mutation status, MGMT promoter methylation status, MRI‐derived features, and clinical features into a survival analysis model to better understand adult primary glioblastoma prognosis‐related markers.MethodA total of 304 adult glioblastoma samples collected after surgical resection were selected for retrospective analysis, and Sanger sequencing was performed to detect IDH and TERT promoter mutations. The methylation of the MGMT promoter was analyzed by pyrosequencing, and MRI‐derived and clinical features were dichotomized into easily acquired variables. Random survival forest analysis, Kaplan‐Meier analysis, Cox proportional hazard regression, and LASSO regression were performed for the survival analysis, and ROC analysis and Pearson's chi‐squared test were employed for the correlation analysis.ResultsWild‐type IDH was present in 89.8% of the adult glioblastoma samples, and TERT promoter mutations and MGMT promoter methylation were observed in 66.42% and 38.49% of all adult primary glioblastomas, respectively. Age and MGMT promoter methylation were identified as independent prognostic biomarkers, and the TERT promoter mutation status and MGMT promoter methylation status, when combined with other tumor‐related factors, generated several different survival subgroups. None of the factors investigated in this study predicted the MGMT promoter status, and MRI‐detected necrosis was positively associated with TERT promoter mutations.ConclusionMGMT promoter methylation and TERT promoter mutations, combined with MRI‐derived and clinical features, revealed different survival subgroups with distinct responses to current treatments, and this information increases the ability to predict the survival of adult primary glioblastoma patients. MRI‐detected necrosis often indicates the presence of TERT promoter mutations.

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“…The presence of recurrent somatic point mutations in IDH1 was first identified in 12% of all adult glioblastoma tumors by high‐throughput DNA sequencing 51. 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.…”

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%

“…However, continued oxygen use in hypoxia is likely to create highly challenging conditions in an IDH1 ‐mutated tumor, as it is likely to further exacerbate the hypoxic microenvironment, potentially leading to increased areas of necrosis. It is important to note that IDH1 mutant gliomas demonstrate improved overall survival compared to their wild‐type counterparts,52 which may well be in some part due to their apparent inability to modify their mitochondrial metabolism in response to hypoxia. Interestingly, IDH2 ‐mutated cells were shown not to exhibit the same alteration in the hypoxia‐mediated mitochondrial metabolic phenotype 117.…”

Section: Mutations Of Mitochondrial (And Associated) Metabolic Enzymementioning

confidence: 99%

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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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IDH1andIDH2Mutations in Gliomas

Cited by 5,194 publications

References 21 publications

RUNX3 is down‐regulated in glioma by Myc‐regulated miR‐4295

RUNX3 is down‐regulated in glioma by Myc‐regulated miR‐4295

The TERT promoter mutation status and MGMT promoter methylation status, combined with dichotomized MRI‐derived and clinical features, predict adult primary glioblastoma survival

Mitochondrial metabolic remodeling in response to genetic and environmental perturbations

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