Isocitrate dehydrogenase 1: what it means to the neurosurgeon

A review

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Isocitrate dehydrogenase 1 (IDH1) mutations have been discovered to be frequent and highly conserved in secondary glioblastoma multiforme and lower-grade gliomas. Although IDH1 mutations confer a unique genotype that has been associated with a favorable prognosis, the role of the mutated IDH1 enzyme and its metabolites in tumor initiation and maintenance remains unresolved. However, given that IDH1 mutations are homogeneously expressed and are limited solely to tumor tissue, targeting this mutation could potentially yield novel treatment strategies for patients with glioblastoma multiforme.

Abbreviations used in this paper:αKG = alpha-ketoglutarate; GBM = glioblastoma multiforme; HIF-1α = hypoxia-inducing factor–1α; IDH1 = isocitrate dehydrogenase 1; PCV = procarbazine, lomustine, and vincristine; TMZ = temozolomide; 2HG = 2-hydroxyglutarate.

Article Information

Address correspondence to: John H. Sampson, M.D., Ph.D., Duke Brain Tumor Immunotherapy Program, Preston Robert Tisch Brain Tumor Center, Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Box 3050, Durham, North Carolina 27710. email:

Please include this information when citing this paper: published online April 12, 2013; DOI: 10.3171/2013.3.JNS122282.

© AANS, except where prohibited by US copyright law.



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    Diagram of the molecular consequences of the IDH1 mutation.



Alderton GK: Genetics: IDH mosaicism in enchondromatosis syndromes. Nat Rev Cancer 12:62012


Amary MFBacsi KMaggiani FDamato SHalai DBerisha F: IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J Pathol 224:3343432011


Andronesi OCKim GSGerstner EBatchelor TTzika AAFantin VR: Detection of 2-hydroxyglutarate in IDH-mutated glioma patients by in vivo spectral-editing and 2D correlation magnetic resonance spectroscopy. Sci Transl Med 4:116ra42012


Balss JMeyer JMueller WKorshunov AHartmann Cvon Deimling A: Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol 116:5976022008


Bleeker FELamba SLeenstra STroost DHulsebos TVandertop WP: IDH1 mutations at residue p.R132 (IDH1(R132)) occur frequently in high-grade gliomas but not in other solid tumors. Hum Mutat 30:7112009


Borthakur GHuang XKantarjian HFaderl SRavandi FFerrajoli A: Report of a phase 1/2 study of a combination of azacitidine and cytarabine in acute myelogenous leukemia and high-risk myelodysplastic syndromes. Leuk Lymphoma 51:73782010


Capper DReuss DSchittenhelm JHartmann CBremer JSahm F: Mutation-specific IDH1 antibody differentiates oligodendrogliomas and oligoastrocytomas from other brain tumors with oligodendroglioma-like morphology. Acta Neuropathol 121:2412522011


Capper DWeissert SBalss JHabel AMeyer JJäger D: Characterization of R132H mutation-specific IDH1 antibody binding in brain tumors. Brain Pathol 20:2452542010


Choi CGanji SKDeBerardinis RJHatanpaa KJRakheja DKovacs Z: 2-hydroxyglutarate detection by magnetic resonance spectroscopy in IDH-mutated patients with gliomas. Nat Med 18:6246292012


Christensen BCSmith AAZheng SCKoestler DCHouseman EAMarsit CJ: DNA methylation, isocitrate dehydrogenase mutation, and survival in glioma. J Natl Cancer Inst 103:1431532011


Dang LWhite DWGross SBennett BDBittinger MADriggers EM: Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462:7397442009


Dubbink HJTaal Wvan Marion RKros JMvan Heuvel IBromberg JE: IDH1 mutations in low-grade astrocytomas predict survival but not response to temozolomide. Neurology 73:179217952009


Elkhaled AJalbert LEPhillips JJYoshihara HAParvataneni RSrinivasan R: Magnetic resonance of 2-hydroxyglutarate in IDH1-mutated low-grade gliomas. Sci Transl Med 4:116ra52012


Gaal JBurnichon NKorpershoek ERoncelin IBertherat JPlouin PF: Isocitrate dehydrogenase mutations are rare in pheochromocytomas and paragangliomas. J Clin Endocrinol Metab 95:127412782010


Gravendeel LAKloosterhof NKBralten LBvan Marion RDubbink HJDinjens W: Segregation of non-p.R132H mutations in IDH1 in distinct molecular subtypes of glioma. Hum Mutat 31:E1186E11992010


Hayden JTFrühwald MCHasselblatt MEllison DWBailey SClifford SC: Frequent IDH1 mutations in supratentorial primitive neuroectodermal tumors (sPNET) of adults but not children. Cell Cycle 8:180618072009


Jiao YKillela PJReitman ZJRasheed ABHeaphy CMde Wilde RF: Frequent ATRX, CIC, and FUBP1 mutations refine the classification of malignant gliomas. Oncotarget 3:7097222012


Jin GPirozzi CJChen LHLopez GYDuncan CGFeng J: Mutant IDH1 is required for IDH1 mutated tumor cell growth. Oncotarget 3:7747822012


Kang MRKim MSOh JEKim YRSong SYSeo SI: Mutational analysis of IDH1 codon 132 in glioblastomas and other common cancers. Int J Cancer 125:3533552009


Kato YJin GKuan CTMcLendon REYan HBigner DD: A monoclonal antibody IMab-1 specifically recognizes IDH1R132H, the most common glioma-derived mutation. Biochem Biophys Res Commun 390:5475512009


Lee SMKoh HJPark DCSong BJHuh TLPark JW: Cytosolic NADP(+)-dependent isocitrate dehydrogenase status modulates oxidative damage to cells. Free Radic Biol Med 32:118511962002


Lu CWard PSKapoor GSRohle DTurcan SAbdel-Wahab O: IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483:4744782012


Mardis ERDing LDooling DJLarson DEMcLellan MDChen K: Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med 361:105810662009


Noushmehr HWeisenberger DJDiefes KPhillips HSPujara KBerman BP: Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17:5105222010


Parsons DWJones SZhang XLin JCLeary RJAngenendt P: An integrated genomic analysis of human glioblastoma multiforme. Science 321:180718122008


Reitman ZJChoi BDSpasojevic IBigner DDSampson JHYan H: Enzyme redesign guided by cancer-derived IDH1 mutations. Nat Chem Biol 8:8878892012


Sanson MMarie YParis SIdbaih ALaffaire JDucray F: Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. J Clin Oncol 27:415041542009


Seltzer MJBennett BDJoshi ADGao PThomas AGFerraris DV: Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1. Cancer Res 70:898189872010


SongTao QLei YSi GYanQing DHuiXia HXueLin Z: IDH mutations predict longer survival and response to temozolomide in secondary glioblastoma. Cancer Sci 103:2692732012


van den Bent MJDubbink HJMarie YBrandes AATaphoorn MJWesseling P: IDH1 and IDH2 mutations are prognostic but not predictive for outcome in anaplastic oligodendroglial tumors: a report of the European Organization for Research and Treatment of Cancer Brain Tumor Group. Clin Cancer Res 16:159716042010


Vander Heiden MGCantley LCThompson CB: Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324:102910332009


Yan HParsons DWJin GMcLendon RRasheed BAYuan W: IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:7657732009


Zhao SLin YXu WJiang WZha ZWang P: Gliomaderived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha. Science 324:2612652009




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