Skip to main content
PMC home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2013 May 1.
Published in final edited form as: Curr Opin Neurol. 2011 Dec;24(6):648–652. doi: 10.1097/WCO.0b013e32834cd415

Isocitrate dehydrogenase mutations in gliomas: mechanisms, biomarkers and therapeutic target

Changcun Guo 1,2, Christopher J Pirozzi 1, Giselle Y Lopez 1, Hai Yan 1,*
PMCID: PMC3640434  NIHMSID: NIHMS463154  PMID: 22002076

Abstract

Purpose of the review

Isocitrate dehydrogenases, IDH1 and IDH2, decarboxylate isocitrate to α-ketoglutarate (α-KG), and reduce NADP to NADPH. Point mutations of IDH1 and IDH2 have been discovered in gliomas. IDH mutations cause loss of native enzymatic activities and confer novel activity of converting α-KG to 2-hydroxyglutarate (2-HG). The mechanisms of IDH mutations in gliomagenesis, their value as diagnostic, prognostic marker and therapeutic target have been extensively studied. This review is to summarize the findings of these studies.

Recent findings

Crystal structural studies revealed conformation changes in mutant IDHs, which may explain the gain of function by mutant IDHs. The product of mutant IDHs, 2-HG, is an inhibitor of α-KG-dependent dioxygenases, which may cause genome-wide epigenetic changes in human gliomas. IDH mutations are a favorable prognostic factor for human glioma and can be used as biomarker for differential diagnosis and subclassification rather than predictor of response to treatment. Preliminary data suggested that inhibiting production of the substrate of mutant IDH enzymes caused slow-down of glioma cell growth.

Summary

As valuable diagnostic and prognostic markers of human gliomas, there is still a lack of knowledge on biological functions of mutant IDHs, making targeting IDHs in glioma both difficult and unsecured.

Keywords: Isocitrate dehydrogenase, somatic mutation, glioma

Introduction

IDH1 and IDH2 are NADP+-dependent isocitrate dehydrogenases, which catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG) and reduce NADP to NADPH. IDH1 and IDH2 are homodimeric enzymes with different subcellular localizations. IDH1 localizes in cytoplasm and peroxisome, whereas IDH2 resides in the mitochondria. IDH1 mutations were found in the majority of human low grade astrocytoma, oligodendroglioma and secondary glioblastomas. IDH2 mutations occurred less frequently in gliomas and were mutually exclusive of IDH1 mutations. Mutations in IDH1 are proposed as an early event during glioma tumorigenesis, occurring preferentially in younger patients and correlating with a favorable outcome [1•-3•]. Following these initial discoveries, somatic mutations in IDH1 and IDH2 have been reported in acute myeloid leukemia (AML), though at a lower frequency [4-6]. Other tumor entities in which IDH1/2 mutations have been identified include colorectal cancer, prostate cancer, thyroid carcinoma and melanoma [7-11] . Enormous effort has been put forth to elucidate the mechanisms of these mutations in the development of these cancers and to determine their value as a diagnostic or prognostic marker, as well as a therapeutic target.

Oncogenic functions of IDH mutations

The majority of mutations identified were amino acid substitution at R132 of IDH1 and its analog, R172 of IDH2. These residues are highly conserved and involved in forming the active site of the enzymes. The enzymatic activity of mutant IDHs is significantly reduced[3, 12]. Dominant negative effects of the mutant IDHs was observed by Zhao et al [13••]. They found that mutant IDH1 dominantly inhibited wild-type IDH1 activity through the formation of heterodimers and thus inhibited degradation of hypoxia-inducible factor 1α (HIF-1α) by α-KG-dependent prolylhydroxylases. HIF-1α is an important transcription factor involved in crucial aspects of cancer biology, including angiogenesis, cell survival, glucose metabolism and invasion. The induction of the HIF-1α by IDH1 mutations was proposed as one of the mechanisms of the oncogenic effects of IDH mutation[14••]. Nevertheless, inconsistent findings have been reported concerning the dominant negative effect of mutant IDHs as well as the association of IDH mutations with HIF-1α expression in human samples[15•-17•].

The finding that IDH mutations are found exclusively in a heterozygous state indicates that these are gain of function mutations. IDH1 R132 and IDH2 R172 mutations confer a neomorphic enzymatic activity by reducing α-KG to 2-hydroxyglutarate (2-HG) while converting NADPH to NADP+[18•, 19]. Both gliomas and AML cells harboring IDH mutations show elevated levels of 2-HG. How the IDH1 R132 and IDH2 R172 mutations confer new enzymatic activity was revealed by crystal structure analysis. Dang et al suggested that IDH1 R132H substitution caused change of open conformation to closed conformation, as well as reorganization of the active site of the enzyme[18•]. These changes favor the binding of NADPH as well as NADPH-dependent reduction of α-KG to R(2)-2=HG. Conversely, another structure study suggested closed pre-transition conformation was required for isocitrate binding and that the mutant IDH1 was less capable of forming the closed conformation [20•]. It was recently found that converting α-KG to 2-HG was not actually a novel activity of the mutant IDH1, as wild-type IDH1 also catalyzes this conversion, albeit less efficiently[21]. In wild type IDH1, R132 interacts with C-3 carboxylate of isocitrate, making isocitrate a potent inhibitor of α-KG binding to wild-type IDH1. Mutation of R132 to other amino acids significantly reduces the isocitrate binding while making α-KG binding more favorable. Regardless of the controversy about the mechanism of the neomorphic enzymatic activity, converting α-KG to 2-HG is a shared feature between mutant IDH1 and IDH2. The significant change in the enzymatic profile indicates that gain of function may be more important than loss of function in the oncogenic effects of IDH mutations.

Clues of how this neomorphic enzymatic activity promotes gliomagenesis emerged from several recent studies. A genome-wide DNA methylation profiling of gliomas identified a subgroup of gliomas with high specific DNA methylation status termed glioma-CpG island methylator phenotype (G-CIMP). Interestingly, G-CIMP correlates significantly with IDH1 and IDH2 mutations[22•]. The correlation of IDH1 and IDH2 mutations with hypermethylation phenotype of gliomas was further confirmed by another 2 studies[23, 24]. The hypermethylation phenotype of gliomas was found to be associated with longer survival and younger age, consistent with the findings of IDH1 and IDH2 mutations. Similarly, in AML, 2-HG-producing IDH mutants induced global DNA hypermethylation[25]. Study in AML suggested that hypermethylation might be caused by inhibition of tet oncogene family member 2 (TET2), an α-KG-dependent dioxygenase enzyme, which functions to catalyze the formation of 5-hydroxymethylcytosine, likely leading to subsequent demethylation of DNA[26•]. The inhibition of TET2 by mutant IDH may be attributed to decreased α-KG production as well as direct inhibition of TET2 by 2-HG. Direct evidence of 2-HG in inducing epigenetic changes was provided by Xu et al who found that 2-HG is a competitive inhibitor of α-KG-dependent dioxygenases including histone dimethylases and TET 5-methlycytosine (5mC) hydroxylase[14••]. Other investigators also confirmed that 2-HG competitively inhibits α-KG-dependent histone lysine demethylases such as JMJD2A[27•]. Taken together, reduced production of α-KG and increased production of 2-HG by mutant IDHs may coordinate to induce histone and DNA hypermethylation, leading to genome-wide epigenetic changes and predisposing the cells for malignant transformation.

In spite of these tremendous strides in our knowledge regarding mutant IDH1 and mutant IDH2, the effects of IDH mutations in glioma tumorigenesis have yet to be fully revealed. Other mechanisms may include oxidative stress damage[28], aberrant glucose sensing[29] and aberrant apoptosis pathways[30-32]. Moreover, IDH mutations were found to be associated with alternative lengthening telomere (ALT) in human glioblastoma[33], and glioma stem cells with ALT were isolated from a human glioblastoma. Given that glioma and AML cells are relatively undifferentiated and that IDH mutations impair the hematopoietic differentiation[25], it will be interesting to investigate whether IDH mutations play a role in glioma stem cells.

IDH mutations as biomarkers of glioma

IDH1 and IDH2 mutations are present in the majority of low-grade diffuse (WHO grade II) and anaplastic (WHO grade III) astrocytic, oligodendroglial, and mixed oligodendroglial neoplasm, as well as secondary glioblastomas. In contrast, IDH mutations are rarely observed in primary glioblastomas and other primary brain tumors. It is speculated that IDH mutations can serve as diagnostic and prognostic markers.

Several studies have investigated the utility of IDH mutations as diagnostic marker. Combination of BRAF and IDH1 genetic status can serve as specific marker to differentiate between pilocytic astrocytoma from diffuse astrocytoma, since the majority of pilocytic astrocytomas have BRAF fusion but neither IDH1 nor IDH2 mutations, while majority of astrocytomas exhibited IDH1 mutations but not BRAF fusions[34]. Another study suggested that examination of chromosome 7 gain, p53-mutant and IDH1 mutations could distinguish diffuse astrocytoma from reactive astrocytosis[35]. By examining the status of IDH mutations in samples originally diagnosed as gangliogliomas, Horbinski et al found that IDH mutations in the samples correlated with early recurrence, malignant transformation and death, suggesting these tumors might be infiltrative gliomas that had been misclassified [36]. IDH status was also found to be useful for subclassification of gliomatosis cerebri (GC)[37, 38]. IDH1 mutations were identified in GC in which there was a discernible, solid tumor mass, but not in classical GC without a solid tumor mass. Not surprisingly, IDH mutations are only found in adult GC patients and these patients tend to have longer survival.

The pioneering study of IDH mutations in glioblastomas identified a significant association between IDH mutations and a longer survival and younger age of onset [1]. In adult glioblastoma patients, IDH mutations predict prolonged progression-free survival as well as increased overall survival[39, 40]. The prognostic value of IDH mutations in predicting clinical outcomes is not limited to glioblastomas, but rather has been confirmed in the whole spectrum of human gliomas [23, 41-43]. However, IDH mutations are rare in pediatric gliomas, and occur at primarily older age (>=14 years old); when present, IDH mutations predict longer survival for these pediatric patients[44, 45]. IDH mutations are also associated with longer survival in other, less common gliomas such as gliomatosis cerebri, a rare primary brain tumor[37, 38, 46]. With regard to response to treatment, though some studies suggested a correlation between the presence of IDH mutations and response to chemotherapy [47], it is generally believed that IDH status is not a marker for response to chemotherapy or radiotherapy [48-50]. It is worthwhile to note that for AML, in which IDH mutations are less frequent than glioma, IDH1 and IDH2 mutations are associated with significantly worse clinical outcomes. More studies in mechanisms of the oncogenic effects of mutant IDH1 and mutant IDH2 will elucidate how the presence of IDH mutations affect outcomes in different tumor types.

Several methods can be used to detect IDH mutations in tumor tissues including sequencing, immunohistochemical staining, PCR-restriction fragment length polymorphism (PCR-RFLP) and high resolution melting curve analysis[40, 51-56]. 2-HG, the product of the mutant IDH1 and IDH2, was found to be elevated in the cancer cells, and detection of this oncometabolite correlated with the presence of IDH mutations [18, 19]. In AML, elevated 2-HG can be detected in the serum of the patients with IDH mutations[57•]. It was recently reported that 2-HG could also be detected by gas-chromatography/mass-spectrometry in formalin-fixed paraffin-embedded glioma specimens [58•]. More recently, a pilot study used proton magnetic resonance spectroscopy (MRS) to examine 2-HG in glioma patients in vivo and found that MRS findings were consistent with the results of detecting 2-HG in resected tumors by liquid chromatography mass spectrometry [59••]. It will be of great interest to investigate if 2-HG can be detected in the cerebrospinal liquid and by non-invasive MRS imaging.

IDH as a therapeutic target

Given that IDH mutations are highly prevalent and specific in human malignant gliomas, they may serve as potential therapeutic targets. However, due to the largely unknown mechanisms underlying the oncogenic effects of IDH mutations and association of IDH mutations with better prognosis of gliomas, it currently remains both difficult and controversial to utilize these mutations for therapeutic purposes. One study exploited the gain of function activity of mutant IDH1 enzymes that use α-KG as substrate to produce 2-HG. Using siRNA and small molecule inhibitor bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES), against glutaminase, an important enzyme in α-KG production, Seltzer et al. was able to inhibit the production of α-KG and observe a slowed growth rate of glioma cells harboring IDH1 mutations [60••]. Although glutamine has been suggested to be the major source of α-KG in myeloid cells, it may not be the case for glioma in vivo. Additionally, cancer cells with IDH mutations demonstrate decreased α-KG and elevated 2-HG, which may be deleterious for multiple α-KG-dependent enzymes [13, 14, 26]. Moreover, the 2-HG in glioma cells was not changed by inhibition of α-KG production in this study. Both biochemical and biological studies indicate that converting α-KG to 2-HG is an important neomorphic feature of the mutant IDHs. Targeting the production of the 2-HG will be more favorable for inhibiting the oncogenic effects of IDH mutations. To achieve this, more basic functional and biological studies will be warranted.

Conclusions

It is now recognized that IDH1/2 mutations cause both loss of function and gain of function of the enzyme. The mutant IDH1 and IDH2 share the capability of converting α-KG to 2-HG. Findings from recent studies suggested IDH mutations may exert their effect by affecting α-KG-dependent enzymes, and may be involved in epigenetic events. However, limited data are available on the biological functions of IDH mutants. Therefore, the mechanisms of mutant IDH1 and mutant IDH2 in glioma genesis remain largely unknown. As a prevalent and specific biomarker, IDH mutations correlate with better clinical outcomes in the whole spectrum of gliomas, and can serve as an important diagnostic and prognostic factor. So far, no association of IDH mutations with response to treatment of any kind has been validated. Targeting mutant IDH for treatment of gliomas is still in its infancy, and will be hardly practical until more fundamental knowledge is acquired about the biology of mutant IDHs.

Key Points.

  • Mutations in IDH1 and IDH2 confer both a loss and gain of function, with a decreased affinity for its substrate, isocitrate, as well as neomorphic enzymatic activity reducing α-KG to 2-HG.

  • Reduced production of α-KG and increased production of 2-HG by mutant IDHs may coordinate to induce histone and DNA hypermethylation, leading to genome-wide epigenetic changes and predisposing the cells to malignant transformation.

  • IDH mutations hold great diagnostic and prognostic value, however there is little evidence in its predictive factor for response to treatment.

  • Despite the prevalence of IDH mutations in WHO Grade II, III, and secondary glioblastomas, the oncogenic mechanisms of the mutations remains unknown, making their utility as therapeutic targets challenging.

References

  • 1•.Parsons DW, et al. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008;321(5897):1807–12. doi: 10.1126/science.1164382. [This article is the first report of IDH mutations in huamn glioblastoma.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Watanabe T, et al. IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas. Am J Pathol. 2009;174(4):1149–53. doi: 10.2353/ajpath.2009.080958. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3•.Yan H, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009;360(8):765–73. doi: 10.1056/NEJMoa0808710. [This article identified IDH1 and IDH2 mutations in the whole spectrum of human glioma.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Paschka P, et al. IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication. J Clin Oncol. 2010;28(22):3636–43. doi: 10.1200/JCO.2010.28.3762. [DOI] [PubMed] [Google Scholar]
  • 5.Schnittger S, et al. IDH1 mutations are detected in 6.6% of 1414 AML patients and are associated with intermediate risk karyotype and unfavorable prognosis in adults younger than 60 years and unmutated NPM1 status. Blood. 2010;116(25):5486–96. doi: 10.1182/blood-2010-02-267955. [DOI] [PubMed] [Google Scholar]
  • 6.Mardis ER, et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med. 2009;361(11):1058–66. doi: 10.1056/NEJMoa0903840. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Hemerly JP, Bastos AU, Cerutti JM. Identification of several novel non-p.R132 IDH1 variants in thyroid carcinomas. Eur J Endocrinol. 2010;163(5):747–55. doi: 10.1530/EJE-10-0473. [DOI] [PubMed] [Google Scholar]
  • 8.Bleeker FE, et al. IDH1 mutations at residue p.R132 (IDH1(R132)) occur frequently in high-grade gliomas but not in other solid tumors. Hum Mutat. 2009;30(1):7–11. doi: 10.1002/humu.20937. [DOI] [PubMed] [Google Scholar]
  • 9.Kang MR, et al. Mutational analysis of IDH1 codon 132 in glioblastomas and other common cancers. Int J Cancer. 2009;125(2):353–5. doi: 10.1002/ijc.24379. [DOI] [PubMed] [Google Scholar]
  • 10.Lopez GY, et al. IDH1(R132) mutation identified in one human melanoma metastasis, but not correlated with metastases to the brain. Biochem Biophys Res Commun. 2010;398(3):585–7. doi: 10.1016/j.bbrc.2010.06.125. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Sjoblom T, et al. The consensus coding sequences of human breast and colorectal cancers. Science. 2006;314(5797):268–74. doi: 10.1126/science.1133427. [DOI] [PubMed] [Google Scholar]
  • 12.Bleeker FE, et al. The prognostic IDH1( R132 ) mutation is associated with reduced NADP+-dependent IDH activity in glioblastoma. Acta Neuropathol. 2010;119(4):487–94. doi: 10.1007/s00401-010-0645-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13•.Zhao S, et al. Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha. Science. 2009;324(5924):261–5. doi: 10.1126/science.1170944. [This article shows dominant negative effect of mutant IDHs and association of IDH mutations with HIF-1 α.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14••.Xu W, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell. 2011;19(1):17–30. doi: 10.1016/j.ccr.2010.12.014. [This article provides evidence of 2-HG in causing epigenetic changes and also stabilization of HIF-1 α by 2-HG.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15•.Metellus P, Colin C, Taieb D, et al. IDH mutation status impact on in vivo hypoxia biomarkers expression: new insights from a clinical, nuclear imaging and immunohistochemical study in 33 glioma patients. J Neurooncol. 2011 Jun 5; doi: 10.1007/s11060-011-0625-2. [Epub ahead of print] [This article shows no correlation between expression of hypoxia biomarkers with IDH mutation status in glioma samples.] [DOI] [PubMed] [Google Scholar]
  • 16•.Williams SC, et al. R132H-mutation of isocitrate dehydrogenase-1 is not sufficient for HIF-1alpha upregulation in adult glioma. Acta Neuropathol. 2011;121(2):279–81. doi: 10.1007/s00401-010-0790-y. [This article shows IDH1 mutation is not association with HIF-1 α expression in clinical glioma samples.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17•.Jin G, et al. 2-hydroxyglutarate production, but not dominant negative function, is conferred by glioma-derived NADP-dependent isocitrate dehydrogenase mutations. PLoS One. 2011;6(2):e16812. doi: 10.1371/journal.pone.0016812. [The study suggests that mutant IDHs do not exhibit dominant negative effects on their wild-type counterparts.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18•.Dang L, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009;462(7274):739–44. doi: 10.1038/nature08617. [This article suggests conformation changes in the mutant IDH1 confers it new enzymatic activity.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Ward PS, et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell. 2010;17(3):225–34. doi: 10.1016/j.ccr.2010.01.020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20•.Yang B, et al. Molecular mechanisms of “off-on switch” of activities of human IDH1 by tumor-associated mutation R132H. Cell Res. 2010;20(11):1188–200. doi: 10.1038/cr.2010.145. [This article proposes different conformation changes caused by IDH1 R132H mutations.] [DOI] [PubMed] [Google Scholar]
  • 21.Pietrak B, et al. A Tale of Two Subunits: How the Neomorphic R132H IDH1 Mutation Enhances Production of alphaHG. Biochemistry. 2011;50(21):4804–12. doi: 10.1021/bi200499m. [DOI] [PubMed] [Google Scholar]
  • 22•.Noushmehr H, et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell. 2010;17(5):510–22. doi: 10.1016/j.ccr.2010.03.017. [This article shows correlation of IDH mutations and specific CpG island methylation status og human glomas.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Christensen BC, et al. DNA methylation, isocitrate dehydrogenase mutation, and survival in glioma. J Natl Cancer Inst. 2011;103(2):143–53. doi: 10.1093/jnci/djq497. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Laffaire J, et al. Methylation profiling identifies 2 groups of gliomas according to their tumorigenesis. Neuro Oncol. 2011;13(1):84–98. doi: 10.1093/neuonc/noq110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25••.Figueroa ME, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 2010;18(6):553–67. doi: 10.1016/j.ccr.2010.11.015. [This shows IDH mutations can induce hypermethylation of the cancer cells.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Ito S, et al. Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature. 2010;466(7310):1129–33. doi: 10.1038/nature09303. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27•.Chowdhury R, et al. The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. EMBO Rep. 2011;12(5):463–9. doi: 10.1038/embor.2011.43. [Futher evidence of 2-HG in inducing epigentic changes of cancer cells can be found here.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Yang ES, Park JW. Knockdown of cytosolic NADP(+) -dependent isocitrate dehydrogenase enhances MPP(+) -induced oxidative injury in PC12 cells. BMB Rep. 2011;44(5):312–6. doi: 10.5483/BMBRep.2011.44.5.312. [DOI] [PubMed] [Google Scholar]
  • 29.Ronnebaum SM, et al. A pyruvate cycling pathway involving cytosolic NADP-dependent isocitrate dehydrogenase regulates glucose-stimulated insulin secretion. J Biol Chem. 2006;281(41):30593–602. doi: 10.1074/jbc.M511908200. [DOI] [PubMed] [Google Scholar]
  • 30.Kil IS, Chung KH, Park JW. Silencing of mitochondrial NADP+-dependent isocitrate dehydrogenase gene enhances selenite-induced apoptosis. Free Radic Res. 2010;44(3):332–9. doi: 10.3109/10715760903494184. [DOI] [PubMed] [Google Scholar]
  • 31.Shin SW, Kil IS, Park JW. Silencing of mitochondrial NADP+-dependent isocitrate dehydrogenase by small interfering RNA enhances heat shock-induced apoptosis. Biochem Biophys Res Commun. 2008;366(4):1012–8. doi: 10.1016/j.bbrc.2007.12.067. [DOI] [PubMed] [Google Scholar]
  • 32.Jung KH, Park JW. Suppression of mitochondrial NADP(+)-dependent isocitrate dehydrogenase activity enhances curcumin-induced apoptosis in HCT116 cells. Free Radic Res. 2011;45(4):431–8. doi: 10.3109/10715762.2010.540574. [DOI] [PubMed] [Google Scholar]
  • 33.McDonald KL, et al. Presence of alternative lengthening of telomeres mechanism in patients with glioblastoma identifies a less aggressive tumor type with longer survival. J Neuropathol Exp Neurol. 2010;69(7):729–36. doi: 10.1097/NEN.0b013e3181e576cf. [DOI] [PubMed] [Google Scholar]
  • 34.Korshunov A, et al. Combined molecular analysis of BRAF and IDH1 distinguishes pilocytic astrocytoma from diffuse astrocytoma. Acta Neuropathol. 2009;118(3):401–5. doi: 10.1007/s00401-009-0550-z. [DOI] [PubMed] [Google Scholar]
  • 35.Camelo-Piragua S, et al. A sensitive and specific diagnostic panel to distinguish diffuse astrocytoma from astrocytosis: chromosome 7 gain with mutant isocitrate dehydrogenase 1 and p53. J Neuropathol Exp Neurol. 2011;70(2):110–5. doi: 10.1097/NEN.0b013e31820565f9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Horbinski C, et al. Isocitrate Dehydrogenase 1 Analysis Differentiates Gangliogliomas from Infiltrative Gliomas. Brain Pathol. 2011;21(5):564–74. doi: 10.1111/j.1750-3639.2011.00480.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Narasimhaiah D, et al. IDH1 mutation, a genetic alteration associated with adult gliomatosis cerebri. Neuropathology. 2011 doi: 10.1111/j.1440-1789.2011.01216.x. doi: 10.1111/j.1440-1789.2011.01216.x. [Epub ahead of print] [DOI] [PubMed] [Google Scholar]
  • 38.Seiz M, et al. Detection of IDH1 mutations in gliomatosis cerebri, but only in tumors with additional solid component: evidence for molecular subtypes. Acta Neuropathol. 2010;120(2):261–7. doi: 10.1007/s00401-010-0701-2. [DOI] [PubMed] [Google Scholar]
  • 39.Weller M, et al. Molecular predictors of progression-free and overall survival in patients with newly diagnosed glioblastoma: a prospective translational study of the German Glioma Network. J Clin Oncol. 2009;27(34):5743–50. doi: 10.1200/JCO.2009.23.0805. [DOI] [PubMed] [Google Scholar]
  • 40.Bujko M, et al. Prognostic value of IDH1 mutations identified with PCR-RFLP assay in glioblastoma patients. Mol Diagn Ther. 2010;14(3):163–9. doi: 10.1007/BF03256369. [DOI] [PubMed] [Google Scholar]
  • 41.Metellus P, et al. Absence of IDH mutation identifies a novel radiologic and molecular subtype of WHO grade II gliomas with dismal prognosis. Acta Neuropathol. 2010;120(6):719–29. doi: 10.1007/s00401-010-0777-8. [DOI] [PubMed] [Google Scholar]
  • 42.Sanson M, et al. Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. J Clin Oncol. 2009;27(25):4150–4. doi: 10.1200/JCO.2009.21.9832. [DOI] [PubMed] [Google Scholar]
  • 43.Hartmann C, et al. Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas. Acta Neuropathol. 2009;118(4):469–74. doi: 10.1007/s00401-009-0561-9. [DOI] [PubMed] [Google Scholar]
  • 44.Pollack IF, et al. IDH1 mutations are common in malignant gliomas arising in adolescents: a report from the Children's Oncology Group. Childs Nerv Syst. 2011;27(1):87–94. doi: 10.1007/s00381-010-1264-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Antonelli M, et al. Prognostic significance of histological grading, p53 status, YKL-40 expression, and IDH1 mutations in pediatric high-grade gliomas. J Neurooncol. 2010;99(2):209–15. doi: 10.1007/s11060-010-0129-5. [DOI] [PubMed] [Google Scholar]
  • 46.Desestret V, et al. Prognostic stratification of gliomatosis cerebri by IDH1(R132H) and INA expression. J Neurooncol. 2011 doi: 10.1007/s11060-011-0587-4. [DOI] [PubMed] [Google Scholar]
  • 47.Houillier C, et al. IDH1 or IDH2 mutations predict longer survival and response to temozolomide in low-grade gliomas. Neurology. 2010;75(17):1560–6. doi: 10.1212/WNL.0b013e3181f96282. [DOI] [PubMed] [Google Scholar]
  • 48.Taal W, et al. First-line temozolomide chemotherapy in progressive low-grade astrocytomas after radiotherapy: molecular characteristics in relation to response. Neuro Oncol. 2011;13(2):235–41. doi: 10.1093/neuonc/noq177. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Dubbink HJ, et al. IDH1 mutations in low-grade astrocytomas predict survival but not response to temozolomide. Neurology. 2009;73(21):1792–5. doi: 10.1212/WNL.0b013e3181c34ace. [DOI] [PubMed] [Google Scholar]
  • 50.van den Bent MJ, et al. 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. 2010;16(5):1597–604. doi: 10.1158/1078-0432.CCR-09-2902. [DOI] [PubMed] [Google Scholar]
  • 51.Felsberg J, et al. Rapid and sensitive assessment of the IDH1 and IDH2 mutation status in cerebral gliomas based on DNA pyrosequencing. Acta Neuropathol. 2010;119(4):501–7. doi: 10.1007/s00401-010-0647-4. [DOI] [PubMed] [Google Scholar]
  • 52.Capper D, et al. Application of mutant IDH1 antibody to differentiate diffuse glioma from nonneoplastic central nervous system lesions and therapy-induced changes. Am J Surg Pathol. 2010;34(8):1199–204. doi: 10.1097/PAS.0b013e3181e7740d. [DOI] [PubMed] [Google Scholar]
  • 53.Chou WC, et al. A single-tube, sensitive multiplex method for screening of isocitrate dehydrogenase 1 (IDH1) mutations. Blood. 2010;116(3):495–6. doi: 10.1182/blood-2010-04-280636. [DOI] [PubMed] [Google Scholar]
  • 54.Meyer J, et al. PCR- and restriction endonuclease-based detection of IDH1 mutations. Brain Pathol. 2010;20(2):298–300. doi: 10.1111/j.1750-3639.2009.00327.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Boisselier B, et al. COLD PCR HRM: a highly sensitive detection method for IDH1 mutations. Hum Mutat. 2010;31(12):1360–5. doi: 10.1002/humu.21365. [DOI] [PubMed] [Google Scholar]
  • 56.Horbinski C, et al. Detection of IDH1 and IDH2 mutations by fluorescence melting curve analysis as a diagnostic tool for brain biopsies. J Mol Diagn. 2010;12(4):487–92. doi: 10.2353/jmoldx.2010.090228. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57•.Gross S, et al. Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations. J Exp Med. 2010;207(2):339–44. doi: 10.1084/jem.20092506. [This article shows elevated 2-HG can be detected in serum of AML patients and corresponds to mutations of IDHs.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58•.Sahm F, et al. Detection of 2-Hydroxyglutarate in formalin-fixed paraffin-embedded glioma specimens by gas-chromatography/mass-spectrometry. Brain Pathol. 2011 doi: 10.1111/j.1750-3639.2011.00506.x. [This article describes a method to detect the 2-HG in section samples of human gliomas.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59••.Nagarajan R, et al. Detection of 2-hydroxyglutarate in Mutant Brain Tumors in vivo using Proton Magnetic Resonance Spectroscopy. Proc Intl Soc Mag Reson Med. 2011;19:184. [This is a pilot study using MRS to detect the mutation status in vivo.] [Google Scholar]
  • 60••.Seltzer MJ, et al. Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1. Cancer Res. 2010;70(22):8981–7. doi: 10.1158/0008-5472.CAN-10-1666. [This article presents the first study targeting mutant IDH1 for therapeutic purposes.] [DOI] [PMC free article] [PubMed] [Google Scholar]

RESOURCES