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Cancer-associated IDH mutations: biomarker and therapeutic opportunities

Abstract

The discovery of somatic mutations in the isocitrate dehydrogenase (IDH) enzymes through a genome-wide mutational analysis in glioblastoma represents a milestone event in cancer biology. The nature of the heterozygous, point mutations mapping to arginine residues involved in the substrate binding inspired several research teams to investigate their impact on the biochemical activity of these enzymes. Soon, it became clear that the mutations identified impaired the ability of IDH1 and IDH2 to catalyze the conversion of isocitrate to α-ketoglutarate (αKG), whereas conferring a gain of a novel enzymatic activity leading to the reduction of αKG to the metabolite D2-hydroxyglutarate (D-2HG). Across glioma as well as several hematologic malignancies, mutations in IDH1 and IDH2 have shown prognostic value. Several hypotheses implicating the elevated levels of D-2HG and tumorigenesis, and the therapeutic potential of targeting mutant IDH enzymes will be discussed.

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References

  • Abbas S, Lugthart S, Kavelaars FG, Schelen A, Koenders J, Zeilemaker A et al. (2010). Acquired mutations in the genes encoding IDH1 and IDH2 both are recurrent aberrations in acute myeloid leukemia (AML): prevalence and prognostic value. Blood 116: 2122–2126.

    Article  CAS  Google Scholar 

  • Abdel-Wahab O, Manshouri T, Patel J, Harris K, Yao J, Hedvat C et al. (2010). Genetic analysis of transforming events that convert chronic myeloproliferative neoplasms to leukemias. Cancer Res 70: 447–452.

    Article  CAS  Google Scholar 

  • Aydin K, Ozmen M, Tatli B, Sencer S . (2003). Single-voxel MR spectroscopy and diffusion-weighted MRI in two patients with l-2-hydroxyglutaric aciduria. Pediatr Radiol 33: 872–876.

    Article  Google Scholar 

  • Balss J, Meyer J, Mueller W, Korshunov A, Hartmann C, von Deimling A . (2008). Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol 116: 597–602.

    Article  CAS  Google Scholar 

  • Baysal BE, Ferrell RE, Willett-Brozick JE, Lawrence EC, Myssiorek D, Bosch A et al. (2000). Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 287: 848–851.

    Article  CAS  Google Scholar 

  • Bleeker FE, Lamba S, Leenstra S, Troost D, Hulsebos T, Vandertop WP et al. (2009). IDH1 mutations at residue p. R132 (IDH1(R132)) occur frequently in high-grade gliomas but not in other solid tumors. Hum Mutat 30: 7–11.

    Article  CAS  Google Scholar 

  • Brandon M, Baldi P, Wallace DC . (2006). Mitochondrial mutations in cancer. Oncogene 25: 4647–4662.

    Article  CAS  Google Scholar 

  • Ceccarelli C, Grodsky NB, Ariyaratne N, Colman RF, Bahnson BJ . (2002). Crystal structure of porcine mitochondrial NADP+-dependent isocitrate dehydrogenase complexed with Mn2+ and isocitrate. Insights into the enzyme mechanism. J Biol Chem 277: 43454–43462.

    Article  CAS  Google Scholar 

  • Chalmers RA, Lawson AM, Watts RW, Tavill AS, Kamerling JP, Hey E et al. (1980). D-2-hydroxyglutaric aciduria: case report and biochemical studies. J Inherit Metab Dis 3: 11–15.

    Article  CAS  Google Scholar 

  • Chou WC, Hou HA, Chen CY, Tang JL, Yao M, Tsay W et al. (2010). Distinct clinical and biological characteristics in adult acute myeloid leukemia bearing isocitrate dehydrogenase 1 (IDH1) mutation. Blood 115: 2749–2754.

    Article  CAS  Google Scholar 

  • Dang CV, Semenza GL . (1999). Oncogenic alterations of metabolism. Trends Biochem Sci 24: 68–72.

    Article  CAS  Google Scholar 

  • Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM et al. (2009). Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462: 739–744.

    Article  CAS  Google Scholar 

  • Frezza C, Tennant DA, Gottlieb E . (2010). IDH1 mutations in gliomas: when an enzyme loses its grip. Cancer Cell 17: 7–9.

    Article  CAS  Google Scholar 

  • Gaal J, Burnichon N, Korpershoek E, Roncelin I, Bertherat J, Plouin PF et al. (2010). Isocitrate dehydrogenase mutations are rare in pheochromocytomas and paragangliomas. J Clin Endocrinol Metab 95: 1274–1278.

    Article  CAS  Google Scholar 

  • Geisbrecht BV, Gould SJ . (1999). The human PICD gene encodes a cytoplasmic and peroxisomal NADP(+)-dependent isocitrate dehydrogenase. J Biol Chem 274: 30527–30533.

    Article  CAS  Google Scholar 

  • Gillies RJ, Gatenby RA . (2007). Hypoxia and adaptive landscapes in the evolution of carcinogenesis. Cancer Metastasis Rev 26: 311–317.

    Article  CAS  Google Scholar 

  • Green A, Beer P . (2010). Somatic mutations of IDH1 and IDH2 in the leukemic transformation of myeloproliferative neoplasms. N Engl J Med 362: 369–370.

    Article  CAS  Google Scholar 

  • Gross S, Cairns RA, Minden MD, Driggers EM, Bittinger MA, Jang HG et al. (2010). Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations. J Exp Med 207: 339–344.

    Article  CAS  Google Scholar 

  • Hanahan D, Weinberg RA . (2000). The hallmarks of cancer. Cell 100: 57–70.

    Article  CAS  Google Scholar 

  • Hartmann C, Meyer J, Balss J, Capper D, Mueller W, Christians A et al. (2009). Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1010 diffuse gliomas. Acta Neuropathol 118: 469–474.

    Article  Google Scholar 

  • Hayden JT, Fruhwald MC, Hasselblatt M, Ellison DW, Bailey S, Clifford SC . (2009). Frequent IDH1 mutations in supratentorial primitive neuroectodermal tumors (sPNET) of adults but not children. Cell Cycle 8: 1806–1807.

    Article  CAS  Google Scholar 

  • Henke B, Girzalsky W, Berteaux-Lecellier V, Erdmann R . (1998). IDP3 encodes a peroxisomal NADP-dependent isocitrate dehydrogenase required for the beta-oxidation of unsaturated fatty acids. J Biol Chem 273: 3702–3711.

    Article  CAS  Google Scholar 

  • Ho PA, Alonzo TA, Kopecky KJ, Miller KL, Kuhn J, Zeng R et al. (2010). Molecular alterations of the IDH1 gene in AML: a Children's Oncology Group and Southwest Oncology Group study. Leukemia 24: 909–913.

    Article  CAS  Google Scholar 

  • Huang PH, Xu AM, White FM . (2009). Oncogenic EGFR signaling networks in glioma. Sci Signal 2: re6.

    Google Scholar 

  • Jones PA, Baylin SB . (2002). The fundamental role of epigenetic events in cancer. Nat Rev Genet 3: 415–428.

    Article  CAS  Google Scholar 

  • Kaelin Jr WG . (2009). SDH5 mutations and familial paraganglioma: somewhere Warburg is smiling. Cancer Cell 16: 180–182.

    Article  CAS  Google Scholar 

  • Kang MR, Kim MS, Oh JE, Kim YR, Song SY, Seo SI et al. (2009). Mutational analysis of IDH1 codon 132 in glioblastomas and other common cancers. Int J Cancer 125: 353–355.

    Article  CAS  Google Scholar 

  • Kaufman EE, Nelson T, Miller D, Stadlan N . (1988). Oxidation of gamma-hydroxybutyrate to succinic semialdehyde by a mitochondrial pyridine nucleotide-independent enzyme. J Neurochem 51: 1079–1084.

    Article  CAS  Google Scholar 

  • King A, Selak MA, Gottlieb E . (2006). Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer. Oncogene 25: 4675–4682.

    Article  CAS  Google Scholar 

  • Kolker S, Pawlak V, Ahlemeyer B, Okun JG, Horster F, Mayatepek E et al. (2002). NMDA receptor activation and respiratory chain complex V inhibition contribute to neurodegeneration in d-2-hydroxyglutaric aciduria. Eur J Neurosci 16: 21–28.

    Article  Google Scholar 

  • Kosmider O, Gelsi-Boyer V, Slama L, Dreyfus F, Beyne-Rauzy O, Quesnel B et al. (2010). Mutations of IDH1 and IDH2 genes in early and accelerated phases of myelodysplastic syndromes and MDS/myeloproliferative neoplasms. Leukemia 24: 1094–1096.

    Article  CAS  Google Scholar 

  • Kroemer G, Pouyssegur J . (2008). Tumor cell metabolism: cancer′s Achilles’ heel. Cancer Cell 13: 472–482.

    Article  CAS  Google Scholar 

  • Lalisang RI, Wils JA, Nortier HW, Burghouts JT, Hupperets PS, Erdkamp FL et al. (1997). Comparative study of dose escalation versus interval reduction to obtain dose-intensification of epirubicin and cyclophosphamide with granulocyte colony-stimulating factor in advanced breast cancer. J Clin Oncol 15: 1367–1376.

    Article  CAS  Google Scholar 

  • Lindahl G, Lindstedt G, Lindstedt S . (1967). Metabolism of 2-amino-5-hydroxyadipic acid in the rat. Arch Biochem Biophys 119: 347–352.

    Article  CAS  Google Scholar 

  • Loenarz C, Schofield CJ . (2008). Expanding chemical biology of 2-oxoglutarate oxygenases. Nat Chem Biol 4: 152–156.

    Article  CAS  Google Scholar 

  • Marcucci G, Maharry K, Wu YZ, Radmacher MD, Mrozek K, Margeson D et al. (2010). IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a cancer and leukemia group B study. J Clin Oncol 28: 2348–2355.

    Article  CAS  Google Scholar 

  • Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K et al. (2009). Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med 361: 1058–1066.

    Article  CAS  Google Scholar 

  • Murugan AK, Bojdani E, Xing M . (2010). Identification and functional characterization of isocitrate dehydrogenase 1 (IDH1) mutations in thyroid cancer. Biochem Biophys Res Commun 393: 555–559.

    Article  CAS  Google Scholar 

  • Noushmehr H, Weisenberger DJ, Diefes K, Phillips HS, Pujara K, Berman BP et al. (2010). Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17: 510–522.

    Article  CAS  Google Scholar 

  • Pardanani A, Lasho TL, Finke CM, Mai M, McClure RF, Tefferi A . (2010a). IDH1 and IDH2 mutation analysis in chronic- and blast-phase myeloproliferative neoplasms. Leukemia 24: 1146–1151.

    Article  CAS  Google Scholar 

  • Pardanani A, Patnaik MM, Lasho TL, Mai M, Knudson RA, Finke C et al. (2010b). Recurrent IDH mutations in high-risk myelodysplastic syndrome or acute myeloid leukemia with isolated del(5q). Leukemia 24: 1370–1372.

    Article  CAS  Google Scholar 

  • Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P et al. (2008). An integrated genomic analysis of human glioblastoma multiforme. Science 321: 1807–1812.

    Article  CAS  Google Scholar 

  • Paschka P, Schlenk RF, Gaidzik VI, Habdank M, Kronke J, Bullinger L et al. (2010). 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 28: 3636–3643.

    Article  CAS  Google Scholar 

  • Pollard PJ, Briere JJ, Alam NA, Barwell J, Barclay E, Wortham NC et al. (2005). Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. Hum Mol Genet 14: 2231–2239.

    Article  CAS  Google Scholar 

  • Rzem R, Vincent MF, Van Schaftingen E, Veiga-da-Cunha M . (2007). L-2-hydroxyglutaric aciduria, a defect of metabolite repair. J Inherit Metab Dis 30: 681–689.

    Article  CAS  Google Scholar 

  • Sanson M, Marie Y, Paris S, Idbaih A, Laffaire J, Ducray F et al. (2009). Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. J Clin Oncol 27: 4150–4154.

    Article  CAS  Google Scholar 

  • Selak MA, Armour SM, MacKenzie ED, Boulahbel H, Watson DG, Mansfield KD et al. (2005). Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell 7: 77–85.

    Article  CAS  Google Scholar 

  • Sener RN . (2003). L-2 hydroxyglutaric aciduria: proton magnetic resonance spectroscopy and diffusion magnetic resonance imaging findings. J Comput Assist Tomogr 27: 38–43.

    Article  Google Scholar 

  • Sjöblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD et al. (2006). The consensus coding sequences of human breast and colorectal cancers. Science 314: 268–274.

    Article  Google Scholar 

  • Thol F, Weissinger EM, Krauter J, Wagner K, Damm F, Wichmann M et al. (2010). IDH1 mutations in patients with myelodysplastic syndromes are associated with an unfavorable prognosis. Haematologica (e-pub ahead of print 21 May 2010; doi:10.3324/haematol.2010.025494).

    Article  CAS  Google Scholar 

  • Tomlinson IP, Alam NA, Rowan AJ, Barclay E, Jaeger EE, Kelsell D et al. (2002). Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet 30: 406–410.

    Article  CAS  Google Scholar 

  • van Roermund CW, Hettema EH, Kal AJ, van den Berg M, Tabak HF, Wanders RJ . (1998). Peroxisomal beta-oxidation of polyunsaturated fatty acids in Saccharomyces cerevisiae: isocitrate dehydrogenase provides NADPH for reduction of double bonds at even positions. EMBO J 17: 677–687.

    Article  CAS  Google Scholar 

  • Vander Heiden MG, Cantley LC, Thompson CB . (2009). Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324: 1029–1033.

    Article  CAS  Google Scholar 

  • Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD et al. (2010). Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17: 98–110.

    Article  CAS  Google Scholar 

  • Voelzke WR, Petty WJ, Lesser GJ . (2008). Targeting the epidermal growth factor receptor in high-grade astrocytomas. Curr Treat Options Oncol 9: 23–31.

    Article  Google Scholar 

  • Vogelstein B, Kinzler KW . (1993). The multistep nature of cancer. Trends Genet 9: 138–141.

    Article  CAS  Google Scholar 

  • Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA et al. (2010). The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17: 225–234.

    Article  CAS  Google Scholar 

  • Watanabe T, Nobusawa S, Kleihues P, Ohgaki H . (2009). IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas. Am J Pathol 174: 1149–1153.

    Article  CAS  Google Scholar 

  • Xu X, Zhao J, Xu Z, Peng B, Huang Q, Arnold E et al. (2004). Structures of human cytosolic NADP-dependent isocitrate dehydrogenase reveal a novel self-regulatory mechanism of activity. J Biol Chem 279: 33946–33957.

    Article  CAS  Google Scholar 

  • Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W et al. (2009). IDH1 and IDH2 mutations in gliomas. N Engl J Med 360: 765–773.

    Article  CAS  Google Scholar 

  • Yoshihara T, Hamamoto T, Munakata R, Tajiri R, Ohsumi M, Yokota S . (2001). Localization of cytosolic NADP-dependent isocitrate dehydrogenase in the peroxisomes of rat liver cells: biochemical and immunocytochemical studies. J Histochem Cytochem 49: 1123–1131.

    Article  CAS  Google Scholar 

  • Zhao S, Lin Y, Xu W, Jiang W, Zha Z, Wang P et al. (2009). Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha. Science 324: 261–265.

    Article  CAS  Google Scholar 

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Yen, K., Bittinger, M., Su, S. et al. Cancer-associated IDH mutations: biomarker and therapeutic opportunities. Oncogene 29, 6409–6417 (2010). https://doi.org/10.1038/onc.2010.444

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  • DOI: https://doi.org/10.1038/onc.2010.444

Keywords

  • IDH
  • mutations
  • cancer

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