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Tumors of the Central Nervous System, Volume 2 pp 47–52Cite as

The Role of IDH1 and IDH2 Mutations in Malignant Gliomas

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Part of the book series: Tumors of the Central Nervous System ((TCNS,volume 2))

Abstract

A recent study identified mutations in the active sites of isocitrate dehydrogenase 1 and 2 (IDH1and IDH2) genes in several types of glioma. All mutations affected a single amino acid located in the binding site of isocitrate (R132 of IDH1 and R172 of IDH2). We analyzed the genomic region spanning wild-type R132 of IDH1 and R172 of IDH2 by direct sequencing in 125 glial tumors. A total of 39 IDH1 mutations and one IDH2 mutation were observed. IDH1 and IDH2 mutations were frequently present in astrocytic and oligodendroglial tumors. However, primary glioblastomas were characterized by a low frequency of mutations (5%) at amino acid position 132 of IDH1. Mutations of IDH1 and IDH2 genes were significantly associated with improved outcome in patients with anaplastic astrocytomas. IDH1 and IDH2 mutations seem to play an important role in early tumor progression of specific types of glioma and might arise from a common glial precursor. The infrequency of IDH1 mutation in primary glioblastomas revealed that these subtypes are entities that are genetically distinct from other glial tumors. Analyses of IDH1 and IDH2 status have significant utility for diagnosis and treatment of patients with gliomas.

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References

  • Aghili M, Zahedi F, Rafiee E (2009) Hydroxyglutaric aciduria and malignant brain tumor: a case report and literature review. J Neurooncol 91:233–236

    Article  PubMed  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  PubMed  CAS  Google Scholar 

  • Bleeker FE, Lamba S, Leenstra S, Troost D, Hulsebos T, Vandertop WP, Frattini M, Molinari F, Knowles M, Cerrato A, Rodolfo M, Scarpa A, Felicioni L, Buttitta F, Malatesta S, Marchetti A, Bardelli A (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  PubMed  CAS  Google Scholar 

  • Camelo-Piragua S, Jansen M, Ganguly A, Kim JC, Louis DN, Nutt CL (2010) Mutant IDH1-specific immunohistochemistry distinguishes diffuse astrocytoma from astrocytosis. Acta Neuropathol 119(4):509–511

    Article  PubMed  Google Scholar 

  • Capper D, Weissert S, Balss J, Habel A, Meyer J, Jager D, Ackermann U, Tessmer C, Korshunov A, Zentgraf H, Hartmann C, Von Deimling A (2010) Characterization of R132H mutation-specific IDH1 antibody binding in brain tumors. Brain Pathol 20:245–254

    Article  PubMed  CAS  Google Scholar 

  • Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, Fantin VR, Jang HG, Jin S, Keenan MC, Marks KM, Prins RM, Ward PS, Yen KE, Liau LM, Rabinowitz JD, Cantley LC, Thompson CB, Vander Heiden MG, Su SM (2009) Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462:739–744

    Article  PubMed  CAS  Google Scholar 

  • Furnari FB, Fenton T, Bachoo RM, Mukasa A, Stommel JM, Stegh A, Hahn WC, Ligon KL, Louis DN, Brennan C, Chin L, Depinho RA, Cavenee WK (2007) Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev 21:2683–2710

    Article  PubMed  CAS  Google Scholar 

  • Hartmann C, Meyer J, Balss J, Capper D, Mueller W, Christians A, Felsberg J, Wolter M, Mawrin C, Wick W, Weller M, Herold-Mende C, Unterberg A, Jeuken JW, Wesseling P, Reifenberger G, Von Deimling A (2009) 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 118:469–474

    Article  PubMed  Google Scholar 

  • Ichimura K, Pearson DM, Kocialkowski S, Backlund LM, Chan R, Jones DT, Collins VP (2009) IDH1 mutations are present in the majority of common adult gliomas but rare in primary glioblastomas. Neuro-oncology 11:341–347

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Kato Y, Jin G, Kuan CT, Mclendon RE, Yan H, Bigner DD (2009) A monoclonal antibody IMab-1 specifically recognizes IDH1R132H, the most common glioma-derived mutation. Biochem Biophys Res Commun 390:547–551

    Article  PubMed  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  PubMed  CAS  Google Scholar 

  • Korshunov A, Meyer J, Capper D, Christians A, Remke M, Witt H, Pfister S, Von Deimling A, Hartmann C (2009) Combined molecular analysis of BRAF and IDH1 distinguishes pilocytic astrocytoma from diffuse astrocytoma. Acta Neuropathol 118:401–405

    Article  PubMed  CAS  Google Scholar 

  • Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114:97–109

    Article  PubMed  Google Scholar 

  • Mardis ER, Ding L, Dooling DJ, Larson DE, Mclellan MD, Chen K, Koboldt DC, Fulton RS, Delehaunty KD, Mcgrath SD, Fulton LA, Locke DP, Magrini VJ, Abbott RM, Vickery TL, Reed JS, Robinson JS, Wylie T, Smith SM, Carmichael L, Eldred JM, Harris CC, Walker J, Peck JB, Du F, Dukes AF, Sanderson GE, Brummett AM, Clark E, Mcmichael JF, Meyer RJ, Schindler JK, Pohl CS, Wallis JW, Shi X, Lin L, Schmidt H, Tang Y, Haipek C, Wiechert ME, Ivy JV, Kalicki J, Elliott G, Ries RE, Payton JE, Westervelt P, Tomasson MH, Watson MA, Baty J, Heath S, Shannon WD, Nagarajan R, Link DC, Walter MJ, Graubert TA, Dipersio JF, Wilson RK, Ley TJ (2009) Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med 361:1058–1066

    Article  PubMed  CAS  Google Scholar 

  • Ohgaki H, Kleihues P (2009) Genetic alterations and signaling pathways in the evolution of gliomas. Cancer Sci 15:6002–6007

    Google Scholar 

  • Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, Mclendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA Jr., Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321:1807–1812

    Article  PubMed  CAS  Google Scholar 

  • Reifenberger J, Reifenberger G, Liu L, James CD, Wechsler W, Collins VP (1994) Molecular genetic analysis of oligodendroglial tumors shows preferential allelic deletions on 19q and 1p. Am J Pathol 145:1175–1190

    PubMed  CAS  Google Scholar 

  • Sanson M, Marie Y, Paris S, Idbaih A, Laffaire J, Ducray F, El Hallani S, Boisselier B, Mokhtari K, Hoang-Xuan K, Delattre JY (2009) Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. J Clin Oncol 27:4150–4154

    Article  PubMed  CAS  Google Scholar 

  • Sonoda Y, Kumabe T, Nakamura T, Saito R, Kanamori M, Yamashita Y, Suzuki H, Tominaga T (2009) Analysis of IDH1 and IDH2 mutations in Japanese glioma patients. Cancer Sci 100:1996–1998

    Article  PubMed  CAS  Google Scholar 

  • Struys EA, Salomons GS, Achouri Y, Van Schaftingen E, Grosso S, Craigen WJ, Verhoeven NM, Jakobs C (2005) Mutations in the D-2-hydroxyglutarate dehydrogenase gene cause D-2-hydroxyglutaric aciduria. Am J Hum Genet 76:358–360

    Article  PubMed  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  PubMed  CAS  Google Scholar 

  • Wick W, Hartmann C, Engel C, Stoffels M, Felsberg J, Stockhammer F, Sabel MC, Koeppen S, Ketter R, Meyermann R, Rapp M, Meisner C, Kortmann RD, Pietsch T, Wiestler OD, Ernemann U, Bamberg M, Reifenberger G, Von Deimling A, Weller M (2009) NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol 27:5874–5880

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Yan H, Bigner DD, Velculescu V, Parsons DW (2009a) Mutant metabolic enzymes are at the origin of gliomas. Cancer Res 69:9157–9159

    Article  PubMed  CAS  Google Scholar 

  • Yan H, Parsons DW, Jin G, Mclendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler KW, Velculescu VE, Vogelstein B, Bigner DD (2009b) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:765–773

    Article  PubMed  CAS  Google Scholar 

  • Zhao S, Lin Y, Xu W, Jiang W, Zha Z, Wang P, Yu W, Li Z, Gong L, Peng Y, Ding J, Lei Q, Guan KL, Xiong Y (2009) Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha. Science 324:261–265

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Neurosurgery, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai-shi, Miyagi, 980-8577, Japan

    Yukihiko Sonoda, Ichiyo Shibahara, Ryuta Saito, Toshihiro Kumabe & Teiji Tominaga

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  1. Yukihiko Sonoda
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  2. Ichiyo Shibahara
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  3. Ryuta Saito
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  4. Toshihiro Kumabe
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  5. Teiji Tominaga
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Correspondence to Yukihiko Sonoda .

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  1. , Kean University, Room 213, Library building, Morris Avenue 1000, Union, 07083, New Jersey, USA

    M.A. Hayat

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Sonoda, Y., Shibahara, I., Saito, R., Kumabe, T., Tominaga, T. (2011). The Role of IDH1 and IDH2 Mutations in Malignant Gliomas. In: Hayat, M. (eds) Tumors of the Central Nervous System, Volume 2. Tumors of the Central Nervous System, vol 2. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-0618-7_6

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  • DOI: https://doi.org/10.1007/978-94-007-0618-7_6

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  • Print ISBN: 978-94-007-0617-0

  • Online ISBN: 978-94-007-0618-7

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