Chapter 6 The Role of IDH1 and IDH2 Mutations in Malignant Gliomas Yukihiko Sonoda, Ichiyo Shibahara, Ryuta Saito, Toshihiro Kumabe, and Teiji Tominaga 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 glioblas- tomas 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. Keywords IDH1 and IDH2 · Mutations · Gliomas · Glioblastomas · Grades of glioma · Arginine Introduction Gliomas are the most common type of primary brain tumor and are grouped into four grades according Y. Sonoda () Department of Neurosurgery, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai-shi, Miyagi 980-8577, Japan e-mail: sono@nsg.med.tohoku.ac.jp to the World Health Organization (WHO) criteria (Louis et al., 2007). Gliomas include several spe- cific histological subtypes; the most common are astrocytomas, oligodendrogliomas, and ependymo- mas. Glioblastomas (GBMs) (WHO grade IV), the most malignant type of glioma, may develop very rapidly de novo (primary glioblastoma) in elderly patients, or develop more slowly from low-grade dif- fuse (DA) (WHO grade II) or anaplastic astrocytoma (AA) (WHO grade III) (secondary glioblastoma) in younger patients (Ohgaki and Kleihues, 2009). Malignant gliomas are believed to develop as the result of stepwise accumulations of genetic lesions. Several genes, including TP53, PTEN, CDKN2A/CDKN2B, and EGFR, are altered in gliomas (Ohgaki and Kleihues, 2009). These alterations tend to occur in a defined order during the progression to a high-grade tumor. TP53 mutation appears to be a relatively early event during the development of an astrocytoma, whereas the loss or mutation of PTEN and amplification of EGFR are characteris- tic of higher-grade tumors (Furnari et al., 2007). Oligodendrogliomas (O) (WHO grade II) and anaplas- tic oligodendrogliomas (AO) (WHO grade III) typ- ically show 1p/19q codeletion (Reifenberger et al., 1994). Recent genome-wide mutational analysis has revealed somatic mutations of the cytosolic nicoti- namide adenine dinucleotide phosphate (NADP + )- dependent isocitrate dehydrogenase (IDH1) gene at 2q33 in approximately 12% of GBMs (Parsons et al., 2008). Isocitrate dehydrogenase catalyzes the oxidative decarboxylation of isocitrate to alpha- ketoglutarate thereby enabling NADPH production. Mutations were found that affect the amino acid argi- nine in position 132 of the amino acid sequence, which is evolutionarily highly conserved, and is located in 47 M.A. Hayat (ed.), Tumors of the Central Nervous System, Volume 2, DOI 10.1007/978-94-007-0618-7_6, © Springer Science+Business Media B.V. 2011