Analysis of IDH1 and IDH2 mutations in Japanese glioma patients

Abstract

A recent study reported on mutations in the active site of the isocitrate dehydrogenase 1 (IDH1) gene in several types of gliomas. All mutations detected resulted in an amino acid exchange at position 132. We analyzed the genomic region spanning wild-type R132 of IDH1 by direct sequencing in 125 glial tumors. A total of 39 IDH1 mutations were observed. Mutations of the IDH2 gene, homologous to IDH1, were often detected in gliomas without IDH1 mutations. In the present study, R172 mutation of the IDH2 gene was detected in one anaplastic astrocytoma. IDH1 or IDH2 mutations were frequently in oligodendrogliomas (67%), anaplastic astrocytomas (62%), anaplastic oligoastrocytomas (75%), anaplastic oligodendrogliomas (50%), secondary glioblastomas (67%), gangliogliomas (38%), and anaplastic gangliogliomas (60%). Primary glioblastomas were characterized by a low frequency of mutations (5%) at amino acid position 132 of IDH1. Mutations of the IDH1 or IDH2 genes were significantly associated with improved outcome in patients with anaplastic astrocytomas. Our data suggest that IDH1 or IDH2 mutation plays a role in early tumor progression of several types of glioma and might arise from a common glial precursor. The infrequency of IDH1 mutation in primary glioblastomas revealed that these subtypes are genetically distinct entities from other glial tumors. (Cancer Sci 2009; 100: 1996-1998) G liomas are the most common primary brain tumors and are grouped into four grades according to the World Health Organization (WHO) criteria.(1) This group of tumors includes specific histological subtypes; the most common are astrocytomas, oligodendrogliomas, and ependymomas. Glioblastomas (GBM; WHO grade IV), the most malignant glioma, may manifest rapidly de novo (primary GBM), or develop slowly from low-grade diffuse or anaplastic astrocytoma (secondary GBM). (2) Recent genomewide mutational analysis revealed somatic mutations of cytosolic NADP + -dependent isocitrate dehydrogenase (IDH1) in approximately 12% of GBM.(3) Isocitrate dehydrogenase catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate thereby leading to NADPH production.(4) Mutations affected the amino acid arginine at position 132 of the amino acid sequence, which is evolutionarily highly conserved, and is located in the binding site of isocitrate.(5) In the vast majority of the cases, wild-type arginine at position 132 was replaced by histidine ( R132H).The IDH2 gene is homologous to IDH1, which uses NADP + as an electron receptor. Gliomas without IDH1 mutations were often found to have mutations at the analogous amino acid (R172) of the IDH2 gene.(6) Both IDH1 and IDH2 mutations reduced the enzymatic activity of the encoded protein. (6) In recent analyses from North American and European groups, IDH1 mutations were more frequent in secondary GBM than primary GBM.(6-8) Similarly, high frequencies of IDH1 mutations were found in diffuse (WHO grade II) or anaplastic astrocytomas ( WHO grade III), oligodendrogliomas ( WHO grade II), and anaplastic oligoden...

Segregation of non-p.R132H mutations inIDH1in distinct molecular subtypes of glioma

“…The IDH1 mutation frequency for all grades II and III gliomas was high and ranged from 49% in anaplastic oligoastrocytic tumors to 79% in low grade oligodendrogliomas ( Table 1). The frequency of genetic changes in our sample cohort is similar to reported by others (Balss, et al, 2008;Ichimura, et al, 2009;Yan, et al, 2009;Sonoda, et al, 2009). The frequency of IDH1 mutations in grade II gliomas (76%, n=110/144) was higher than in grade III tumors (58%, n=102/177, P<0.001) (see also (Sanson, et al, 2009)).…”

“…IDH1 catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate and uses NADP(+) as the electron acceptor (Geisbrecht and Gould 1999;Margittai and Banhegyi 2008). Additional analysis showed that IDH1 mutations occur at a very high frequency (up to 80%) in all grade II and III gliomas (astrocytic, oligodendrocytic and oligoastrocytic) and secondary GBMs (Balss et al, 2008;Parsons, et al, 2008;Yan et al, 2009;Dubbink et al, 2009;Watanabe et al, 2009a;Ichimura et al, 2009;Sanson et al, 2009;Sonoda et al, 2009). IDH1 mutations do not occur at significant frequencies in other tumor types, with the notable exception of acute myeloid leukemia (AML) Yan, et al, 2009;Mardis et al, 2009).…”

Establishment of a Multi-Specific Monoclonal Antibody MsMab-1 Recognizing Both IDH1 and IDH2 Mutations

“…Because other IDH1/2 mutations such as IDH1-R132V (von Deimling et al 2011), IDH2-R172S (Sonoda et al 2009;Pansuriya et al 2011), IDH2-R172G Pansuriya et al 2011), and IDH2-R140Q (Paschka et al 2010) have been reported in gliomas, AML, or cartilaginous tumors, the cross-reaction of MsMab-1 with those IDH1/2 mutations might increase the diagnostic rate in immunohistochemistry.…”

“…In astrocytomas, oligodendrogliomas, oligoastrocytomas, and secondary glioblastomas, IDH1/2 mutations have been identified as early and frequent genetic alterations (50-93%). They might be the initiating event in these glioma subtypes (Balss et al 2008;Parsons et al 2008;Sonoda et al 2009;Yan et al 2009). In contrast, primary glioblastomas rarely contain IDH1/2 mutations (< 5%).…”

Genetic characterization of skull base chondrosarcomas

“…Exon 4 of IDH1 and IDH2, which included codon 132 and 172, respectively, was amplified as described previously. 26,28 After purification of the PCR products, sequence reactions were performed using a 3130xl Genetic Analyzer (Applied Biosystems).…”