3417

IDH1

IDCD|IDH|IDP|IDPC|PICD;isocitrate dehydrogenase 1 (NADP+), soluble;IDH1;isocitrate dehydrogenase 1 (NADP+), soluble

NADP(+)-specific ICDH|NADP-dependent isocitrate dehydrogenase, cytosolic|NADP-dependent isocitrate dehydrogenase, peroxisomal|isocitrate dehydrogenase [NADP] cytoplasmic|oxalosuccinate decarboxylase

2q33.3

protein-coding

A recent study reported on mutations in the active site of the isocitrate dehydrogenase (IDH1) gene in 12% of glioblastomas. ALL mutations detected resulted in an amino acid exchange in position 132. We analyzed the genomic region spanning wild type R132 of IDH1 by direct sequencing in 685 brain tumors including 41 pilocytic astrocytomas, 12 subependymal giant cell astrocytomas, 7 pleomorphic xanthoastrocytomas, 93 diffuse astrocytomas, 120 adult glioblastomas, 14 pediatric glioblastomas, 105 oligodendrogliomas, 83 oligoastrocytomas, 31 ependymomas, 58 medulloblastomas, 9 supratentorial primitive neuroectodermal tumors, 17 schwannomas, 72 meningiomas and 23 pituitary adenomas. A total of 221somatic IDH1 mutations were detected and the highest frequencies occurred in diffuse astrocytomas (68%), oligodendrogliomas (69%), oligoastrocytomas (78%) and secondary glioblastomas (88%). Primary glioblastomas and other entities were characterized by a low frequency or absence of mutations in amino acid position 132 of IDH1. The very high frequency of IDH1 mutations in WHO grade II astrocytic and oligodendroglial gliomas suggests a role in early tumor development.

Although monoallelic expression (MAE) is a frequent genomic event in normal tissues, its role in tumorigenesis remains unclear. Here we carried out single-nucleotide polymorphism arrays on DNA and RNA from a large cohort of pediatric and adult brain tumor tissues to determine the genome-wide rate of MAE, its role in specific cancer-related genes, and the clinical consequences of MAE in brain tumors. We also used targeted genotyping to examine the role of tumor-related genes in brain tumor development and specifically examined the clinical consequences of MAE at TP53 and IDH1. The genome-wide rate of tumor MAEwas higher than in previously described normal tissue and increased with specific tumor grade. Oncogenes, but not tumor suppressors, exhibited significantly higher MAE in high-grade compared with low-grade tumors. This method identified nine novel genes highly associated with MAE. Within cancer-related genes, MAE was gene specific; hTERT was most significantly affected, with a higher frequency of MAE in adult and advanced tumors. Clinically, MAE at TP53 exists only in mutated tumors and increases with tumor aggressiveness. MAE toward the normal allele at IDH1 conferred worse survival even in IDH1 mutated tumors. Taken together, our findings suggest that MAE is tumor and gene specific, frequent in brain tumor subtypes, and may be associated with tumor progression/aggressiveness. Further exploration of MAE at relevant genes may contribute to better understanding of tumor development and determine survival in brain tumor patients.#CI- (c)2012 AACR.

Somatic mutations of the isocitrate dehydrogenase-1 gene (IDH1), most commonly resulting in replacement of arginine at position 132 by histidine (p.R132H), have been reported for WHO grade II and III diffuse gliomas and secondary glioblastomas. We investigated IDH1/2 mutations in a retrospective series of 165pediatric brain tumors, including atypical teratoid/rhabdoid tumors (AT/RT) and choroid plexus tumors, which had not previously been investigated. mutation analysis was performed by use of pyrosequencing and, additionally, data were validated for a cohort of 70 gliomas from among the series by use of the arrayedprimer extension technique. We identified one tumor which harbored mutation of IDH1 at codon 132 and no alteration was identified in the matched-germline DNA. No IDH2 mutations were detected. Most noteworthy, the IDH1 mutant tumor was an anaplastic astrocytoma involving the cortex in the left frontal lobe which appeared seven years after radiation treatment for an extensive sellar/suprasellar craniopharyngioma. This anaplastic astrocytoma was regarded as secondary to radiation treatment because it seemed to originate within the irradiation field that received a dose varying from a maximum of 30.6 Gy of 4 MVX-rays down to very few Gy of lower-energy scattered radiation. In this work ourobservations agree with those in previous reports showing the rarity of IDH1/2 mutations in childhood tumors. The interesting identification of an IDH1 mutation in a radiation-induced secondary malignant glioma raises the likelihood that these types of tumor may develop IDH1/2 mutations. Thus, caution is needed when dealing with these tumors, and further genetic analysis is warranted.

BACKGROUND: Dysembryoplastic Neuroepithelial tumours (DNT) are benign brain lesions arising during childhood that are characterized by early onset partial seizures, no neurological deficit and cortical location. Pathological diagnosis is easy when the glioneuronal element is present. Its absence might lead to the diagnosis of non-specific DNT or low-grade glioma (LGG). OBJECTIVE: The aim of this retrospective study was to analyse clinicopathological and molecular features of a series of cortical tumours, in order to find diagnostic and prognostic markers to better custom treatment next. METHODS: Twenty four children with cortical neuroepithelial tumour were included. Clinical and radiological data were collected. Histological diagnosis was reviewed for ALL patients. 1p19qand p53 status were obtained by FISH and immunohistochemistry respectively. IDH1-2 gene mutations were assessed by DNA sequencing. CGH-array was performed in 6/24 samples. Results: We recorded 13 DNT and 11 cortical LGG. Median age at surgery was 11.5 years. Overall survival was 100% and event-free survival at 10 years was 70%. No tumour displayed chromosomal alteration or 1p19q deletion or p53 expression. Only one patient with grade-II oligoastrocytoma had an IDH1 mutation. No statistical difference was found between the two populations in terms of age, sex, tumour location, type of surgical resection, disease progression and clinical status at last follow-up. Only the occurrence of septations on preoperative MRI was significantly associated with pathological features of DNT. CONCLUSION: Patients with DNT and cortical LGG share excellent outcome. Our genetic analysis could not distinguish DNT from LGG. In particular,CGH-array analysis was strictly normal in both tumor types. In attempt to find molecular markers, diagnosis of these lesions remains difficult when the glioneuronal element is lacking.