IDH1andIDH2Mutations in Gliomas

Abstract

BACKGROUND A recent genomewide mutational analysis of glioblastomas (World Health Organization [WHO] grade IV glioma) revealed somatic mutations of the isocitrate dehydrogenase 1 gene (IDH1) in a fraction of such tumors, most frequently in tumors that were known to have evolved from lower-grade gliomas (secondary glioblastomas). METHODS We determined the sequence of the IDH1 gene and the related IDH2 gene in 445 central nervous system (CNS) tumors and 494 non-CNS tumors. The enzymatic activity of the proteins that were produced from normal and mutant IDH1 and IDH2 genes was determined in cultured glioma cells that were transfected with these genes. RESULTS We identified mutations that affected amino acid 132 of IDH1 in more than 70% of WHO grade II and III astrocytomas and oligodendrogliomas and in glioblastomas that developed from these lower-grade lesions. Tumors without mutations in IDH1 often had mutations affecting the analogous amino acid (R172) of the IDH2 gene. Tumors with IDH1 or IDH2 mutations had distinctive genetic and clinical characteristics, and patients with such tumors had a better outcome than those with wild-type IDH genes. Each of four tested IDH1 and IDH2 mutations reduced the enzymatic activity of the encoded protein. CONCLUSIONS Mutations of NADP+-dependent isocitrate dehydrogenases encoded by IDH1 and IDH2 occur in a majority of several types of malignant gliomas.

RUNX3 is down‐regulated in glioma by Myc‐regulated miR‐4295

“…Isocitrate dehydrogenase gene mutations, estimated to occur in 70–90% of diffuse lower grade gliomas, are strongly implicated in both tumourigenesis and prognosis 23, 24, 25. Loss of heterozygosity of 1p19q, was occurred in 60–80% of oligodendroglioma and up to 45% of oligoastrocytoma 26.…”

The TERT promoter mutation status and MGMT promoter methylation status, combined with dichotomized MRI‐derived and clinical features, predict adult primary glioblastoma survival

“…Isocitrate dehydrogenase 1 and 2 (IDH1/2) mutations are recognized as definitive diagnostic molecular biomarkers of secondary GBM and are more prognostically valuable than the history of tumor onset 3. Correspondingly, wild‐type IDH1/2 genotypes are considered robust biomarkers of primary GBM (<5%) 4, 5.…”

Mitochondrial metabolic remodeling in response to genetic and environmental perturbations

“…The presence of recurrent somatic point mutations in IDH1 was first identified in 12% of all adult glioblastoma tumors by high‐throughput DNA sequencing 51. Deep sequencing further revealed that mutated IDH1 and IDH2 occur in a high proportion (>70%) of low‐grade (grade II–III) astrocytomas and oligodendrogliomas and secondary glioblastoma 51, 52, 88, 89. Since these initial reports, mutations in IDH1 and IDH2 have also been found in other diverse cancers including 16–17% of patients with AML,53 20% of patients with angioimmunoblastic T‐cell lymphomas,90 and more rarely in cholangiocarcinomas,91 breast carcinomas,92 acute lymphoblastic leukemias,93 prostate cancer,93 osteosarcoma,94 and others 53, 91, 92, 93, 95, 96, 97.…”

“…It appears that the removal of the arginine, rather than the substitution of a specific residue, is the critical feature of this mutation, although the most frequent replacement observed is a histidine residue (R132H) 51, 52, 93, 98. Mutations in IDH2 in gliomas occur at a much lower frequency (0–6%) than IDH1 88 in the paralogous amino acid residue—R140—but also at R172.…”

“…However, continued oxygen use in hypoxia is likely to create highly challenging conditions in an IDH1 ‐mutated tumor, as it is likely to further exacerbate the hypoxic microenvironment, potentially leading to increased areas of necrosis. It is important to note that IDH1 mutant gliomas demonstrate improved overall survival compared to their wild‐type counterparts,52 which may well be in some part due to their apparent inability to modify their mitochondrial metabolism in response to hypoxia. Interestingly, IDH2 ‐mutated cells were shown not to exhibit the same alteration in the hypoxia‐mediated mitochondrial metabolic phenotype 117.…”