IDH1 and IDH2 mutations 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.

Figure 1. IDH1 and IDH2 Mutations in Human Gliomas

Panel A shows mutations at codon R132 in IDH1 and R172 in IDH2 that were identified in human gliomas, along with the number of patients who carried each mutation. Codons 130 to 134 of IDH1 and 170 to 174 of IDH2 are shown. Panel B shows the number and frequency of IDH1 and IDH2 mutations in gliomas and other types of tumors. The roman numerals in parentheses are the tumor grades, according to histopathological and clinical criteria established by the World Health Organization. CNS denotes central nervous system.

Figure 2. Enzymatic Activity of Wild-Type and Mutant IDH1 and IDH2 Proteins

Cell lysates were extracted from a human oligodendroglioma cell line without IDH1 or IDH2 mutations that had been transfected with vectors encoding the indicated proteins. Panel A shows the expression of proteins encoded by wild-type and mutant IDH1 and IDH2, as determined by Western blotting, with the use of an anti-FLAG antibody. Panel B shows the activity levels of these proteins, as analyzed by monitoring the production of NADPH. GAPDH denotes glyceraldehyde 3-phosphate dehydrogenase.

Figure 3. Survival of Adult Patients with Malignant Gliomas with or without IDH Gene Mutations

For patients with glioblastomas, the median survival was 31 months for the 14 patients with mutated IDH1 or IDH2, as compared with 15 months for the 115 patients with wild-type IDH1 or IDH2 (Panel A). For patients with anaplastic astrocytomas, the median survival was 65 months for the 38 patients with mutated IDH1 or IDH2, as compared with 20 months for the 14 patients with wild-type IDH1 or IDH2 (Panel B). Patients with both primary and secondary tumors were included in the analysis. For patients with secondary glioblastomas, survival was calculated from the date of the secondary diagnosis. Survival distributions were compared with the use of the logrank test.