IDH1 mutations are present in the majority of common adult gliomas but rare in primary glioblastomas

Abstract

We screened exon 4 of the gene isocitrate dehydrogenase 1 (NADP+), soluble (IDH1) for mutations in 596 primary intracranial tumors of all major types. Codon 132 mutation was seen in 54% of astrocytomas and 65% of oligodendroglial tumors but in only 6% of glioblastomas (3% of primary and 50% of secondary glioblastomas). There were no mutations in any other type of tumor studied. While mutations in the tumor protein p53 gene (TP53) and total 1p/19q deletions were mutually exclusive, IDH1 mutations were strongly correlated with these genetic abnormalities. All four types of mutant IDH1 proteins showed decreased enzymatic activity. The data indicate that IDH1 mutation combined with either TP53 mutation or total 1p/19q loss is a frequent and early change in the majority of oligodendroglial tumors, diffuse astrocytomas, anaplastic astrocytomas, and secondary glioblastomas but not in primary glioblastomas.

Fig. 1.

Enzymatic assay of the wild-type and mutant IDH1 (isocitrate dehydrogenase 1 [NADP+], soluble). (A) Western blotting of the COS-7 transfectants with an antihemagglutinin (anti-HA) antibody (top). The HA-tagged recombinant IDH1 (46 kDa) is strongly expressed in the wild-type (Wt) and mutant transfectants (His, Arg132His; Gly, Arg132Gly; Ser, Arg132Ser; Cys, Arg132Cys). A comparable result was obtained using a goat anti-IDH1 antibody (data not shown). The blot was reprobed with anti–α-tubulin antibody to control for lane loading (bottom). (B) Enzymatic activity of wild-type and mutant IDH1. The relative activity is shown as a ratio to wild type (Wt, 1.00). The error bar shows standard error of the quadruplicated assays. The enzymatic activities in all four mutants were significantly decreased compared with wild-type (p <0.001). The activity detected in the vector transfectants (Vec) compared with the vector transfectants without isocitrate (Vec-IC) represents the activity of endogenous IDH1 in COS-7 cells. Reproducible results were obtained from independent transfection experiments.

Fig. 2.

A model for the development/progression of astrocytic and oligodendroglial tumors. Abbreviations: CDKN2A, cyclin-dependent kinase inhibitor 2A; HD, homozygous deletion; CDK4/6, cyclin-dependent kinase 4/6; amp, amplification; RB1, retinoblastoma 1; mut, mutation; CCND, cyclin D1/D2/D3; RB1 pathway, CDKN2A, CDK4/6, RB1, or CCND ; EGFR, epithelial growth factor receptor; PTEN, phosphatase and tensin homolog; pGB, primary glioblastoma; TP53, tumor protein p53; MDM2/4, Mdm2/4 p53 binding protein homolog (mouse); p14ARF, the p14 alternative reading frame product of cyclin-dependent kinase inhibitor 2A; p53 pathway, TP53, MDM2/4, or p14ARF; A, diffuse astrocytoma; AA, anaplastic astrocytoma; sGB, secondary glioblastoma; IDH1, isocitrate dehydrogenase 1 (NADP+), soluble; OA, oligoastrocytoma; AOA, anaplastic oligoastrocytoma; O, oligodendroglioma grade II; AO, anaplastic oligodendroglioma; t(1;19), unbalanced t(1;19)(q10;p10) translocation; PA, pilocytic astrocytoma; BRAF, v-raf murine sarcoma viral oncogene homolog B1.