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Review
. 2020 Aug 20;8(9):294.
doi: 10.3390/biomedicines8090294.

Isocitrate Dehydrogenase Mutations in Glioma: Genetics, Biochemistry, and Clinical Indications

Yang Liu  1 , Fengchao Lang  1 , Fu-Ju Chou  1 , Kareem A Zaghloul  2 , Chunzhang Yang  1
Affiliations
Review

Isocitrate Dehydrogenase Mutations in Glioma: Genetics, Biochemistry, and Clinical Indications

Yang Liu et al. Biomedicines. .

Abstract

Mutations in isocitrate dehydrogenase (IDH) are commonly observed in lower-grade glioma and secondary glioblastomas. IDH mutants confer a neomorphic enzyme activity that converts α-ketoglutarate to an oncometabolite D-2-hydroxyglutarate, which impacts cellular epigenetics and metabolism. IDH mutation establishes distinctive patterns in metabolism, cancer biology, and the therapeutic sensitivity of glioma. Thus, a deeper understanding of the roles of IDH mutations is of great value to improve the therapeutic efficacy of glioma and other malignancies that share similar genetic characteristics. In this review, we focused on the genetics, biochemistry, and clinical impacts of IDH mutations in glioma.

Keywords: IDH mutation; cancer; glioma; therapy resistance.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Isocitrate dehydrogenase (IDH) mutation in glioma. (A) The prevalence of the IDH1 mutation in glioma based on the pathologic grade. (B) Common genetic alterations in lower-grade glioma (LGG). IDH1/2 missense mutations are frequently observed in LGG. IDH-mutated LGG frequently harbors missense or truncating mutations in TP53, ATRX, capicua transcriptional repressor (CIC), and far upstream element binding protein 1 (FUBP1). EGFR gene amplifications and/or missense mutations are observed frequently in IDH wild-type gliomas, but rarely so in IDH-mutated cases. The data are visualized through cBioPortal [46,47].
Figure 2
Figure 2
Cancer-associated-IDH1 mutation. (A) Ribbon diagrams of the IDH1 structure in Homo sapiens. NADP is highlighted in yellow. α-Ketoglutarate (α-KG) is highlighted in red. The structure is visualized based on the known crystallography 4KZO [55]. (B) The structure of the catalytic center of the IDH1 enzyme. NADPH is highlighted in yellow. α-KG is highlighted in red. The structure is visualized based on the known crystallography 4KZO. (C). The frequency of IDH1 somatic mutations (upper panel) and IDH1 mutations in human malignancies (lower panel). Percentages were calculated from the Catalogue of Somatic Mutations in Cancer (COSMIC) database [56].
Figure 3
Figure 3
Clinical features of the World Health Organization (WHO) grade II/III IDH-mutated glioma. (A) Overall survival (OS) of glioma patients according to IDH1 status. IDH1 mutations are associated with prolonged OS. (B) Disease-free survival (DFS) of glioma patients according to IDH1 status. IDH1 mutations are associated with prolonged DFS. (C) Age at diagnosis among glioma patients according to IDH1 status. IDH1 mutations are associated with a younger age at diagnosis. (D) The distribution of genome alterations in glioma according to IDH1 status. IDH1 mutations are associated with fewer genome alterations. The data are visualized in cBioPortal [46,47].
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