IDH mutation in glioma: molecular mechanisms and potential therapeutic targets

Abstract

Isocitrate dehydrogenase (IDH) enzymes catalyse the oxidative decarboxylation of isocitrate and therefore play key roles in the Krebs cycle and cellular homoeostasis. Major advances in cancer genetics over the past decade have revealed that the genes encoding IDHs are frequently mutated in a variety of human malignancies, including gliomas, acute myeloid leukaemia, cholangiocarcinoma, chondrosarcoma and thyroid carcinoma. A series of seminal studies further elucidated the biological impact of the IDH mutation and uncovered the potential role of IDH mutants in oncogenesis. Notably, the neomorphic activity of the IDH mutants establishes distinctive patterns in cancer metabolism, epigenetic shift and therapy resistance. Novel molecular targeting approaches have been developed to improve the efficacy of therapeutics against IDH-mutated cancers. Here we provide an overview of the latest findings in IDH-mutated human malignancies, with a focus on glioma, discussing unique biological signatures and proceedings in translational research.

The Value of Enhanced MR Radiomics in Estimating the IDH1 Genotype in High-Grade Gliomas

“…Moreover, studies have shown that IDH1-mutant and wild-type gliomas are different disease entities [ 14 ]. IDH1-mutant glioma grows slower than wild-type glioma and is associated with longer overall survival and progression-free survival and with a better prognosis and survival rate [ 2 – 9 ]. This prognostic difference has no significant relationship with the grade of the glioma itself [ 15 ].…”

“…Subsequently, a large number of studies showed significant differences in prognosis between IDH1-mutant and wild-type gliomas. The prognosis of IDH1-mutant glioma is significantly better than that of wild-type glioma [ 2 – 9 ]. However, at present, conventional imaging and functional magnetic resonance imaging (such as DWI, ASL, and DCE) could not predict the glioma genotypes before surgery and could not evaluate the glioma genotypes before clinical surgery.…”

A SEMA3 Signaling Pathway-Based Multi-Biomarker for Prediction of Glioma Patient Survival

“…As shown in Figure 4 C, in some cases, short survival is observed at a young age (39-year patient survived only 14 months) and GBM patients with poor prognosis survive more than 2- or 3-years. IDH status is also useful in predicting the OS of patients diagnosed with GBM, and in the selection of appropriate therapeutic strategies [ 40 , 41 ], however, the majority of grade II and III gliomas have a mutant-type of IDH ( Figure 2 ), while survival times vary between these patients ( Figure 4 C). These exceptions appear due to the heterogeneity of gliomas, which hinders the accurate identification of tumor malignancies.…”

Present and Future of Anti-Glioblastoma Therapies: A Deep Look into Molecular Dependencies/Features

“…Isocitrate dehydrogenase (IDH) enzymes, which contain three isoforms, play key roles in several major cellular metabolic processes, such as the tricarboxylic acid (TCA) cycle, glutamine metabolism, lipogenesis, and redox regulation [ 32 ]. Wild-type IDH1 and 2 localize in the cytoplasm and mitochondria, respectively, and catalyze the decarboxylation of isocitrate to alpha-ketoglutarate (α-KG) with reduction of NADP+ to NADPH [ 33 ].…”