Abstract

In 2009, the discovery of isocitrate dehydrogenase (IDH) mutations in gliomas is a powerful example of understanding of the relationship between tumor genetics and human diseases. IDHs, catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate with production of NADH/NADPH, is the key enzymes in the Krebs cycle. IDH mutations, which occur early in gliomagenesis, change the function of the enzymes, causing them to produce 2–hydroxyglutarate, and to not create NADPH. Gliomas with mutated IDH have improved prediction of patient outcomes compared to its with wild-type IDH. Thus, the WHO Classification of Tumors of the Central Nervous System was revised in 2016 to incorporate molecular biomarkers (including the IDH mutations) – together with classic histological features – in an integrated diagnosis, in order to define distinct glioma entities as precisely as possible. The aim of this chapter is to review the findings on the epidemiology and significance of IDH mutations in human gliomas, from discovery to the current knowledge about their molecular pathogenesis.

Highlights

  • Isocitrate dehydrogenase (IDH) is a key enzyme in the Krebs cycle and plays an important role in energy metabolism

  • IDH1, encoded by IDH1 gene on 2q33.3, is configured as a homodimer with two enzymatically active sites and most of its activity is detected in the cytosol and in peroxysomes, Main function of IDH1 is believed to be the synthesis of NADPH, required for reducing reactions and for lipid synthesis [1–3]

  • IDH mutant gliomas likely harbour defects in multiple DNA repair pathways, which render them vulnerable to radiotherapy- or chemotherapy-induced DNA damage [54, 55]. These findings indicate that IDH mutation could serve as an important predictive factor for treatment response among glioma patients

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Summary

Introduction

Isocitrate dehydrogenase (IDH) is a key enzyme in the Krebs cycle and plays an important role in energy metabolism. This enzyme is involved in a number of cellular processes, such as mitochondrial oxidative phosphorylation, regulation of cellular redox status, glutamine metabolism as well as lipogenesis or glucose sensing. The WHO classification of Tumors of the Central Nervous System of 2016, gliomas are subdivided based on combined classical histological with molecular markers (including the IDH mutations). This reclassification is expected to guide treatment decisions and improve outcome prediction. The aim of this chapter is to review the findings on the epidemiology and significance of IDH mutations, from current knowledge about molecular pathogenesis to the value these mutations in gliomas

Genetics and classification enzymes
Mechanism and function of IDH enzymes
Molecular pathogenesis of IDH mutations
Enzymatic properties of mutant IDHs
Mutant IDH enzymes control cellular growth
IDH mutation involvement human cancers
IDH mutations in human gliomas
Diagnosis
Prognostic
Novel therapies
IDH-mutated inhibitors
Targeting redox homoeostasis
Immunotherapies
Vaccines
Other therapies
Findings
Conclusion

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