The clinical use of IDH1 and IDH2 mutations in gliomas

Abstract

Introduction: Mutations in the genes isocitrate dehydrogenase (IDH) 1 and 2 have been reported in a limited number of tumors. In gliomas, IDH mutations are primarily detected in WHO grade II-III tumors and represent a major biomarker with diagnostic, prognostic, and predictive implications. The recent development of IDH inhibitors and vaccines suggests that the IDH mutation is also an appealing target for therapy. Areas covered: This review focuses on the role of IDH mutations in diffuse gliomas. Besides discussing their role in gliomagenesis, we will emphasize the role of IDH mutations in clinical practice as a diagnostic, prognostic and predictive biomarker, and as a potential therapeutic target. Noninvasive detection of the IDH mutation by means of liquid biopsy and MR spectroscopy will also be discussed. Expert commentary: While IDH mutation is a consolidated diagnostic and prognostic biomarker in clinical practice, its role in oncogenesis is far from being elucidated, and there are several pending issues. The routine use of noninvasive techniques for detection and monitoring of the IDH status remains challenging. Although the IDH mutation is a very early alteration in gliomagenesis, it may then be omitted during tumor progression. This observation has important implications when designing targeted clinical trials. KEYWORDS IDH1and IDH2 mutations; gliomagenesis; grade II and III gliomas; biomarkers; target therapy 65 mutations, common in acute myeloid leukemia [11], have not been reported in gliomas [12]. Mutations arising in IDH1 G97 [13,14], IDH1 R100 [14-16] (the homologous of IDH2 R140), IDH1 R109 [17], and IDH1 R314 [18] have been anecdotally reported in gliomas. 70 IDH1 and IDH2 are enzymes that physiologically convert isocitrate to α-ketoglutarate (α-KG). These two enzymes have similar function but different cell compartmentalization: IDH1 is located in the cytosol, while IDH2 in mitochondria. Mutations in either IDH1 or IDH2 result in a neomorphic enzy-75 matic activity, causing the stereospecific conversion of α-KG

Patient-derived xenografts of different grade gliomas retain the heterogeneous histological and genetic features of human gliomas

“…Therefore, it is plausible that the success rate is high for grade IV, and gradually decreases for grades III and II. From the IDH status perspective, IDH-wild type gliomas significantly increased the success rate compared to IDH-mutant gliomas, possibly because the IDH mutation is an early driver of gliomagenesis [19]. Ki67 is directly associated with proliferative ability; the expression of Ki67 significantly enhanced the success rate of the engrafts by more than 5%.…”

Biological Roles and Therapeutic Applications of IDH2 Mutations in Human Cancer

“…This leads to the activation of pro-apoptotic Bax and BAK, which triggers hypoxia-induced cell death ( 33 ). 2-HG released from the microenvironment may also alter the function of non-tumor cells around the tumor, such as neurons and immune cells ( 34 ). In fact, there is now direct evidence that 2-HG accumulation plays an immunosuppressive role.…”

m1A RNA Methylation Regulators Contribute To Malignant Progression And Have Clinical Prognostic Impact In Gliomas

“…2.3. YTHDF1 and YTHDF2 were dysregulated in IDH mutated or 1p19q co-deleted glioma IDH mutation was found to be a common genetic mutation promotor in glioma, while chromosome 1p/19q codeletion is increasingly being recognized as the crucial genetic marker for glioma patients and have been included in WHO classi cation of glioma in 2016 [13,14]. Hence, the expression level of YTHDF1 and YTHDF2 in IDH mutated or 1p19q co-deleted glioma were also explored.…”