IDH1 p.R132 mutations may not be actively involved in the carcinogenesis of hepatocellular carcinoma

Abstract

BackgroundRecent studies have identified prevalent isocitrate dehydrogenase 1 (IDH1) codon 132 mutations (p.R132) in gliomas and acute myeloid leukemia (AML). The IDH1 mutations lead to a loss of its normal enzymatic activity and acquisition of neomorphic activity in production of α-ketoglutarate (α-KG) and 2-hydroxyglutarate (2-HG), which finally cause alterations of multiple gene expression of tumorigenesis-associated α-KG-dependent enzymes. The aim of this study was to determine whether IDH1 p.R132 mutations are involved in the carcinogenesis of hepatocellular carcinoma.Material/MethodsA total of 87 Han Chinese patients with primary hepatocellular carcinoma (HCC) were analyzed by direct DNA sequencing for IDH1 p.R132 mutations. The expression levels of multiple α-KG-dependent enzymes and associated genes were quantified in HepG2 cells overexpressing IDH1 p.R132 mutants by Western blotting and real-time PCR.ResultsNone of 87 Han Chinese patients with HCC harbored any IDH1 p.R132 mutations. The protein levels of HIF-1α and histone methylation marker (H3K4me3 and H3K79me2) were determined in HepG2 cells overexpressing IDH1 p.R132 mutants, but we discerned no difference. Measurement of mRNA expression levels of VEGF, GLUT1, and HOXA genes also showed no significant difference between cells overexpressing IDH1 wild-type and p.R132 mutants.ConclusionsOur negative results, together with some previous reports of the absence of IDH1 p.R132 mutations in HCC tissues, suggests that IDH1 p.R132 mutations are not actively involved in the development of HCC.

MicroRNA-29a induces loss of 5-hydroxymethylcytosine and promotes metastasis of hepatocellular carcinoma through a TET–SOCS1–MMP9 signaling axis

“…17, 29, 30 HCC harbors no IDH1 mutations, 31 recent studies found IDH2 protein decreased in HCC. 9 Herein, we demonstrated IDH1 and IDH2 had similar RNA expressions in both HCC and peritumoral liver tissues.…”

“…Two mechanisms have been reported that dysfunction of IDH and / or TET enzymes, two key factors in 5-hmC generation, that would lead to greatly decreased 5-hmC levels in human tumors: loss-of-function mutations target TET2 and IDH1/2 mutations that result in TET activity inhibition via α -KG reduction and 2-hydroxyglutarate accumulation. 17 , 29 , 30 HCC harbors no IDH1 mutations, 31 recent studies found IDH2 protein decreased in HCC. 9 Herein, we demonstrated IDH1 and IDH2 had similar RNA expressions in both HCC and peritumoral liver tissues.…”

IDH1 R132C mutation is detected in clear cell hepatocellular carcinoma by pyrosequencing

“…There has been no study of IDH1 mutations in specific subtypes of HCC. HCCs in general showed no remarkable increase of IDH1 mutations [ 4 , 8 , 10 , 11 ]. We performed pyrosequencing for IDH1 mutation analysis in clear cell HCCs and pseudoglandular HCCs.…”

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

“…2-HG also promotes the activity of the Egl nine homolog prolyl-hydroxylases by hypoxia inducible factors [ 42 ]. Similarly, increased 2-HG levels caused by IDH1 mutations activate HIF1α-inducible genes, such as the vascular endothelial growth factor (VEGF) and GLUT-1 [ 43 , 44 ]. IDH1/2 mutations were discovered to occur concomitantly to mutations in TP53 , ATRX , and TERT promoter, to codeletions of 1p/19q, and to molecular alterations in PTEN and EGFR [ 45 , 46 ].…”