Abstract
Mutations in isocitrate dehydrogenase 1 and 2 genes (IDH1/2) frequently occur in lower-grade gliomas and secondary glioblastomas. Mutant IDH1/2 proteins gain a new ability to produce the oncometabolite 2-hydroxyglutarate (2HG), however, the clinical impact of 2HG is not clear. In this study, we analyzed 2HG levels in both serum and tumor tissue and evaluated the role of 2HG in diffuse gliomas. We measured 2HG concentrations in 123 serums and in 78 tumor tissues by using liquid chromatography-tandem mass spectrometry method. IDH1/2 mutations status were determined by direct sequencing and/or immunohistochemistry. O-6-methylguanine DNA methyltransferase (MGMT) promoter methylations were analyzed using pyrosequencing and defined the mean level of methylation at the 16 CpG sites.Serum levels of 2HG in 42 patients with IDH-Mut tumors did not differ from those in 81 patients with IDH-WT tumors (median: 19.9 ng/mL for IDH-Mut vs 22.8 ng/mL for IDH-WT, p=0.86), however, tissue levels of 2HG in 28 patients with IDH-Mut tumors were significantly higher than those in 50 patients with IDH-WT tumors (median: 4.9 ug/mg for IDH-Mut vs 0.09 ug/mg for IDH-WT, p<0.0001). In 28 patients with IDH-Mut tumors, serum levels of 2HG were significantly correlated with tissue levels of 2HG (R2 = 0.39, p=0.0004), but in 50 patients with IDH-WT tumors, serum and tissue levels of 2HG did not show the relationship (R2 = 0.067, p=0.070). Tissue levels of 2HG showed a significant correlation with MGMT promoter methylations (R2= 0.15, p=0.0024).Our results suggest that tumor-derived 2HG is released in serum in the patients with IDH1/2 Mut tumors, however, their amounts are too small to detect the difference of serum 2HG levels in between patients with IDH-Mut and IDH-WT tumors. Accumulation of 2HG in tumor tissue may have an impact on MGMT promoter methylations.
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