Tissue 2-hydroxyglutarate as a biomarker for isocitrate dehydrogenase (IDH) mutations in gliomas

Purpose:Isocitrate dehydrogenase (IDH) mutations are common in low grade gliomas and the IDH mutation status is now integrated into the WHO classification of gliomas. IDH mutations lead to preferential accumulation of the R- relative to the S- enantiomer of 2-hydroxyglutarate (2-HG). We investigated the utility of tissue total 2-HG, R-2-HG and the R-2-HG/S-2-HG ratio (rRS) as diagnostic and prognostic biomarkers for IDH mutations in gliomas. Experimental Design: Glioma tissue and blood samples from 87 patients were analyzed with HPLC-MS/MS coupled with a CHIROBIOTIC^Ò column to quantify both enantiomers of 2-HG. Receiver operator curve (ROC) analysis was conducted to evaluate the sensitivity and specificity of 2-HG, R-2-HG and rRS. The feasibility of real-time determination of IDH status was evaluated in 11 patients intra-operatively. The prognostic value of rRS was evaluated using the Kaplan-Meier method. Results: The rRS in glioma tissues clearly distinguished patients with IDH mutant versus wildtype tumors (p<0.001). Sensitivity and specificity using an rRS cut-off value of 32.26 were 97% and 100% respectively. None of total 2-HG, R-2-HG or rRS was elevated in serum samples. Among patients with IDH mutant tumors, tissue rRS stratifies overall survival. The duration of tissue analysis is approximately 60 minutes. Conclusions: Our study demonstrates that rRS is a reliable biomarker of IDH mutation status. This technique can be used to determine IDH mutation status intra-operatively, and to guide treatment decisions based on IDH mutation status in real time. Lastly, rRS values may provide additional prognostic information and further validation is required.

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