Selective detection of the D-enantiomer of 2-hydroxyglutarate in the CSF of glioma patients with mutated isocitrate dehydrogenase

Juliya Kalinina, Jun Ahn, Narra S. Devi, Liya Wang, Yuancheng Li, Jeffrey J. Olson, Michael Glantz, Thomas Smith, Ella L. Kim, Alf Giese, Randy L. Jensen, Clark C. Chen, Bob S. Carter, Hui Mao, Miao He, Erwin G. Van Meir

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Abstract

Purpose: Elevation in D-2-Hydroxyglutarate (D-2HG) has recently emerged as a mandatory byproduct of mutated Isocitrate Dehydrogenase (IDH) genes 1 and 2 in glioma patients. The goal of the present study was to demonstrate the feasibility of detection of elevated levels of D-2HG in the cerebrospinal fluid (CSF) of glioma patients that carry point substitutions in the IDH gene. Experimental Design: We developed a mass spectrometry (MS)-based platform to detect and quantify the D- and L-forms of 2HG in the CSF of glioma patients. Three independent cohorts of patients were analyzed, comprising a total of 176 samples derived from 84 patients. The levels of D- and L-2HG were used to stratify patients into IDH wild-type or IDH-mutated groups using an empirically obtained threshold of 0.69 μmol/L. Results: Using this platform, a greater than 17-fold mean increase in D-2HG was observed in the CSF of patients with IDH mutant versus wild-type gliomas. The means for the D-2HG levels in CSF were 0.427 μmol/L in wild-type and 7.439 μmol/L in mutant groups. The C statistic for the receiver operator curve was 0.938, with 84% sensitivity, 90% specificity, and 89% accuracy to detect D-2HG. The levels of D- and L-2HG in CSF from wild-type patients varied by location of CSF draw (cisternal>ventricular>lumbar). Conclusions: Our findings demonstrate that the CSF of patients harboring IDH mutant gliomas contain increased levels of D-2HG, which can be reliably detected with a MS-based platform.

Original languageEnglish (US)
Pages (from-to)6256-6265
Number of pages10
JournalClinical Cancer Research
Volume22
Issue number24
DOIs
StatePublished - Dec 15 2016

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All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Kalinina, J., Ahn, J., Devi, N. S., Wang, L., Li, Y., Olson, J. J., Glantz, M., Smith, T., Kim, E. L., Giese, A., Jensen, R. L., Chen, C. C., Carter, B. S., Mao, H., He, M., & Van Meir, E. G. (2016). Selective detection of the D-enantiomer of 2-hydroxyglutarate in the CSF of glioma patients with mutated isocitrate dehydrogenase. Clinical Cancer Research, 22(24), 6256-6265. https://doi.org/10.1158/1078-0432.CCR-15-2965