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

Academic Article

Abstract

  • ©2016 AACR. 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.
  • Authors

    Published In

    Digital Object Identifier (doi)

    Pubmed Id

  • 11088035
  • Author List

  • Kalinina J; Ahn J; Devi NS; Wang L; Li Y; Olson JJ; Glantz M; Smith T; Kim EL; Giese A
  • Start Page

  • 6256
  • End Page

  • 6265
  • Volume

  • 22
  • Issue

  • 24