title: Accumulation of 2-hydroxyglutarate is not a biomarker for malignant progression in IDH-mutated low-grade gliomas.
abstract: OBJECTIVE
  To determine whether accumulation of 2-hydroxyglutarate in IDH-mutated low-grade gliomas (LGG; WHO grade II) correlates with their malignant transformation and to evaluate changes in metabolite levels during malignant progression.
  
  
  METHODS
  Samples from 54 patients were screened for IDH mutations: 17 patients with LGG without malignant transformation, 18 patients with both LGG and their consecutive secondary glioblastomas (sGBM; n = 36), 2 additional patients with sGBM, 10 patients with primary glioblastomas (pGBM), and 7 patients without gliomas. The cellular tricarboxylic acid cycle metabolites, citrate, isocitrate, 2-hydroxyglutarate, α-ketoglutarate, fumarate, and succinate were profiled by liquid chromatography-tandem mass spectrometry. Ratios of 2-hydroxyglutarate/isocitrate were used to evaluate differences in 2-hydroxyglutarate accumulation in tumors from LGG and sGBM groups, compared with pGBM and nonglioma groups.
  
  
  RESULTS
  IDH1 mutations were detected in 27 (77.1%) of 37 patients with LGG. In addition, in patients with LGG with malignant progression (n = 18), 17 patients were IDH1 mutated with a stable mutation status during their malignant progression. None of the patients with pGBM or nonglioma tumors had an IDH mutation. Increased 2-hydroxyglutarate/isocitrate ratios were seen in patients with IDH1-mutated LGG and sGBM, in comparison with those with IDH1-nonmutated LGG, pGBM, and nonglioma groups. However, no differences in intratumoral 2-hydroxyglutarate/isocitrate ratios were found between patients with LGG with and without malignant transformation. Furthermore, in patients with paired samples of LGG and their consecutive sGBM, the 2-hydroxyglutarate/isocitrate ratios did not differ between both tumor stages.
  
  
  CONCLUSIONS
  Although intratumoral 2-hydroxyglutarate accumulation provides a marker for the presence of IDH mutations, the metabolite is not a useful biomarker for identifying malignant transformation or evaluating malignant progression.
authors: Department of Neurosurgery, University Hospital Carl Gustav Carus, Dresden University of Technology, Fetscherstrasse 74, D-01307 Dresden, Germany. tareq.juratli@uniklinikum-dresden.de
authors: Tareq A
authors: TA
authors: Juratli
authors: Mirko
authors: M
authors: Peitzsch
authors: Kathrin
authors: K
authors: Geiger
authors: Gabriele
authors: G
authors: Schackert
authors: Graeme
authors: G
authors: Eisenhofer
authors: Dietmar
authors: D
authors: Krex
mesh_terms: D000328:Adult; D000368:Aged; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D002853:Chromatography, Liquid; D018450:Disease Progression; D005260:Female; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D005977:Glutarates / Q000378:metabolism*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D060787:Neoplasm Grading; D011379:Prognosis; D015996:Survival Rate; D053719:Tandem Mass Spectrometry; D055815:Young Adult
chemical_list: D005977:Glutarates; C019417:alpha-hydroxyglutarate; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human
keywords: 2-hydroxyglutarate; liquid chromatography–tandem mass spectrometry; low-grade gliomas; secondary glioblastomas; α-ketoglutarate, IDH1 mutations