Accumulation of 2-hydroxyglutarate is not a biomarker for malignant progression in IDH-mutated low-grade gliomas.

Abstract

OBJECTIVES:

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.

CONCLUSION:

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: Tareq A Juratli, Mirko Peitzsch, Kathrin Geiger, Gabriele Schackert, Graeme Eisenhofer, Dietmar Krex
• Journal: Neuro-oncology (Neuro Oncol) Vol. 15 Issue 6 Pg. 682-90 (Jun 2013) ISSN: 1523-5866 [Electronic] England
• PMID: 23410661 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Glutarates
• alpha-hydroxyglutarate
• IDH2 protein, human
• Isocitrate Dehydrogenase
• IDH1 protein, human

Topics

• Adult
• Aged
• Brain Neoplasms (genetics, metabolism, mortality, pathology)
• Chromatography, Liquid
• Disease Progression
• Female
• Glioma (genetics, metabolism, mortality, pathology)
• Glutarates (metabolism)
• Humans
• Isocitrate Dehydrogenase (genetics)
• Male
• Middle Aged
• Mutation (genetics)
• Neoplasm Grading
• Prognosis
• Survival Rate
• Tandem Mass Spectrometry
• Young Adult