gms | German Medical Science

Objective: To determine whether the accumulation of 2-hydroxyglutarate in IDH-mutated low-grade gliomas WHO grade II (LGG) correlates with their malignant transformation and to evaluate changes in metabolite levels during malignant progression.

Method: Samples from 54 patients were screened for IDH mutations: 18 patients with both LGG and their consecutive secondary glioblastomas (sGBM) (n=36), 19 patients with LGG without malignant transformation, 10 patients with primary glioblastomas (pGBM), and 7 non-glioma patients. 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 to pGBM and non-glioma groups.

Results: IDH1 mutations were detected in 27 out of 37 LGG patients (77.1%). In addition, in LGG patients with malignant progression (n=18), 16 patients were IDH1 mutated with a stable mutation status during their malignant progression. None of the pGBM or non-glioma tumor patients had an IDH mutation. Increased 2-hydroxyglutarate/isocitrate ratios were seen in patients with IDH1 mutated LGG and sGBM in comparison to those with IDH1 non-mutated LGG, pGBM, and non-glioma groups. However, no differences in intratumoral 2-hydroxyglutarate/isocitrate ratios were found between LGG patients 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 the two 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.