Accumulation of 2-hydroxyglutarate in gliomas correlates with survival: a study by 3.0-tesla magnetic resonance spectroscopy

Natsumeda, Manabu; Igarashi, Hironaka; Nomura, Tadashi; Ogura, Ryosuke; Tsukamoto, Yoshihiro; Kobayashi, Tsutomu; Aoki, Hiroshi; Okamoto, Kouichirou; Kakita, Akiyoshi; Takahashi, Hitoshi; Nakada, Tsutomu; Fujii, Yukihiko

doi:10.1186/s40478-014-0158-y

Cited by 48 publications

(57 citation statements)

References 42 publications

(54 reference statements)

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“…Using these techniques, (D)-2HG can be detected in milimolar ranges (1.7–8.9 mM) in IDH1/2 mutant but not in wild-type gliomas. Further, the detection of (D)-2HG in vivo correlates with better prognosis, mirroring previously reported next generation sequencing data 55, 68, 69 However, while the detection of (D)-2HG may be sensitive in the assessment of IDH1/2 mutations, the specificity may depend on the size and cellularity of the tumor. A recent study suggests that the sensitivity may be as low as 8% for small tumors (defined as <3.4 mL volume) in contrast to 91% sensitivity for larger tumors (> 8 mL in volume) 70 .…”

Section: (D)-2-hydroxyglutarate: Idh1 Mutant Oncometabolite and Mrs Isupporting

confidence: 81%

“…Multiple studies have shown worse outcome with elevated choline/NAA ratio pre-treatment or prior to adjuvant chemoradiation 135, 136 . As IDH 1/2 mutant gliomas have better prognosis compared to IDH wild-type tumors, evaluating (D)-2HG levels could also serve as a prognostic indicator 68, 137 .…”

Section: Integrating Metabolic Imaging With Clinical Care In Brain Tumentioning

confidence: 99%

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Non-invasive metabolic imaging of brain tumours in the era of precision medicine

et al. 2016

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The genomic revolution in cancer has uncovered a variety of mutations in primary brain tumors. This has created an urgent need to develop non-invasive imaging biomarkers to assess and integrate this genetic information in the clinical management of patients. Metabolic reprogramming is a central hallmark of cancers including brain tumors. Many of the molecular pathways implicated in brain tumors directly reprogram metabolism. This provides the opportunity to devise in vivo metabolism-based imaging modalities for patient stratification, to improve diagnosis, and to monitor treatment response. Metabolic phenomena like the Warburg effect and altered mitochondrial metabolism can be leveraged to image brain tumors using techniques like positron emission tomography (PET) imaging and Magnetic Resonance (MR) metabolic imaging. Moreover, genetic alterations such as isocitrate dehydrogenase mutations produced unique metabolic signatures that can be detected using MR spectroscopy. There is a growing need to translate our understanding of the molecular aspects of brain tumors to in vivo imaging in patients. Metabolism-based imaging provides a unique platform to achieve this. In this review we examine the molecular basis for metabolic reprograming in brain tumors and examine current non-invasive metabolic imaging strategies to interrogate them, for the ultimate goal of guiding and improving patient care.

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Section: (D)-2-hydroxyglutarate: Idh1 Mutant Oncometabolite and Mrs Isupporting

confidence: 81%

Section: Integrating Metabolic Imaging With Clinical Care In Brain Tumentioning

confidence: 99%

Non-invasive metabolic imaging of brain tumours in the era of precision medicine

et al. 2016

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“…R -2HG was shown to accumulate up to ~5–35 μmol/g in IDH -mutated glioma tumors, which could be equivalent to 5–35 mM assuming a tissue density of 1 g/ml19. In addition, R -2HG detected by non-invasive magnetic resonance spectroscopy also confirmed this metabolite was accumulated to 5–15 mM level in tumors with IDH mutations2021. The intracellular R-2HG level of stromal cells determined by mass spectrometry was very low (~8 pmol/mg protein).…”

Section: Resultsmentioning

confidence: 73%

The oncometabolite R-2-hydroxyglutarate activates NF-κB-dependent tumor-promoting stromal niche for acute myeloid leukemia cells

Chen

Lai

Tsai

et al. 2016

Sci Rep

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Mutations of isocitrate dehydrogenase 1 (IDH1) and IDH2 in acute myeloid leukemia (AML) cells produce the oncometabolite R-2-hydroxyglutarate (R-2HG) to induce epigenetic alteration and block hematopoietic differentiation. However, the effect of R-2HG released by IDH-mutated AML cells on the bone marrow microenvironment is unclear. Here, we report that R-2HG induces IκB kinase-independent activation of NF-κB in bone marrow stromal cells. R-2HG acts via a reactive oxygen species/extracellular signal-regulated kinase (ERK)-dependent pathway to phosphorylate NF-κB on the Thr254 residue. This phosphorylation enhances the interaction of NF-κB and the peptidyl-prolyl cis-trans isomerase PIN1 and increases the protein stability and transcriptional activity of NF-κB. As a consequence, R-2HG enhances NF-κB-dependent expression of cytokines including IL-6, IL-8 and complement 5a to stimulate proliferation of AML cells. In addition, R-2HG also upregulates vascular endothelial adhesion molecule 1 and CXCR4 in stromal cells to enhance the contact between AML and stromal cells and attenuates chemotherapy-induced apoptosis. More importantly, we validated the R-2HG-activated gene signature in the primary bone marrow stromal cells isolated from IDH-mutated AML patients. Collectively, our results suggest that AML cell-derived R-2HG may be helpful for the establishment of a supportive bone marrow stromal niche to promote AML progression via paracrine stimulation.

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“…Significantly lowered GSH concentrations (1418) as well as a trend of lower GSH (21) are also reported in IDH-MT glioma patients. This may be due to reduced nicotinamide adenine dinucleotide phosphate hydrate as a result of IDH-mutation, which is involved in the regeneration of the reduced form of GSH, and therefore may potentially be associated with the pathogenesis and progression of the IDH-MT gliomas (14).…”

Section: Reviews On In-vivo 1h-mrs Studies In Idh-mt Gliomasmentioning

confidence: 80%

In-VivoProton Magnetic Resonance Spectroscopy of 2-Hydroxyglutarate in Isocitrate Dehydrogenase-Mutated Gliomas: A Technical Review for Neuroradiologists

Kim

Lee

et al. 2016

Korean J Radiol

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The diagnostic and prognostic potential of an onco-metabolite, 2-hydroxyglutarate (2HG) as a proton magnetic resonance spectroscopy (1H-MRS) detectable biomarker of the isocitrate dehydrogenase (IDH)-mutated (IDH-MT) gliomas has drawn attention of neuroradiologists recently. However, due to severe spectral overlap with background signals, quantification of 2HG can be very challenging. In this technical review for neuroradiologists, first, the biochemistry of 2HG and its significance in the diagnosis of IDH-MT gliomas are summarized. Secondly, various 1H-MRS methods used in the previous studies are outlined. Finally, wereview previous in vivo studies, and discuss the current status of 1H-MRS in the diagnosis of IDH-MT gliomas.

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Accumulation of 2-hydroxyglutarate in gliomas correlates with survival: a study by 3.0-tesla magnetic resonance spectroscopy

Cited by 48 publications

References 42 publications

Non-invasive metabolic imaging of brain tumours in the era of precision medicine

Non-invasive metabolic imaging of brain tumours in the era of precision medicine

The oncometabolite R-2-hydroxyglutarate activates NF-κB-dependent tumor-promoting stromal niche for acute myeloid leukemia cells

In-VivoProton Magnetic Resonance Spectroscopy of 2-Hydroxyglutarate in Isocitrate Dehydrogenase-Mutated Gliomas: A Technical Review for Neuroradiologists

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