Diagnostic value of glutamate with 2-hydroxyglutarate in magnetic resonance spectroscopy for IDH1 mutant glioma

Mutations in the isocitrate dehydrogenase 1 (IDH1) gene that are frequently observed in low-grade glioma are strongly associated with the accumulation of 2-hydroxyglutarate (2HG), which is a valuable diagnostic and prognostic biomarker of IDH1 mutant glioma. However, conventional MR spectroscopy (MR...

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Published inNeuro-oncology (Charlottesville, Va.) Vol. 18; no. 11; pp. 1559 - 1568
Main Authors Nagashima, Hiroaki, Tanaka, Kazuhiro, Sasayama, Takashi, Irino, Yasuhiro, Sato, Naoko, Takeuchi, Yukiko, Kyotani, Katsusuke, Mukasa, Akitake, Mizukawa, Katsu, Sakata, Junichi, Yamamoto, Yusuke, Hosoda, Kohkichi, Itoh, Tomoo, Sasaki, Ryohei, Kohmura, Eiji
Format Journal Article
LanguageEnglish
Published England Oxford University Press 01.11.2016
Subjects
Adolescent
Adult
Aged
Aged, 80 and over
Basic and Translational Investigation
Biomarkers - metabolism
Brain Neoplasms - diagnosis
Brain Neoplasms - genetics
Brain Neoplasms - metabolism
Glioma - diagnosis
Glioma - genetics
Glioma - metabolism
Glutamate Dehydrogenase - metabolism
Glutamic Acid - metabolism
Glutarates - metabolism
Humans
Isocitrate Dehydrogenase - genetics
Magnetic Resonance Spectroscopy
Metabolomics
Middle Aged
Mutation
Sensitivity and Specificity
Transaminases - metabolism
Young Adult
IDH1 mutation
glioma
2-hydroxyglutarate
glutamate
MR spectroscopy
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Abstract Mutations in the isocitrate dehydrogenase 1 (IDH1) gene that are frequently observed in low-grade glioma are strongly associated with the accumulation of 2-hydroxyglutarate (2HG), which is a valuable diagnostic and prognostic biomarker of IDH1 mutant glioma. However, conventional MR spectroscopy (MRS)-based noninvasive detection of 2HG is challenging. In this study, we aimed to determine the additional value of other metabolites in predicting IDH1 mutations with conventional MRS. Forty-seven patients with glioma underwent conventional single voxel short echo time MRS prior to surgery. A stereotactic navigation-guided operation was performed to resect tumor tissues in the center of the MRS voxel. MRS-based measurements of metabolites were validated with gas chromatography-mass spectrometry. We also conducted integrated analyses of glioma cell lines and clinical samples to examine the other metabolite levels and molecular findings in IDH1 mutant gliomas. A metabolomic analysis demonstrated higher levels of 2HG in IDH1 mutant glioma cells and surgical tissues. Interestingly, glutamate levels were significantly decreased in IDH1 mutant gliomas. Through an analysis of metabolic enzyme genes in glutamine pathways, it was shown that the expressions of branched-chain amino acid transaminase 1 were reduced and glutamate dehydrogenase levels were elevated in IDH1 mutant gliomas. Conventional MRS detection of glutamate and 2HG resulted in a high diagnostic accuracy (sensitivity 72%, specificity 96%) for IDH1 mutant glioma. IDH1 mutations alter glutamate metabolism. Combining glutamate levels optimizes the 2HG-based monitoring of IDH1 mutations via MRS and represents a reliable clinical application for diagnosing IDH1 mutant gliomas.
AbstractList Mutations in the isocitrate dehydrogenase 1 (IDH1) gene that are frequently observed in low-grade glioma are strongly associated with the accumulation of 2-hydroxyglutarate (2HG), which is a valuable diagnostic and prognostic biomarker of IDH1 mutant glioma. However, conventional MR spectroscopy (MRS)-based noninvasive detection of 2HG is challenging. In this study, we aimed to determine the additional value of other metabolites in predicting IDH1 mutations with conventional MRS. Forty-seven patients with glioma underwent conventional single voxel short echo time MRS prior to surgery. A stereotactic navigation-guided operation was performed to resect tumor tissues in the center of the MRS voxel. MRS-based measurements of metabolites were validated with gas chromatography-mass spectrometry. We also conducted integrated analyses of glioma cell lines and clinical samples to examine the other metabolite levels and molecular findings in IDH1 mutant gliomas. A metabolomic analysis demonstrated higher levels of 2HG in IDH1 mutant glioma cells and surgical tissues. Interestingly, glutamate levels were significantly decreased in IDH1 mutant gliomas. Through an analysis of metabolic enzyme genes in glutamine pathways, it was shown that the expressions of branched-chain amino acid transaminase 1 were reduced and glutamate dehydrogenase levels were elevated in IDH1 mutant gliomas. Conventional MRS detection of glutamate and 2HG resulted in a high diagnostic accuracy (sensitivity 72%, specificity 96%) for IDH1 mutant glioma. IDH1 mutations alter glutamate metabolism. Combining glutamate levels optimizes the 2HG-based monitoring of IDH1 mutations via MRS and represents a reliable clinical application for diagnosing IDH1 mutant gliomas.
BACKGROUNDMutations in the isocitrate dehydrogenase 1 (IDH1) gene that are frequently observed in low-grade glioma are strongly associated with the accumulation of 2-hydroxyglutarate (2HG), which is a valuable diagnostic and prognostic biomarker of IDH1 mutant glioma. However, conventional MR spectroscopy (MRS)-based noninvasive detection of 2HG is challenging. In this study, we aimed to determine the additional value of other metabolites in predicting IDH1 mutations with conventional MRS.METHODSForty-seven patients with glioma underwent conventional single voxel short echo time MRS prior to surgery. A stereotactic navigation-guided operation was performed to resect tumor tissues in the center of the MRS voxel. MRS-based measurements of metabolites were validated with gas chromatography-mass spectrometry. We also conducted integrated analyses of glioma cell lines and clinical samples to examine the other metabolite levels and molecular findings in IDH1 mutant gliomas.RESULTSA metabolomic analysis demonstrated higher levels of 2HG in IDH1 mutant glioma cells and surgical tissues. Interestingly, glutamate levels were significantly decreased in IDH1 mutant gliomas. Through an analysis of metabolic enzyme genes in glutamine pathways, it was shown that the expressions of branched-chain amino acid transaminase 1 were reduced and glutamate dehydrogenase levels were elevated in IDH1 mutant gliomas. Conventional MRS detection of glutamate and 2HG resulted in a high diagnostic accuracy (sensitivity 72%, specificity 96%) for IDH1 mutant glioma.CONCLUSIONSIDH1 mutations alter glutamate metabolism. Combining glutamate levels optimizes the 2HG-based monitoring of IDH1 mutations via MRS and represents a reliable clinical application for diagnosing IDH1 mutant gliomas.
Author Takeuchi, Yukiko
Sato, Naoko
Kyotani, Katsusuke
Sakata, Junichi
Sasayama, Takashi
Yamamoto, Yusuke
Kohmura, Eiji
Nagashima, Hiroaki
Tanaka, Kazuhiro
Mizukawa, Katsu
Mukasa, Akitake
Hosoda, Kohkichi
Sasaki, Ryohei
Irino, Yasuhiro
Itoh, Tomoo
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ContentType Journal Article
Copyright The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. 2016
Copyright_xml – notice: The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
– notice: The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. 2016
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Issue 11
Keywords IDH1 mutation
glioma
2-hydroxyglutarate
glutamate
MR spectroscopy
Language English
License The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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PublicationTitle Neuro-oncology (Charlottesville, Va.)
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Snippet Mutations in the isocitrate dehydrogenase 1 (IDH1) gene that are frequently observed in low-grade glioma are strongly associated with the accumulation of...
BACKGROUNDMutations in the isocitrate dehydrogenase 1 (IDH1) gene that are frequently observed in low-grade glioma are strongly associated with the...
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StartPage 1559
SubjectTerms Adolescent
Adult
Aged
Aged, 80 and over
Basic and Translational Investigation
Biomarkers - metabolism
Brain Neoplasms - diagnosis
Brain Neoplasms - genetics
Brain Neoplasms - metabolism
Glioma - diagnosis
Glioma - genetics
Glioma - metabolism
Glutamate Dehydrogenase - metabolism
Glutamic Acid - metabolism
Glutarates - metabolism
Humans
Isocitrate Dehydrogenase - genetics
Magnetic Resonance Spectroscopy
Metabolomics
Middle Aged
Mutation
Sensitivity and Specificity
Transaminases - metabolism
Young Adult
Title Diagnostic value of glutamate with 2-hydroxyglutarate in magnetic resonance spectroscopy for IDH1 mutant glioma
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