Abstract
BackgroundMutations in the isocitrate dehydrogenase enzyme are present in a majority of lower-grade gliomas and secondary glioblastomas. This mis-sense mutation results in the neomorphic reduction of isocitrate dehydrogenase resulting in an accumulation of the “oncometabolite” 2-hydroxyglutarate (2HG). Detection of 2HG can thus serve as a surrogate biomarker for these mutations, with significant translational implications including improved prognostication. Two dimensional localized correlated spectroscopy (2D L-COSY) at 7T is a highly-sensitive non-invasive technique for assessing brain metabolism. This study aims to assess tumor metabolism using 2D L-COSY at 7T for the detection of 2HG in IDH-mutant gliomas.MethodsNine treatment-naïve patients with suspected intracranial neoplasms were scanned at 7T MRI/MRS scanner using the 2D L-COSY technique. 2D-spectral processing and analyses were performed using a MATLAB-based reconstruction algorithm. Cross and diagonal peak volumes were quantified in the 2D L-COSY spectra and normalized with respect to the creatine peak at 3.0 ppm and quantified data were compared with previously-published data from six normal subjects. Detection of 2HG was validated using findings from immunohistochemical (IHC) staining in patients who subsequently underwent surgical resection.Results2HG was detected in both of the IDH-mutated gliomas (grade III Anaplastic Astrocytoma and grade II Diffuse Astrocytoma) and was absent in IDH wild-type gliomas and in a patient with breast cancer metastases. 2D L-COSY was also able to resolve complex and overlapping resonances including phosphocholine (PC) from glycerophosphocholine (GPC), lactate (Lac) from lipids and glutamate (Glu) from glutamine (Gln).ConclusionsThis study demonstrates the ability of 2D L-COSY to unambiguously detect 2HG in addition to other neuro metabolites. These findings may aid in establishing 2HG as a biomarker of malignant progression as well as for disease monitoring in IDH-mutated gliomas.
Highlights
Mutations in the isocitrate dehydrogenase enzyme are present in a majority of lower-grade gliomas and secondary glioblastomas
isocitrate dehydrogenase (IDH)-mutation status has taken on greater clinical significance in this era of molecular diagnostics, with recent major restructuring of central nervous system (CNS) tumors as published in the 2016 World Health Organization (WHO) classification [8]
Important is to understand the alteration in the glutamate (Glu), glutamine (Gln) and gamma-aminobutyric acid (GABA) cycle as Glu is involved in the cellular anabolic pathways and in facilitating tumor invasion [10]
Summary
Mutations in the isocitrate dehydrogenase enzyme are present in a majority of lower-grade gliomas and secondary glioblastomas This mis-sense mutation results in the neomorphic reduction of isocitrate dehydrogenase resulting in an accumulation of the “oncometabolite” 2-hydroxyglutarate (2HG). Glioma patients, whose lesions harbor IDH mutations are associated with better prognosis, are more sensitive to chemo-radiation therapy and demonstrate longer survival than those with wild-type IDH [4, 5]. These mis-sense mutations may confer the neomorphic ability to reduce isocitrate dehydrogenase, resulting in the accumulation of the “oncometabolite” 2-hydroxyglutarate (2HG) [6, 7] rather than its normal catalysis into α-ketoglutarate. Important is to understand the alteration in the glutamate (Glu), glutamine (Gln) and gamma-aminobutyric acid (GABA) cycle as Glu is involved in the cellular anabolic pathways and in facilitating tumor invasion [10]
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