Glycine by MR spectroscopy is an imaging biomarker of glioma aggressiveness

Abstract

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>High-grade gliomas likely remodel the metabolic machinery to meet the increased demands for amino acids and nucleotides during rapid cell proliferation. Glycine, a non-essential amino acid and intermediate of nucleotide biosynthesis, may increase with proliferation. Non-invasive measurement of glycine by magnetic resonance spectroscopy (MRS) was evaluated as an imaging biomarker for assessment of tumor aggressiveness.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>We measured glycine, 2-hydroxyglutarate (2HG), and other tumor-related metabolites in 35 glioma patients using an MRS sequence tailored for co-detection of glycine and 2HG in gadolinium-enhancing and non-enhancing tumor regions on 3T MRI. Glycine and 2HG concentrations as measured by MRS were correlated with tumor cell proliferation (MIB-1 labeling index), expression of mitochondrial serine hydroxymethyltransferase (SHMT2), and glycine decarboxylase (GLDC) enzymes, and patient overall survival.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>Elevated glycine was strongly associated with presence of gadolinium enhancement, indicating more rapidly proliferative disease. Glycine concentration was positively correlated with MIB-1, and levels higher than 2.5 mM showed significant association with shorter patient survival, irrespective of isocitrate dehydrogenase status. Concentration of 2HG did not correlate with MIB-1 index. A high glycine/2HG concentration ratio, &amp;gt;2.5, was strongly associated with shorter survival (P &amp;lt; 0.0001). GLDC and SHMT2 expression were detectable in all tumors with glycine concentration, demonstrating an inverse correlation with GLDC.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>The data suggest that aggressive gliomas reprogram glycine-mediated one-carbon metabolism to meet the biosynthetic demands for rapid cell proliferation. MRS evaluation of glycine provides a non-invasive metabolic imaging biomarker that is predictive of tumor progression and clinical outcome.</jats:p> </jats:sec> <jats:sec> <jats:title>Key Points</jats:title> <jats:p>1. Glycine and 2-hydroxyglutarate in glioma patients are precisely co-detected using MRS at 3T.</jats:p> <jats:p>2. Tumors with elevated glycine proliferate and progress rapidly.</jats:p> <jats:p>3. A high glycine/2HG ratio is predictive of shortened patient survival.</jats:p> </jats:sec>

Non-Invasive Prediction of IDH Mutation in Patients with Glioma WHO II/III/IV Based on F-18-FET PET-Guided In Vivo 1H-Magnetic Resonance Spectroscopy and Machine Learning

“…In line with our results, Miyata et al had also shown previously a clear reduction of Gly in IDH-mutated glioma [40]. On the other hand, increased Gly levels and Gly/2-HG ratios have been associated with a more aggressive type of glioma with rapid progression and shorter patient survival [37]. Non-essential amino acids such as Gly are generated from or degraded to intermediates of glycolysis and the TCA cycle.…”

“…Different post-processing techniques have also been applied in various settings, mostly in a limited number of patients (e.g., 38 patients in Reference [35]). Interestingly, independent of 2-HG, peak alterations of other metabolites were frequently seen (e.g., Cho, Glu, Gly, glutathione, cystathionine [36][37][38]) and sometimes used to improve detection of IDH mutation status, for example, combination of 2-HG and Glu levels [39] The described techniques are frequently not suitable for clinical routine as they need extensive technical and personal capacities [24]. For example, ultra-high-field MRI (7T) [31,32] is only available at a few quaternary university hospitals but not in daily clinical practice.…”

“…Different post-processing techniques have also been applied in various settings, mostly in a limited number of patients (e.g., 38 patients in Reference [ 35 ]). Interestingly, independent of 2-HG, peak alterations of other metabolites were frequently seen (e.g., Cho, Glu, Gly, glutathione, cystathionine [ 36 , 37 , 38 ]) and sometimes used to improve detection of IDH mutation status, for example, combination of 2-HG and Glu levels [ 39 ]…”

Robust detection of oncometabolic aberrations by 1H–13C heteronuclear single quantum correlation in intact biological specimens

“…While here, we have demonstrated the utility of this technique for two specific metabolic aberrations caused by specific genomic alterations, this technique is applicable to typing of any other metabolites whether genetic or epigenetic in nature. For example, the amino acid glycine is elevated in poor prognosis cases of IDH1-mutant glioma patients 38 . We show that glycine is easily visualizable in the 1 H-13 C HSQC spectra of intact human GBMs in a manner that closely corresponds to the glycine levels as determined in extracts by mass spectroscopy (Supplementary Fig.…”

Measuring the metabolic evolution of glioblastoma throughout tumor development, regression, and recurrence with hyperpolarized magnetic resonance

“…Glycine is derived from serine in one-carbon metabolism to maintain redox balance through antioxidant production such as glutathione as well as to produce metabolites involved in purine nucleotide and lipid synthesis, all of which are important for cancer survival and proliferation (59). Glycine production through serine hydroxymethyltransferase (SHMT)- a transcriptional target of c-Myc (60)- has been implicated as a driver of cancer cell proliferation in glioma (61) and many other types of tumors (62–66).…”