Glycine by MR spectroscopy is an imaging biomarker of glioma aggressiveness

Tiwari Vivek, V. Daoud Elena, J. Hatanpaa Kimmo, Gao Ang, Zhang Song, An Zhongxu, K. Ganji Sandeep, M. Raisanen Jack, M. Lewis Cheryl, Askari Pegah, Baxter Jeannie, Levy Michael, Dimitrov Ivan, P. Thomas Binu, C. Pinho Marco, J. Madden Christopher, Pan Edward, R. Patel Toral, J. De Berardinis Ralph, A. Dean SherryE. Mickey Bruce, R. Malloy Craig, A. Maher Elizabeth, Choi Changho

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Background. 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. Methods. 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 nonenhancing 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. Results. 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, >2.5, was strongly associated with shorter survival (P < 0.0001). GLDC and SHMT2 expression were detectable in all tumors with glycine concentration, demonstrating an inverse correlation with GLDC. Conclusions. 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.

Original languageEnglish (US)
Pages (from-to)1018-1029
Number of pages12
JournalNeuro-oncology
Volume22
Issue number7
DOIs
StatePublished - Jul 1 2020

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

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