NIMG-13. GLYCINE IS A METABOLIC BIOMARKER OF MALIGNANCY IN GLIOMAS: IN VIVO MAGNETIC RESONANCE SPECTROSCOPY STUDY

Abstract

Abstract Malignant tumors reprogram cellular metabolism, resulting in altered concentration of some metabolites. We measured glycine (GLY) and 2-hydroxyglutarate (2HG) in 37 adult subjects with gliomas noninvasively using proton magnetic resonance spectroscopy and examined their association with immunochemical analyses of tumor biopsies and overall patient survival. MRS data were acquired using optimized point-resolved spectroscopy (PRESS TE 97ms) at 3T and the millimolar concentrations of metabolites were estimated with reference to water. The GLY concentration was positively correlated with MIB-1 proliferation index (p=1.7×10−7). The GLY estimation was inversely correlated with expression of glycine decarboxylase (GLDC) (p=0.02), without showing significant correlation with expression of serine hydroxymethyltransferase 2 (SHMT2). There was a strong association between elevated GLY and breakdown of blood-brain barrier, as indicated by higher GLY in post-gadolinium enhancing tumors than in non-enhancing tumors (p=10−6). In contrast, 2HG did not show significant correlation with MIB-1 index or post-gadolinium enhancement. In Kaplan-Meier survival analysis, patients with GLY level above 2.5 mM were significantly associated with poor survival (log-rank p value 0.003; median survival 8.8 months), compared to those with GLY level below 2.5 mM. The hazard ratio of the high-GLY tumors with respect to the low-GLY tumors was 6.7. 2HG level lower than a detection threshold (1 mM), which may represent IDH wildtype tumors, was associated with poor survival (p=0.01). In addition, we performed Kaplan-Meier analysis for the GLY-to-2HG ratio. 2HG estimates less than 1 mM were put as unity. Tumors with GLY/2HG > 2 showed strong association with poor survival (p=5.2×10−9; medial survival 5.4 months), with a 12-fold higher hazard rate compared to those with GLY/2HG < 2. Together, our data suggest that GLY-mediated one-carbon metabolism may underlie rapid cell proliferation in malignant gliomas and that elevation of GLY provides a noninvasive imaging biomarker predictive of cell proliferation and patient outcome.