Diagnostic Value of Plasma and Urinary 2-Hydroxyglutarate to Identify Patients With Isocitrate Dehydrogenase-Mutated Glioma

Abstract

Background. Mutant isocitrate dehydrogenase (IDH) 1/2 enzymes can convert a-ketoglutarate into 2-hydroxyglutarate (2HG). The aim of the present study was to explore whether 2HG in plasma and urine could predict the presence of IDH1/2 mutations in patients with glioma. Materials and Methods. All patients had histological confirmation of glioma and a recent brain magnetic resonance imaging scan showing the neoplastic lesion. Plasma and urine samples were taken from all patients, and the 2HG concentrations were determined using liquid chromatography tandem mass spectrometry. Results. A total of 84 patients were enrolled: 38 with R132H-IDH1 mutatedand46with wild type.Among the38patients with mutant IDH1, 21 had high-grade glioma and 17 had low-grade glioma. Among the 46 patients with IDH1 wild-type glioma, 35 and 11 had high-and low-grade glioma, respectively. In all

Elevation of Urinary 2-Hydroxyglutarate in IDH-Mutant Glioma

“…Although it would appear intuitive that urine 2-HG levels would be comparatively elevated, as we have found, among a population of patients with IDH-mutant disease, the reason for the discordance with a previous report that observed lower urinary 2-HG levels in patients with IDH1-mutant compared with IDH-WT gliomas is unclear [28]. However, when comparing absolute 2-HG levels in both the circulating and urinary compartments, a significant difference in absolute urine 2-HG levels in patients with IDH-WT disease is noted between the two studies.The absolute plasma 2-HG values reported by Lombardi et al [28] (97.0 ng/mL for IDH-WT and 97.2 ng/mL for IDHmutant) were similar to values we detected in the serum, as were the creatinine-corrected median urinary 2-HG values in IDH1/2-mutant patients (4.6 mg/mL in Lombardi et al [28] vs. 2.926 mg/mL in our study).…”

“…However, when comparing absolute 2-HG levels in both the circulating and urinary compartments, a significant difference in absolute urine 2-HG levels in patients with IDH-WT disease is noted between the two studies.The absolute plasma 2-HG values reported by Lombardi et al [28] (97.0 ng/mL for IDH-WT and 97.2 ng/mL for IDHmutant) were similar to values we detected in the serum, as were the creatinine-corrected median urinary 2-HG values in IDH1/2-mutant patients (4.6 mg/mL in Lombardi et al [28] vs. 2.926 mg/mL in our study). However, there is a large disparity in absolute urinary 2-HG values in patients with IDH-WT glioma, with the prior study reporting a median value of 7.3 mg/mL versus 1.694 mg/mL in our study.…”

“…In our study, the mean serum 2-HG level was higher in IDH-mutant cases but did not reach statistical significance, a similar finding to a recent report of 16 serum samples (9 IDH1-R132H, 1 IDH2-R172K mutant, and 6 IDH-WT cases) [27]. Another recently published series [28] of 38 patients with IDH1 R132-mutant disease and 56 patients with IDH-WT mutations similarly did not detect a difference in plasma 2-HG levels, and absolute levels of circulating 2-HG were similar. However, their additional results did not correspond to ours, in that they did not note a significant increase in urine 2-HG levels among IDH-mutant patients, but did report a significant difference when they compared the ratio of plasma to urine 2-HG levels, with patients with IDH1 mutations displaying a significantly higher ratio, despite no difference in plasma 2-HG levels.…”

“…A study of 16 grade 2/3 glioma samples, of which 10 demonstrated IDH1 R132 mutations, found no correlation between serum 2-HG levels and the presence of IDH mutations [27]. Another, more recently published study of 38 patients with IDH1 R132H mutations and 46 patients with IDH-WT did not detect a difference in plasma or urine 2-HG levels but, interestingly, reported a significantly higher plasma-to-urine 2-HG ratio in patients with IDH1 mutations [28]. Given the prevalence and prognostic value of IDH mutations in gliomas, we sought to better characterize 2-HG levels in the serum, urine, and cerebrospinal fluid (CSF) in our larger patient population with IDH1 mutations.…”

Study protocol of a phase IB/II clinical trial of metformin and chloroquine in patients withIDH1-mutated orIDH2-mutated solid tumours

“…Conversely, serum 2HG levels correlate poorly with the IDH1/2 mutational status in glioma due to a limited BBB passage of D -2HG 56. Urine 2HG levels are higher in patients with IDH1 -mutated glioma than in patients with IDH1 wild-type glioma,57 although another study reported decreased 2HG levels in the urine of patients with IDH1 -mutated glioma and showed that the ratio of serum 2HG levels to urine 2HG levels is most predictive for the IDH1 mutational status in glioma 58. Most aforementioned measurements determined total 2HG levels and thus did not discriminate between the D -enantiomer of 2HG (which is specific for IDH1/2 mutations) and the L -enantiomer of 2HG (which is unspecific and is generated during hypoxia) 59 60.…”