Cystathionine as a marker for 1p/19q codeleted gliomas by in vivo magnetic resonance spectroscopy

Abstract

Background. Codeletion of chromosome arms 1p and 19q (1p/19q codeletion) highly benefits diagnosis and prognosis in gliomas. In this study, we investigated the effect of 1p/19q codeletion on cancer cell metabolism and evaluated possible metabolic targets for tailored therapies. Methods. We combined in vivo 1 H (proton) magnetic resonance spectroscopy (MRS) measurements in human gliomas with the analysis of a series of standard amino acids by liquid chromatography-mass spectroscopy (LC-MS) in human glioma biopsies. Sixty-five subjects with low-grade glioma were included in the study: 31 underwent the MRI/MRS examination, 47 brain tumor tissue samples were analyzed with LC-MS, and 33 samples were analyzed for gene expression with quantitative PCR. Additionally, we performed metabolic tracer experiments in cell models with 1p deletion. Results. We report the first in vivo detection of cystathionine by MRS in 1p/19q codeleted gliomas. Selective accumulation of cystathionine was observed in codeleted gliomas in vivo, in brain tissue samples, as well as in cells harboring heterozygous deletions for serine-and cystathionine-pathway genes located on 1p: phosphoglycerate dehydrogenase (PHGDH) and cystathionine gamma-lyase (CTH). Quantitative PCR analyses showed 40-50% lower expression of both PHGDH and CTH in 1p/19q codeleted gliomas compared with their non-codeleted counterparts. Conclusions. Our results provide strong evidence of a selective vulnerability of codeleted gliomas to serine and glutathione depletion and point to cystathionine as a possible noninvasive marker of treatment response. Key Points 1. This study represents the first in vivo detection of cystathionine by MRS. 2. Cystathionine accumulates selectively in 1p/19q codeleted gliomas.

In vivo 1H MRS detection of cystathionine in human brain tumors

“…The cystathionine concentration in gliomas ranged from 0.2 mM to 4.1 mM, as reported previously . Cystathionine was not detectable in normal brain tissue (Figure ).…”

“…The cystathionine signal at 2.72 ppm, as well as the 2HG signal at 4 ppm, are detected with no overlap with other metabolites when using edited MRS. The cystathionine signal was unexpectedly observed during our previous study focusing on the measurement of 2HG and identified as cystathionine based on the agreement with phantom and simulated spectra . Whereas the editing efficiency is optimal for 2HG detection using an editing pulse placed at 1.9 ppm, a significant improvement can be achieved with regard to cystathionine detection by tuning the editing pulse frequency.…”

“…Although cystathionine is also present in small concentrations in healthy tissue, in this study it was not detectable in normal brain tissue. We have recently shown that higher cystathionine levels are associated with 1p/19q codeletion and that cystathionine could represent a noninvasive marker of abnormal expression of cystathionine‐pathway genes such as cystathionine gamma‐lyase and cystathionine beta‐synthase . In a previous ex vivo study, the changed profile of cystathionine gamma‐lyase activity and cystathionine levels in gliomas were correlated, and both of them decreased with the increase of the grade of glioma malignancy .…”

“…Additional inclusion criteria were: age > 18 years, Karnofsky performance status > 60, and ability to provide written informed consent prior to inclusion in the study. These subjects were part of a larger cohort studied in our recent publication . The study was approved by the local ethical committee comité de protection des personnes (CPP‐Paris 6) in accordance with Declaration of Helsinki principles.…”

“…Edited MRS has been used in a number of studies to measure 2‐hydroxyglutarate (2HG), a noninvasive marker of mutations in isocitrate dehydrogenase 1 and 2 genes ( IDH1/2 ) in gliomas . Recently, we reported the detection of cystathionine using edited MRS and explored the clinical utility of noninvasive cystathionine quantification in tumors, showing evidence of an association between cystathionine accumulation and 1p/19q codeletion in gliomas with IDH mutations …”