Determination Of Isocitrate Dehydrogenase Status Research Articles

The role of 2-hydroxyglutarate magnetic resonance spectroscopy for the determination of isocitrate dehydrogenase status in lower grade gliomas versus glioblastoma: a systematic review and meta-analysis of diagnostic test accuracy.

Magnetic resonance spectroscopy (MRS) provides a non-invasive means of determining isocitrate dehydrogenase (IDH) status. Determination of 2-hydroxyglutarate (2-HG) presence through MRS is a means of determining IDH status; however, differences may be seen by grade. The goal of this paper is to perform a diagnostic test accuracy (DTA) meta-analysis on 2-HG MRS for IDH status in both lower-grade glioma (LGG) and glioblastoma (GBM) in preoperative patients. A systematic review and meta-analysis were performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses-Diagnostic Test Accuracy guidelines. Quality assessment was performed using the Quality Assessment of Diagnostic Accuracy Studies 2. The search was up to date as of 09/02/2021. Nine English-language journal articles were included. The meta-analysis found a pooled sensitivity of 93% (95% CI 58-99%) and specificity of 84% (95% CI 51-96%) for LGG (n= 181). For GBM (n= 77), the pooled sensitivity was 84% (95% CI 25.0-99%) and the specificity was 97% (95% CI 43-100%). 2-HG MRS shows promise as a non-invasive means of determining IDH status, with specificity higher for GBM and sensitivity higher for LGG. The wide confidence intervals are notable, however, in particular related to the small number of IDH-mutant GBM studied. Diagnostic heterogeneity was particularly present for LGG, and the hierarchical summary receiver operator curves showed poor predictive accuracy in both groups. For more conclusive results, diagnostic test accuracy statistics need to be quantified with larger studies and more deliberate study design.

Comparison of 2-hydroxyglutarate (2HG) levels in tissue and serum of isocitrate dehydrogenase (IDH)-mutated (MUT) versus wild-type (WT) gliomas.

2037 Background: IDH mutations are common in low-grade gliomas and confer significantly improved prognosis. IDH catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate, and subsequently to the oncometabolite 2HG. Mutant IDH leads to preferential accumulation of the R relative to the S enantiomer of 2HG. We analyzed the ratio of R to S enantiomers (rRS) in glioma tissues and matched serum samples, and correlated findings with IDH status, 1p19q codeletion status and survival. Methods: Fresh frozen glioma tissues and matched serum samples were obtained from the University of Toronto Brain Tumor Bank. IDH status was determined by immunohistochemistry and confirmed by 450K methylation profile or direct sequencing. 1p19q codeletion status was determined by loss-of-heterozygosity PCR analysis. R-2HG and S-2HG levels were quantified using HPLC tandem mass spectrometry coupled with a CHIROBIOTIC column. Results: Glioma tissues from 70 patients were analyzed – 52 with IDH MUT and 18 WT. 30 had matched serum samples. Using glioma tissues, rRS clearly distinguished MUT vs WT (median 574 vs 1.3, p < 1x10-9) with only three outliers. In contrast, rRS was not elevated in serum samples (median 1.5 vs 1.2, p = 0.13). Overall survival (OS) was significantly longer for MUT vs WT (median 178 vs 33 months, p < 1×10-7). Stratifying MUT by tissue rRS, median OS was 197, 178, 178 and 122 months for lowest to highest quartiles of rRS respectively. 1p19q codeletion status and tumor latency did not explain this trend, given rRS was similar in codeleted vs non-codeleted MUT, and similar in MUT operated < 3 vs ≥3 months from diagnosis. Progression-free survival results corresponded to OS. Conclusions: rRS from glioma tissues effectively differentiated MUT vs WT, whereas serum samples were unreliable. Unlike current methods, tissue rRS enables real-time determination of IDH status, and thus may guide clinical practice such as extent of surgical resection intraoperatively and upfront selection of adjuvant therapy. rRS potentially stratifies survival within MUT patients, providing detailed correlative information.