Diagnostic value of glutamate with 2-hydroxyglutarate in magnetic resonance spectroscopy for<i>IDH1</i>mutant glioma

Nagashima, Hiroaki; Tanaka, Kazuhiro; Sasayama, Takashi; Irino, Yasuhiro; Sato, Naoko; Takeuchi, Kosei; Kyotani, Katsusuke; Mukasa, Akitake; Mizukawa, Katsu; Sakata, Junichi; Yamamoto, Yusuke; Hosoda, Kohkichi; Itoh, Tomoo; Sasaki, Ryohei; Kohmura, Eiji

doi:10.1093/neuonc/now090

Cited by 58 publications

(62 citation statements)

References 40 publications

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“…We could not find any pertinent study regarding glutamine metabolism in PCNSL, but myc-driven lymphomas are dependent on glutamine uptake and metabolism and the glutaminase splice variant C is enriched in lymphoma [31]. Recent work showed that the IDH1 mutation alters Glu metabolism and leads to a lower Glu concentration [32].…”

Section: Discussionmentioning

confidence: 87%

Myo-inositol concentration in MR spectroscopy for differentiating high grade glioma from primary central nervous system lymphoma

et al. 2017

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It is sometimes difficult to distinguish gliomas from other tumors on routine imaging. In this study, we assessed whether 3-T magnetic resonance spectroscopy (MRS) with LCModel software might be useful for discriminating glioma from other brain tumors, such as primary central nervous system lymphomas (PCNSLs) and metastatic tumors. A total of 104 cases of brain tumor (66 gliomas, 20 PCNSLs, 6 metastatic tumors, 12 other tumors) were preoperatively investigated with short echo time (35 ms) single-voxel 3-T MRS. LCModel software was used to evaluate differences in the absolute concentrations of choline, N-acetylaspartate, N-acetylaspartylglutamate, glutamate + glutamine, myo-inositol (mIns), and lipid. mIns levels were significantly increased in high-grade glioma (HGG) compared with PCNSL (p < 0.001). In multivariate logistic regression analysis, mIns was the best marker for differentiating HGG from PCNSL (p < 0.0001, odds ratio 1.9927, 95% confidence interval 1.3628-3.2637). Conventional MRS detection of mIns resulted in a high diagnostic accuracy (sensitivity, 64%; specificity, 90%; area under the receiver operator curve, 0.80) for HGG. The expression of inositol 3-phosphate synthase (ISYNA1) was significantly higher in gliomas than in PCNSLs (p < 0.05), suggesting that the increased level of mIns in glioma is due to high expression of ISYNA1, the rate-limiting enzyme in the mIns-producing pathway. In conclusion, noninvasive analysis of mIns using single-voxel MRS may be useful in distinguishing gliomas from other brain tumors, particularly PCNSLs.

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Section: Discussionmentioning

confidence: 87%

Myo-inositol concentration in MR spectroscopy for differentiating high grade glioma from primary central nervous system lymphoma

et al. 2017

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“…The TCA cycle has been implicated as a potential therapeutic target in IDH1-mutant gliomas [30] and our observation that the TCA cycle is compromised in IDH1 R132H cells supports this possibility. Altered metabolism in IDH1-mutant tumors can also be used for diagnostic purposes: high levels of 2-HG or decreased levels of glutamate can be detected using in vivo magnetic resonance spectroscopy (MRS) [31,32].…”

Section: Discussionmentioning

confidence: 99%

Mutant IDH1 Differently Affects Redox State and Metabolism in Glial Cells of Normal and Tumor Origin

Biedermann

Preussler

Conde

et al. 2019

Cancers

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IDH1R132H (isocitrate dehydrogenase 1) mutations play a key role in the development of low-grade gliomas. IDH1wt converts isocitrate to α-ketoglutarate while reducing nicotinamide adenine dinucleotide phosphate (NADP+), whereas IDH1R132H uses α-ketoglutarate and NADPH to generate the oncometabolite 2-hydroxyglutarate (2-HG). While the effects of 2-HG have been the subject of intense research, the 2-HG independent effects of IDH1R132H are still ambiguous. The present study demonstrates that IDH1R132H expression but not 2-HG alone leads to significantly decreased tricarboxylic acid (TCA) cycle metabolites, reduced proliferation, and enhanced sensitivity to irradiation in both glioblastoma cells and astrocytes in vitro. Glioblastoma cells, but not astrocytes, showed decreased NADPH and NAD+ levels upon IDH1R132H transduction. However, in astrocytes IDH1R132H led to elevated expression of the NAD-synthesizing enzyme nicotinamide phosphoribosyltransferase (NAMPT). These effects were not 2-HG mediated. This suggests that IDH1R132H cells utilize NAD+ to restore NADP pools, which only astrocytes could compensate via induction of NAMPT. We found that the expression of NAMPT is lower in patient-derived IDH1-mutant glioma cells and xenografts compared to IDH1-wildtype models. The Cancer Genome Atlas (TCGA) data analysis confirmed lower NAMPT expression in IDH1-mutant versus IDH1-wildtype gliomas. We show that the IDH1 mutation directly affects the energy homeostasis and redox state in a cell-type dependent manner. Targeting the impairments in metabolism and redox state might open up new avenues for treating IDH1-mutant gliomas.

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“…Furthermore, other genetic alterations including ATRX and TERT mutations as well as EGFR expression and PTEN mutations were not consistently assessed and a proportion of the midline tumors may have represented histone H3 K27M mutant DGs. It should also be noted that detection of accumulated 2-hydroxyglutarate seen in IDH -mutant tumors by MR spectroscopy is a promising new tool in the non-invasive characterization of glioma, however, as this requires optimized techniques not typically available on clinical scanners and was not routinely performed in our cohort, we did not assess this in our study [42–44]. As molecular testing becomes routine and our imaging techniques improve, future studies could address these limitations and image-guided tissue sampling could directly correlate imaging characteristics with histology and molecular markers.…”

Section: Discussionmentioning

confidence: 99%

MRI Features and IDH Mutational Status of Grade II Diffuse Gliomas: Impact on Diagnosis and Prognosis

Villanueva-Meyer

Wood

Choi

et al. 2018

American Journal of Roentgenology

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BACKGROUND Grade II diffuse gliomas (DGs) with isocitrate dehydrogenase (IDH) mutations are associated with better prognosis than their IDH-wildtype counterparts. We sought to determine MRI characteristics associated with IDH mutational status and whether MRI, combined with IDH mutational status, can better predict clinical outcomes of grade II DGs. METHODS Preoperative MRIs were retrospectively studied for qualitative tumor characteristics including location, extent, cortical involvement, margin sharpness, cystic component, mineralization or hemorrhage, and contrast enhancement. Quantitative diffusion and perfusion metrics were also assessed. Logistic regression and receiver operating characteristic analyses were used to evaluate the relationship between MRI features and IDH mutational status. The association between IDH mutational status, 1p19q co-deletion, MRI features, extent of resection, and clinical outcomes was assessed by Kaplan-Meier and Cox proportional hazards models. RESULTS Of 100 grade II DGs, 78 were IDH-mutant and 22 were IDH-wildtype. IDH-wildtype tumors were associated with older age, multifocality, brainstem involvement, lack of cystic change, and lower ADC. Multivariable regression showed that age >45 years as well as ADCmin, ADCmean, and ADCmax were independently associated with IDH mutational status. Of these, an ADCmin threshold of 0.9 × 10−3 mm2/s provided greatest sensitivity and specificity (91% and 76%, respectively) in defining IDH-wildtype grade II DGs. Combining low ADCmin with IDH-wildtype status conferred worse outcomes than IDH-wildtype status alone. CONCLUSION IDH-wildtype grade II DGs are associated with lower ADC and poor clinical outcomes. Combining IDH mutational status and ADC may allow for more accurate prediction of clinical outcomes in patients with grade II DGs.

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Diagnostic value of glutamate with 2-hydroxyglutarate in magnetic resonance spectroscopy forIDH1mutant glioma

Abstract: IDH1 mutations alter glutamate metabolism. Combining glutamate levels optimizes the 2HG-based monitoring of IDH1 mutations via MRS and represents a reliable clinical application for diagnosing IDH1 mutant gliomas.

Cited by 58 publications

References 40 publications

Myo-inositol concentration in MR spectroscopy for differentiating high grade glioma from primary central nervous system lymphoma

Myo-inositol concentration in MR spectroscopy for differentiating high grade glioma from primary central nervous system lymphoma

Mutant IDH1 Differently Affects Redox State and Metabolism in Glial Cells of Normal and Tumor Origin

MRI Features and IDH Mutational Status of Grade II Diffuse Gliomas: Impact on Diagnosis and Prognosis

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