Noninvasive Quantification of 2-Hydroxyglutarate in Human Gliomas with IDH1 and IDH2 Mutations

Abstract

Mutations in the isocitrate dehydrogenase genes (IDH1/2) occur often in diffuse gliomas, where they are associated with abnormal accumulation of the oncometabolite 2-hydroxyglutarate (2-HG). Monitoring 2-HG levels could provide prognostic information in this disease, but detection strategies that are noninvasive and sufficiently quantitative have yet to be developed. In this study, we address this need by presenting a proton magnetic resonance spectroscopy ( 1 H-MRS) acquisition scheme that uses an ultrahigh magnetic field (!7T) capable of noninvasively detecting 2-HG with quantitative measurements sufficient to differentiate mutant cytosolic IDH1 and mitochondrial IDH2 in human brain tumors. Untargeted metabolomics analysis of in vivo 1 H-MRS spectra discriminated between IDHmutant tumors and healthy tissue, and separated IDH1 from IDH2 mutations. High-quality spectra enabled the quantification of neurochemical profiles consisting of at least eight metabolites, including 2-HG, glutamate, lactate, and glutathione in both tumor and healthy tissue voxels. Notably, IDH2 mutation produced more 2-HG than IDH1 mutation, consistent with previous findings in cell culture. By offering enhanced sensitivity and specificity, this scheme can quantitatively detect 2-HG and associated metabolites that may accumulate during tumor progression, with implications to better monitor patient responses to therapy. Cancer Res; 76(1); 43-49. Ó2015 AACR.

Isocitrate Dehydrogenase Mutations in Human Cancers: Physiopathologic Mechanisms and Therapeutic Targeting

“…39 Furthermore, in vitro and in vivo studies have shown that, in human gliomas, the IDH2 mutation leads to greater production of 2-HG than does the IDH1 mutation. 40 The presence of IDH1/2 mutations in gliomas has a prognostic impact: particularly, glioma patients with IDH-mutant tumors and low/normal Ki67 values have a significantly better prognosis than patients with IDH-WT gliomas showing high Ki67 labeling. 41 A large portion of IDH-mutant gliomas display ATRX nuclear loss (about 90% of astrocytomas with ATRX nuclear loss display IDH1/2 mutations and have an astrocytic morphology and a younger age of onset); in contrast, IDH-mutant gliomas with ATRX retention are strongly associated with loss of heterozygosity at 1p/19q and oligodendroglioma cell morphology.…”

“…52 Analyses of the prognostic impact of IDH mutations in AMLs emerged as a matter of great controversy, with contrasting evidence either supporting a positive, a negative or a neutral impact on AML prognosis (reviewed in 40). 40 However, a recent study based on a large set of AML patients provided clear evidence that overall survival for IDH-WT AMLs and IDH-mutated AMLs is comparable. 53 The large majority of leukemia-associated IDH1 and IDH2 mutations occur at the level of arginine residues present in the catalytic pocket of the enzyme, with the IDH1 mutations occurring mostly at arginine 132 (R132H or R132C or R132L or R132S or R132G) and those of IDH2 occurring mostly at arginine 172 or 140.…”

“…This problem can be avoided, however, by using ultrahigh magnetic fields (UHF; ≥7T) because the in vivo 1 H-MRS detection of 2-HG and other metabolites in this condition gains in signal-tonoise ratio and in spectral resolution, thus allowing the detection of small changes in 2-HG levels from small volumes of interest and with a higher specificity compared to techniques with the 3T magnetic field. 40 Using this improved technique, it was demonstrated that IDH2-mutant gliomas produced more 2-HG than IDH1-mutant tumors. 40 Importantly, this technology offers the opportunity to quantify the neurochemical profiles of at least eight metabolites, including 2-HG, glutamate, glutamine, lactate and glutathione, in both tumoral and normal tissues.…”

“…40 Using this improved technique, it was demonstrated that IDH2-mutant gliomas produced more 2-HG than IDH1-mutant tumors. 40 Importantly, this technology offers the opportunity to quantify the neurochemical profiles of at least eight metabolites, including 2-HG, glutamate, glutamine, lactate and glutathione, in both tumoral and normal tissues. 40 Other studies have confirmed the efficacy of 7T MRS for in vivo detection of 2-HG in brain tumors, with discrimination of this metabolite from glutamine, glutamate and GABA.…”

“…40 Importantly, this technology offers the opportunity to quantify the neurochemical profiles of at least eight metabolites, including 2-HG, glutamate, glutamine, lactate and glutathione, in both tumoral and normal tissues. 40 Other studies have confirmed the efficacy of 7T MRS for in vivo detection of 2-HG in brain tumors, with discrimination of this metabolite from glutamine, glutamate and GABA. 123 Finally, the in vivo imaging of IDH-mutant tumors may have a fundamental impact on the discovery of new drugs with inhibitory activity against these tumors.…”