Noninvasive Quantification of 2-Hydroxyglutarate in Human Gliomas with IDH1 and IDH2 Mutations.
Noninvasive Quantification of 2-Hydroxyglutarate in Human Gliomas with IDH1 and IDH2 Mutations.
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DOI：
10.1158/0008-5472.can-15-0934
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发表时间：
2016-01-01
期刊：
影响因子：
11.2
通讯作者：
Ansorge O
中科院分区：
文献类型：
--
作者：
Emir UE;Larkin SJ;de Pennington N;Voets N;Plaha P;Stacey R;Al-Qahtani K;Mccullagh J;Schofield CJ;Clare S;Jezzard P;Cadoux-Hudson T;Ansorge O
异柠檬酸脱氢酶基因(IDH1/2)突变常发生在弥漫性胶质瘤中，与肿瘤代谢物2-羟基戊二酸(2-HG)的异常积聚有关。监测2-HG水平可以提供这种疾病的预后信息，但非侵入性和足够定量的检测策略尚未开发出来。在这项研究中，我们提出了一种质子磁共振波谱(1HMRS)采集方案，该方案使用超高磁场(≥7T)能够非侵入性地检测2-HG，并进行足以区分突变的细胞质IDH1和线粒体IDH2的定量测量。体内1HMRS谱的非靶向代谢组学分析区分了IDH突变肿瘤和健康组织，并将IDH1和IDH2突变分开。高质量的光谱能够量化肿瘤和健康组织体素中至少由8种代谢物组成的神经化学图谱，包括2-HG、谷氨酸、乳酸和谷胱甘肽。值得注意的是，IDH2突变比IDH1突变产生更多的2-HG，这与之前在细胞培养中的发现一致。通过提供更高的灵敏度和特异度，该方案可以定量检测肿瘤进展过程中可能积累的2-HG和相关代谢物，从而更好地监测患者对治疗的反应。
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 non-invasive and sufficiently quantitative have yet to be developed. In this study, we address this need by presenting a proton magnetic resonance spectroscopy (1H MRS) acquisition scheme that uses an ultra-high 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 1H MRS spectra discriminated between IDH mutant 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.