Selective Detection of the D-enantiomer of 2-Hydroxyglutarate in the CSF of Glioma Patients with Mutated Isocitrate Dehydrogenase.
Selective Detection of the D-enantiomer of 2-Hydroxyglutarate in the CSF of Glioma Patients with Mutated Isocitrate Dehydrogenase.
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DOI：
10.1158/1078-0432.ccr-15-2965
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发表时间：
2016-12-15
期刊：
影响因子：
--
通讯作者：
Van Meir EG
中科院分区：
文献类型：
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作者：
Kalinina J;Ahn J;Devi NS;Wang L;Li Y;Olson JJ;Glantz M;Smith T;Kim EL;Giese A;Jensen RL;Chen CC;Carter BS;Mao H;He M;Van Meir EG
d -2-羟基戊二酸盐（D-2HG）升高最近被认为是胶质瘤患者异柠檬酸脱氢酶（IDH）基因1和2突变的强制性副产物。本研究的目的是证明检测携带IDH基因点替换的胶质瘤患者脑脊液（CSF）中D-2HG升高水平的可行性。我们开发了一种基于质谱（MS）的平台来检测和量化胶质瘤患者脑脊液中2HG的D和l型。分析了三个独立的患者队列，包括来自84名患者的总共176份样本。采用经验得出的阈值0.69 μmol/L，采用D-和L- 2hg水平将患者分为IDH野生型或IDH突变组。使用该平台，观察到IDH突变型与野生型胶质瘤患者脑脊液中D-2HG平均增加17倍以上。野生型小鼠脑脊液中D-2HG含量平均值为0.427 μmol/L，突变型小鼠脑脊液中D-2HG含量平均值为7.439 μmol/L。受试者操作曲线的C统计量为0.938，检测D-2HG的灵敏度为84%，特异性为90%，准确度为89%。野生型患者脑脊液中D-和L-2HG水平随脑脊液抽吸位置（池血、脑室血、腰椎血）的不同而不同。我们的研究结果表明，IDH突变胶质瘤患者的脑脊液中含有更高水平的D-2HG，这可以通过基于ms的平台可靠地检测到。
Elevation in D-2-Hydroxyglutarate (D-2HG) has recently emerged as a mandatory byproduct of mutated Isocitrate Dehydrogenase (IDH) genes 1 and 2 in glioma patients. The goal of the present study was to demonstrate the feasibility of detection of elevated levels of D-2HG in the cerebrospinal fluid (CSF) of glioma patients that carry point substitutions in the IDH gene. We developed a mass spectrometry (MS)–based platform to detect and quantify the D- and L-forms of 2HG in the CSF of glioma patients. Three independent cohorts of patients were analyzed, comprising a total of 176 samples derived from 84 patients. The levels of D- and L-2HG were used to stratify patients into IDH wild-type or IDH-mutated groups using an empirically obtained threshold of 0.69 μmol/L. Using this platform, a greater than 17-fold mean increase in D-2HG was observed in the CSF of patients with IDH mutant versus wild-type gliomas. The means for the D-2HG levels in CSF were 0.427 μmol/L in wild-type and 7.439 μmol/L in mutant groups. The C statistic for the receiver operator curve was 0.938, with 84% sensitivity, 90% specificity, and 89% accuracy to detect D-2HG. The levels of D- and L-2HG in CSF from wild-type patients varied by location of CSF draw (cisternal>ventricular>lumbar). Our findings demonstrate that the CSF of patients harboring IDH mutant gliomas contain increased levels of D-2HG, which can be reliably detected with a MS-based platform.