IDH1 R132H Mutation Generates a Distinct Phospholipid Metabolite Profile in Glioma
IDH1 R132H Mutation Generates a Distinct Phospholipid Metabolite Profile in Glioma
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DOI：
10.1158/0008-5472.can-14-0008
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发表时间：
2014-09-01
期刊：
影响因子：
11.2
通讯作者：
Heerschap, Arend
中科院分区：
文献类型：
--
作者：
Esmaeili, Morteza;Hamans, Bob C.;Heerschap, Arend
许多胶质瘤患者在异柠檬酸脱氢酶基因IDH 1中具有特异性突变，这与相对较好的预后相关。IDH 1突变的肿瘤产生癌代谢产物2-羟基戊二酸。由于IDH 1也调节几种导致脂质合成的途径，我们假设IDH 1突变型肿瘤具有改变的磷脂代谢产物谱，这将影响肿瘤病理生物学。为了研究这一假设，我们在四个人胶质瘤的小鼠异种移植模型中进行了P-31-MRS成像，其中一个含有IDH 1-R132 H突变。IDH 1突变型肿瘤的P-31-MR谱显示出与三种IDH 1野生型肿瘤不同的模式，其特征在于磷酸乙醇胺水平降低和甘油磷酸胆碱水平升高。这种光谱轮廓通过肿瘤提取物的离体分析得到证实，并且还通过P-31高分辨率魔角旋转光谱在IDH 1突变肿瘤的人类手术活检中观察到。通过过表达IDH 1或IDH 1-R132 H的细胞提取物的体外P-31-NMR确定该谱对IDH 1-R132 H突变的特异性。总的来说，我们的研究结果提供了IDH 1-R132 H突变改变神经胶质瘤中涉及磷酸乙醇胺和甘油磷酸胆碱的磷脂代谢的证据。这些新的非侵入性生物标志物可以帮助识别突变和研究针对IDH 1突变胶质瘤异常代谢的新治疗方法。(C)2014年AACR。
Many patients with glioma harbor specific mutations in the isocitrate dehydrogenase gene IDH1 that associate with a relatively better prognosis. IDH1-mutated tumors produce the oncometabolite 2-hydroxyglutarate. Because IDH1 also regulates several pathways leading to lipid synthesis, we hypothesized that IDH1-mutant tumors have an altered phospholipid metabolite profile that would impinge on tumor pathobiology. To investigate this hypothesis, we performed P-31-MRS imaging in mouse xenograft models of four human gliomas, one of which harbored the IDH1-R132H mutation. P-31-MR spectra from the IDH1-mutant tumor displayed a pattern distinct from that of the three IDH1 wild-type tumors, characterized by decreased levels of phosphoethanolamine and increased levels of glycerophosphocholine. This spectral profile was confirmed by ex vivo analysis of tumor extracts, and it was also observed in human surgical biopsies of IDH1-mutated tumors by P-31 high-resolution magic angle spinning spectroscopy. The specificity of this profile for the IDH1-R132H mutation was established by in vitro P-31-NMR of extracts of cells overexpressing IDH1 or IDH1-R132H. Overall, our results provide evidence that the IDH1-R132H mutation alters phospholipid metabolism in gliomas involving phosphoethanolamine and glycerophosphocholine. These new noninvasive biomarkers can assist in the identification of the mutation and in research toward novel treatments that target aberrant metabolism in IDH1-mutant glioma. (C) 2014 AACR.