Rapid diagnosis of IDH1-mutated gliomas by 2-HG detection with gas chromatography mass spectrometry.,Laboratory Investigation

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Rapid diagnosis of IDH1-mutated gliomas by 2-HG detection with gas chromatography mass spectrometry.
Laboratory Investigation ( IF 5.1 ) Pub Date : 2018-Dec-20 , DOI: 10.1038/s41374-018-0163-z
Hao Xu ₁ , Yu-Kun Xia ₂ , Chun-Jie Li ₂ , Jin-Ye Zhang ₂ , Ying Liu ₃ , Wei Yi ₄ , Zhi-Yong Qin ₁ , Liang Chen ₁ , Zhi-Feng Shi ₁ , Kai Quan ₁ , Zi-Xiao Yang ₁ , Kun-Liang Guan _{2,

5} , Yue Xiong _{2,

6} , Ho-Keung Ng _{7,

8} , Dan Ye ₂ , Wei Hua ₁ , Ying Mao _{1,

9}

Affiliation

Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China.
The Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
Department of Pathology, Shanghai Medical College, Fudan University, Shanghai, China.
China Novartis Institutes for BioMedical Research Co. Ltd, Shanghai, China.
Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Centre, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
State Key Laboratory of Southern China in Oncology, The Chinese University of Hong Kong, Hong Kong, China.
State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences, and The Collaborative Innovation Centre for Brain Science, Fudan University, Shanghai, China.

The metabolic genes encoding isocitrate dehydrogenase (IDH1, 2) are frequently mutated in gliomas. Mutation of IDH defines a distinct subtype of glioma and predicts therapeutic response. IDH mutation has a remarkable neomorphic activity of converting α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG), which is now commonly referred to as an oncometabolite and biomarker for gliomas. PCR-sequencing (n = 220), immunohistochemistry staining (IHC, n = 220), and gas chromatography mass spectrometry (GC-MS, n = 87) were applied to identify IDH mutation in gliomas, and the sensitivity and specificity of these strategies were compared. PCR-sequencing and IHC staining are reliable for retrospective assessment of IDH1 mutation in gliomas, but both methods usually take 1-2 days, which hinders their application for rapid diagnosis. GC-MS-based methods can detect 2-HG qualitatively and quantitatively, offering information on the IDH1 mutation status in gliomas with the sensitivity and specificity being 100%. Further optimization of the GC-MS based methodology (so called as the mini-column method) enabled us to determine 2-HG within 40 min in glioma samples without complex or time-consuming preparation. Most importantly, the ratio of 2-HG/glutamic acid was shown to be a reliable parameter for determination of mutation status. The mini-column method enables rapid identification of 2-HG, providing a promising strategy for intraoperative diagnosis of IDH1-mutated gliomas in the future.

中文翻译：

通过气相色谱质谱法检测 2-HG 快速诊断 IDH1 突变神经胶质瘤。

编码异柠檬酸脱氢酶 (IDH1, 2) 的代谢基因在神经胶质瘤中经常发生突变。IDH 的突变定义了一种独特的神经胶质瘤亚型并预测治疗反应。IDH 突变具有将 α-酮戊二酸 (α-KG) 转化为 2-羟基戊二酸 (2-HG) 的显着新变体活性，现在通常将其称为神经胶质瘤的致癌代谢物和生物标志物。应用 PCR 测序（n = 220）、免疫组织化学染色（IHC，n = 220）和气相色谱质谱法（GC-MS，n = 87）来鉴定胶质瘤中的 IDH 突变，以及这些策略的敏感性和特异性进行了比较。PCR 测序和 IHC 染色对于胶质瘤中 IDH1 突变的回顾性评估是可靠的，但这两种方法通常需要 1-2 天，这阻碍了它们在快速诊断中的应用。基于 GC-MS 的方法可以定性和定量检测 2-HG，提供胶质瘤中 IDH1 突变状态的信息，灵敏度和特异性均为 100%。进一步优化基于 GC-MS 的方法（所谓的小柱法）使我们能够在 40 分钟内测定神经胶质瘤样本中的 2-HG，而无需复杂或耗时的准备工作。最重要的是，2-HG/谷氨酸的比率被证明是确定突变状态的可靠参数。迷你柱法能够快速识别 2-HG，为未来 IDH1 突变神经胶质瘤的术中诊断提供了一种有前途的策略。进一步优化基于 GC-MS 的方法（所谓的小柱法）使我们能够在 40 分钟内测定神经胶质瘤样本中的 2-HG，而无需复杂或耗时的准备工作。最重要的是，2-HG/谷氨酸的比率被证明是确定突变状态的可靠参数。迷你柱法能够快速识别 2-HG，为未来 IDH1 突变神经胶质瘤的术中诊断提供了一种有前途的策略。进一步优化基于 GC-MS 的方法（所谓的小柱法）使我们能够在 40 分钟内测定神经胶质瘤样本中的 2-HG，而无需复杂或耗时的准备工作。最重要的是，2-HG/谷氨酸的比率被证明是确定突变状态的可靠参数。迷你柱法能够快速识别 2-HG，为未来 IDH1 突变神经胶质瘤的术中诊断提供了一种有前途的策略。

更新日期：2019-02-21

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