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首页> 外文期刊>Neoplasia: an international journal for oncology research >Metabolome Profiling by HRMAS NMR Spectroscopy of Pheochromocytomas and Paragangliomas Detects SDH Deficiency: Clinical and Pathophysiological Implications
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Metabolome Profiling by HRMAS NMR Spectroscopy of Pheochromocytomas and Paragangliomas Detects SDH Deficiency: Clinical and Pathophysiological Implications

机译：通过Hrmas NMR光谱的代谢物谱分析Pheochromocytomas和Paragangliomas检测SDH缺乏：临床和病理生理学意义

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Succinate dehydrogenase gene (SDHx) mutations increase susceptibility to develop pheochromocytomas/paragangliomas (PHEOs/PGLs). In the present study, we evaluate the performance and clinical applications of 1H high-resolution magic angle spinning (HRMAS) nuclear magnetic resonance (NMR) spectroscopy–based global metabolomic profiling in a large series of PHEOs/PGLs of different genetic backgrounds. Eighty-seven PHEOs/PGLs (48 sporadic/23 SDHx/7 von Hippel-Lindau/5 REarranged during Transfection/3 neurofibromatosis type 1/1 hypoxia-inducible factor 2α), one SDHD variant of unknown significance, and two Carney triad (CTr)–related tumors were analyzed by HRMAS-NMR spectroscopy. Compared to sporadic, SDHx-related PHEOs/PGLs exhibit a specific metabolic signature characterized by increased levels of succinate (P & .0001), methionine (P = .002), glutamine (P = .002), and myoinositol (P & .0007) and decreased levels of glutamate (P & .0007), regardless of their location and catecholamine levels. Uniquely, ATP/ascorbate/glutathione was found to be associated with the secretory phenotype of PHEOs/PGLs, regardless of their genotype (P & .0007). The use of succinate as a single screening test retained excellent accuracy in distinguishing SDHx versus non–SDHx-related tumors (sensitivity/specificity: 100/100%). Moreover, the quantification of succinate could be considered a diagnostic alternative for assessing SDHx-related mutations of unknown pathogenicity. We were also able, for the first time, to uncover an SDH-like pattern in the two CTr-related PGLs. The present study demonstrates that HRMAS-NMR provides important information for SDHx-related PHEO/PGL characterization. Besides the high succinate–low glutamate hallmark, SDHx tumors also exhibit high values of methionine, a finding consistent with the hypermethylation pattern of these tumors. We also found important levels of glutamine, suggesting that glutamine metabolism might be involved in the pathogenesis of SDHx-related PHEOs/PGLs.
机译：琥珀酸脱氢酶基因（SDHX）突变增加了开发嗜铬细胞瘤/伞菌（PHEOS / PGL）的易感性。在本研究中，我们评估了1H高分辨率魔角旋转（HRMA）核磁共振（NMR）核磁共振（NMR）光谱的全球代谢组分的性能和临床应用在大量的PHEOS / PGL中不同的遗传背景下。八十七个Pheos / PGL（48 Sporadic / 23 SDHX / 7 von Hippel-Lindau / 5在转染/ 3神经纤维瘤病型1/1缺氧诱导因子2α），一个SDHD变体，具有未知意义，以及两个Carney Triads（CTR通过HRMA-NMR光谱分析 - 重新化肿瘤。与散发性相比，SDHX相关的PHEOS / PGLS表现出特定的代谢特征，其特征在于琥珀酸盐的增加（P <.0001），甲硫氨酸（P = .002），谷氨酰胺（P = .002）和肌肌醇（P＆LT ;0007）和谷氨酸水平降低（P＆ .0007），无论其位置和儿茶酚胺水平如何。唯一地，发现ATP /抗坏血酸/谷胱甘肽与PHEOS / PGLS的分泌表型相关，无论其基因型如何（P <.0007）。在区分SDHX与非SDHX相关的肿瘤中，使用琥珀酸盐作为单一筛选试验的优异精度保留了优异的精度（敏感/特异性：100/100％）。此外，琥珀酸盐的定量可以被认为是评估未知致病性的SDHX相关突变的诊断替代物。我们也能够首次在两个CTR相关的PGL中揭开类似SDH样式的模式。本研究表明，HRMA-NMR为SDHX相关的PHEO / PGL表征提供了重要信息。除了高琥珀酸钠的谷氨酸标志外，SDHX肿瘤还表现出高值的蛋氨酸，一种与这些肿瘤的高甲基化模式一致的发现。我们还发现了重要的谷氨酰胺水平，表明谷氨酰胺代谢可能参与SDHX相关的PHEOS / PGL的发病机制。

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