Metabolome profiling by HRMAS NMR spectroscopy of pheochromocytomas and paragangliomas detects SDH deficiency: clinical and pathophysiological implications.
Metabolome profiling by HRMAS NMR spectroscopy of pheochromocytomas and paragangliomas detects SDH deficiency: clinical and pathophysiological implications.
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DOI：
10.1016/j.neo.2014.10.010
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发表时间：
2015-01
期刊：
影响因子：
4.8
通讯作者：
Taieb, david
中科院分区：
文献类型：
--
作者：
Imperiale, Alessio;Moussallieh, Franois-Marie;Roche, Philippe;Battini, Stephanie;Cicek, A. Ercument;Sebag, Frederic;Brunaud, Laurent;Barlier, Anne;Elbayed, Karim;Loundou, Anderson;Bachellier, Philippe;Goichot, Bernard;Stratakis, Constantine A.;Pacak, Karel;Namer, Izzie-Jacques;Taieb, david
琥珀酸脱氢酶基因(SDHx)突变增加了患嗜铬细胞瘤/副神经节瘤(PHEOS/PGLS)的易感性。在本研究中，我们评估了基于1H高分辨率魔角旋转(HRMAS)核磁共振(核磁共振)谱的全球代谢组谱在一大系列不同遗传背景的PHEO/PGL中的性能和临床应用。用高分辨核磁共振波谱分析了87例PHEO/PGL(48例散发性/23例SDHx/7例von Hippel-Lindau/5重排/3例神经纤维瘤病1/1缺氧诱导因子2α)、1例意义不明的SDHD变异体和2例与Carney triad相关的肿瘤。与散发性PHEO/PGL相比，SDHx相关的PHEO/PGL表现出特定的代谢特征，其特征是琥珀酸(P<；.0001)、蛋氨酸(P=.002)、谷氨酰胺(P=.002)和肌醇(P<；.0007)水平升高，而谷氨酸(P<；.0007)水平降低(P<；.0007)，无论其位置和儿茶酚胺水平如何。独一无二的是，发现ATP/抗坏血酸/谷胱甘肽与PHEOS/PGLS的分泌表型相关，与它们的基因型无关(P<；.0007)。在区分SDHx和非SDHx相关肿瘤方面，使用琥珀酸酯作为单一筛查试验保持了极高的准确性(灵敏度/特异度：100/100%)。此外，琥珀酸定量可以被认为是评估SDHx相关致病性未知突变的一种诊断替代方法。我们还首次在两个与CTR相关的PGL中发现了类似SDH的模式。本研究表明，HRMAS-核磁共振为SDHx相关的Pheo/PGL表征提供了重要的信息。除了高琥珀酸-低谷氨酸的特征外，SDHx肿瘤还表现出高蛋氨酸水平，这一发现与这些肿瘤的高甲基化模式一致。我们还发现了重要的谷氨酰胺水平，提示谷氨酰胺代谢可能参与了SDHx相关PHEOS/PGLS的发病机制。
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.
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影响因子：
3.9
作者：
Vicha A;Taieb D;Pacak K
通讯作者：
Pacak K
影响因子：
4.3
作者：
Dang, Chi V.
通讯作者：
Dang, Chi V.
影响因子：
11.5
作者：
Rao, Jyotsna U.;Engelke, Udo F. H.;Timmers, Henri J. L. M.
通讯作者：
Timmers, Henri J. L. M.
DOI：
10.1146/annurev.anchem.1.031207.113026
发表时间：
2008-01-01
影响因子：
8
作者：
Lindon, John C.;Nicholson, Jeremy K.
通讯作者：
Nicholson, Jeremy K.
影响因子：
2.9
作者：
Martínez-Bisbal, MC;Martí-Bonmatí, L;Celda, B
通讯作者：
Celda, B