Metabolomics in paraganglioma: applications and perspectives from genetics to therapy.
Metabolomics in paraganglioma: applications and perspectives from genetics to therapy.
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DOI：
10.1530/erc-22-0376
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发表时间：
2023-06-01
影响因子：
3.9
通讯作者：
Ghayee, Hans K.
中科院分区：
文献类型：
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作者：
Richter, Susan;Garrett, Timothy J.;Bechmann, Nicole;Clifton-Bligh, Roderick J.;Ghayee, Hans K.
关键词：
代谢物代表了生物信息的最高层。它们不同的化学性质使化学反应网络成为可能，而这些化学反应对维持生命至关重要，因为它们提供了能量和构件。针对嗜铬细胞瘤/副神经节瘤(PPGL)，通过使用质谱学或核磁共振波谱的靶向和非靶向分析方法进行量化，以期提高诊断和治疗水平。PPGL具有独特的特征，为靶向治疗提供了有用的生物标志物和线索。首先，儿茶酚胺和甲肾上腺素的高产生率使人们能够在血浆或尿液中特异性和灵敏地检测到这种疾病。其次，在大约40%的病例中，PPGL与可遗传的致病变异(PV)有关，其中许多发生在编码酶的基因中，如琥珀酸脱氢酶(SDH)和富马酸水合酶(FH)。这些基因异常分别导致肿瘤和血液中肿瘤代谢物琥珀酸或富马酸的过量产生。这种代谢失调可以用于诊断，目的是确保对基因变异的适当解释，特别是那些意义未知的基因变异，并通过定期患者随访促进肿瘤的早期发现。此外，SDHx和FH PV改变了细胞通路，包括DNA高甲基化、低氧信号、氧化还原动态平衡、DNA修复、钙信号、激酶级联和中心碳代谢。针对这些特征的药物干预有可能发现针对转移性PPGL的治疗方法，其中约50%与SDHx中的生殖系PV有关。随着组学技术可用于所有层次的生物信息，个性化诊断和治疗近在咫尺。
Metabolites represent the highest layer of biological information. Their diverse chemical nature enables networks of chemical reactions that are critical for maintaining life by providing energy and building blocks. Quantification by targeted and untargeted analytical methods using either mass spectrometry or nuclear magnetic resonance spectroscopy has been applied to pheochromocytoma/paraganglioma (PPGL) with the long-term goal to improve diagnosis and therapy. PPGLs have unique features that provide useful biomarkers and clues for targeted treatments. First, high production rates of catecholamines and metanephrines allow for specific and sensitive detection of the disease in plasma or urine. Secondly, PPGLs are associated with heritable pathogenic variants (PVs) in around 40% of cases, many of which occur in genes encoding enzymes, such as succinate dehydrogenase (SDH) and fumarate hydratase (FH). These genetic aberrations lead to the overproduction of oncometabolites succinate or fumarate, respectively, and are detectable in tumors and blood. Such metabolic dysregulation can be exploited diagnostically, with the aim to ensure appropriate interpretation of gene variants, especially those with unknown significance, and facilitate early tumor detection through regular patient follow-up. Furthermore, SDHx and FH PV alter cellular pathways, including DNA hypermethylation, hypoxia signaling, redox homeostasis, DNA repair, calcium signaling, kinase cascades, and central carbon metabolism. Pharmacological interventions targeted toward such features have the potential to uncover treatments against metastatic PPGL, around 50% of which are associated with germline PV in SDHx. With the availability of omics technologies for all layers of biological information, personalized diagnostics and treatment is in close reach.
影响因子：
4.1
作者：
William D;Erdmann K;Ottemöller J;Mangelis A;Conrad C;Peitzsch M;Schröck E;Eisenhofer G;Zacharis A;Füssel S;Aust D;Klink B;Richter S
通讯作者：
Richter S
影响因子：
1.9
作者：
Kim, Edward;Wright, Michael J. P.;Sioson, Loretta;Novos, Talia;Gill, Anthony J.;Benn, Diana E.;White, Christopher;Dwight, Trisha;Clifton-Bligh, Roderick J.
通讯作者：
Clifton-Bligh, Roderick J.
影响因子：
4.1
作者：
通讯作者：
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