Institute for Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse, Dresden, Germany.
Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA.
Endocr Relat Cancer. 2023 May 11;30(6). doi: 10.1530/ERC-22-0376. Print 2023 Jun 1.
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.
代谢物代表了最高层次的生物信息。它们多样的化学性质使化学反应网络得以形成，为提供能量和构建块，从而维持生命的正常运转。通过使用质谱或核磁共振波谱学的靶向和非靶向分析方法对嗜铬细胞瘤/副神经节瘤（PPGL）进行定量分析，一直是为了改善诊断和治疗而努力的目标。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，儿茶酚胺和代谢产物的高产生率允许在血浆或尿液中特异性和敏感地检测到该疾病。其次，PPGL 与遗传性致病性变异（PV）有关，约 40%的病例存在这种变异，其中许多变异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）。这些遗传异常分别导致致癌代谢物琥珀酸或富马酸的过度产生，并且可以在肿瘤和血液中检测到。这种代谢失调可以在诊断上加以利用，目的是确保对基因变异的适当解释，特别是那些具有未知意义的变异，并通过定期对患者进行随访，促进早期肿瘤检测。此外，SDHx 和 FH PV 改变了细胞途径，包括 DNA 超甲基化、缺氧信号转导、氧化还原稳态、DNA 修复、钙信号转导、激酶级联和中央碳代谢。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，约 50%的转移性 PPGL 与 SDHx 中的种系 PV 有关。随着所有生物信息层次的组学技术的可用性，个性化诊断和治疗已近在咫尺。
