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.