Metabolomics in paraganglioma: applications and perspectives from genetics to therapy

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

Abstract

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.

Details

OriginalspracheEnglisch
Aufsatznummere220376
FachzeitschriftEndocrine-related cancer
Jahrgang30
Ausgabenummer6
PublikationsstatusVeröffentlicht - 1 Juni 2023
Peer-Review-StatusJa

Externe IDs

PubMedCentral PMC10228374
Scopus 85159740258
Mendeley 94aa9a90-bcd6-3514-ae97-514cb6595ed5
ORCID /0000-0002-6932-333X/work/142239678
ORCID /0000-0002-3549-2477/work/142244906

Schlagworte

Forschungsprofillinien der TU Dresden

Ziele für nachhaltige Entwicklung

Schlagwörter

  • Humans, Paraganglioma/genetics, Pheochromocytoma/genetics, Metabolomics, Succinate Dehydrogenase/genetics, Adrenal Gland Neoplasms/genetics, Catecholamines, fumarate hydratase, oncometabolites, nuclear magnetic resonance spectroscopy, mass spectrometry, succinate dehydrogenase