THU612 SDHx Pheochromocytoma/Paraganglioma Has Elevation Of Arginine And Lysine Metabolites

Abstract Disclosure: H.K. Ghayee: None. S. Richter: None. N. Bechmann: None. S. Kalavalapalli: None. G. Joy: None. Y. Xu: None. K. Cusi: None. A. Tischler: None. J.F. Powers: None. F. Beuschlein: None. M. Robledo: None. S. Fliedner: None. M. Quinkler: None. M. Fassnacht: None. H. Timmers: None. K. Pacak: None. G. Eisenhofer: None. T.J. Garrett: None. Background: Pheochromocytomas and paragangliomas are rare neuroendocrine tumors that arise from the chromaffin cells of the adrenal medulla or sympathetic/parasympathetic paraganglia respectively. There are more than 25 genetic drivers identified in these tumors. These genetic mutations are categorized into the three main clusters. However, cluster 1 and cluster 2 comprise most of the known genes. Within cluster 1, SDHx mutations are associated with aggressive disease. To better understand the metabolic signature of these tumors, our group performed untargeted metabolomics of over 200 pheochromocytomas and paraganglioma tissue samples. Methods: Frozen tissues were processed and sent to the University of Florida and analyzed in 2 batches. Analysis was conducted using liquid chromatography high-resolution mass spectrometry with full blinding and randomization. Raw data were converted to mzXML and then processed using MZmine to identify features. Blank feature filtering was conducted to filter noise and very low abundant features. Metabolite identification was first conducted with reference to an in-house retention time library of 1200 metabolites and further identification was conducted by searching the human metabolome database. Statistical analysis was performed in R. Results: Comparing cluster 1 vs cluster 2, we observed an overall increase in purine metabolites specifically adenine, AMP, GMP, UMP, CMP, cytidine, and dihydrothymine in cluster 2. Arginine metabolism was lower in cluster 2, specifically dimethylarginine, citrulline, and N-methyl-L-arginine. Comparing SDHx vs cluster 1, we observed an overall increase in arginine metabolism with ornithine, citrulline, N-acetyl-ornithine, proline and hydroxy-proline. We also observed an increase in lysine metabolism in SDHx vs cluster 1 with lysine, N-acetyl-lysine, cadaverine, glutarate, 2-hydroxyglutarte, 2-oxoglutarate, succinate and trimethyllysine all being elevated. A decrease in serotonin in SDHx compared to cluster 1 was seen. Conclusion: Global metabolomic analysis of pheochromocytomas and paragangliomas has uncovered important pathways that drive the metabolic functions depending on the gene cluster. Most notably, arginine and lysine metabolites were increased in SDHx tumors. Presentation: Thursday, June 15, 2023