title: Metabolome profiling by HRMAS NMR spectroscopy of pheochromocytomas and paragangliomas detects SDH deficiency: clinical and pathophysiological implications.
abstract: Succinate dehydrogenase gene (SDHx) mutations increase susceptibility to develop pheochromocytomas/paragangliomas (PHEOs/PGLs). In the present study, we evaluate the performance and clinical applications of (1)H high-resolution magic angle spinning (HRMAS) nuclear magnetic resonance (NMR) spectroscopy-based global metabolomic profiling in a large series of PHEOs/PGLs of different genetic backgrounds. Eighty-seven PHEOs/PGLs (48 sporadic/23 SDHx/7 von Hippel-Lindau/5 REarranged during Transfection/3 neurofibromatosis type 1/1 hypoxia-inducible factor 2α), one SDHD variant of unknown significance, and two Carney triad (CTr)-related tumors were analyzed by HRMAS-NMR spectroscopy. Compared to sporadic, SDHx-related PHEOs/PGLs exhibit a specific metabolic signature characterized by increased levels of succinate (P < .0001), methionine (P = .002), glutamine (P = .002), and myoinositol (P < .0007) and decreased levels of glutamate (P < .0007), regardless of their location and catecholamine levels. Uniquely, ATP/ascorbate/glutathione was found to be associated with the secretory phenotype of PHEOs/PGLs, regardless of their genotype (P < .0007). The use of succinate as a single screening test retained excellent accuracy in distinguishing SDHx versus non-SDHx-related tumors (sensitivity/specificity: 100/100%). Moreover, the quantification of succinate could be considered a diagnostic alternative for assessing SDHx-related mutations of unknown pathogenicity. We were also able, for the first time, to uncover an SDH-like pattern in the two CTr-related PGLs. The present study demonstrates that HRMAS-NMR provides important information for SDHx-related PHEO/PGL characterization. Besides the high succinate-low glutamate hallmark, SDHx tumors also exhibit high values of methionine, a finding consistent with the hypermethylation pattern of these tumors. We also found important levels of glutamine, suggesting that glutamine metabolism might be involved in the pathogenesis of SDHx-related PHEOs/PGLs.
authors.affiliation: Department of Biophysics and Nuclear Medicine, Hautepierre Hospital, University Hospitals of Strasbourg, Strasbourg, France; ICube, UMR 7357, University of Strasbourg/CNRS and FMTS, Faculty of Medicine, Strasbourg, France. Electronic address: alessio.imperiale@chru-strasbourg.fr.
authors.forename: Alessio
authors.initials: A
authors.lastname: Imperiale
authors.affiliation: ICube, UMR 7357, University of Strasbourg/CNRS and FMTS, Faculty of Medicine, Strasbourg, France.
authors.forename: François-Marie
authors.initials: FM
authors.lastname: Moussallieh
authors.affiliation: Integrative Structural and Chemical Biology (iSCB) and INT-3D Molecular Modeling Platform, Cancer Research Centre of Marseille, CNRS UMR7258, INSERM U1068, Institut Paoli Calmettes, Aix-Marseille University UM105, Marseille, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Roche
authors.affiliation: Department of Biophysics and Nuclear Medicine, Hautepierre Hospital, University Hospitals of Strasbourg, Strasbourg, France; ICube, UMR 7357, University of Strasbourg/CNRS and FMTS, Faculty of Medicine, Strasbourg, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Battini
authors.affiliation: Lane Center for Computational Biology, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA, USA.
authors.forename: A Ercument
authors.initials: AE
authors.lastname: Cicek
authors.affiliation: Department of Endocrine Surgery, La Timone University Hospital, Aix-Marseille University, Marseille, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Sebag
authors.affiliation: Department of Digestive, Hepato-Biliary and Endocrine Surgery, Brabois University Hospital, Nancy, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Brunaud
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, Conception Hospital, Aix-Marseille University, Marseille, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Barlier
authors.affiliation: ICube, UMR 7357, University of Strasbourg/CNRS and FMTS, Faculty of Medicine, Strasbourg, France.
authors.forename: Karim
authors.initials: K
authors.lastname: Elbayed
authors.affiliation: Department of Public Health, Aix-Marseille University, Marseille, France.
authors.forename: Anderson
authors.initials: A
authors.lastname: Loundou
authors.affiliation: Department of Visceral Surgery and Transplantation, Hautepierre Hospital, University Hospitals of Strasbourg, Strasbourg, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Bachellier
authors.affiliation: Department of Internal Medicine, Diabetes and Metabolic Disorders, Hautepierre Hospital, University Hospitals of Strasbourg, Strasbourg, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Goichot
authors.affiliation: Section on Genetics and Endocrinology (SEGEN), Program on Developmental Endocrinology and Genetics (PDEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
authors.affiliation: Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Karel
authors.initials: K
authors.lastname: Pacak
authors.affiliation: Department of Biophysics and Nuclear Medicine, Hautepierre Hospital, University Hospitals of Strasbourg, Strasbourg, France; ICube, UMR 7357, University of Strasbourg/CNRS and FMTS, Faculty of Medicine, Strasbourg, France.
authors.forename: Izzie-Jacques
authors.initials: IJ
authors.lastname: Namer
authors.affiliation: La Timone University Hospital, European Center for Research in Medical Imaging, Aix-Marseille University, Marseille, France.
authors.forename: David
authors.initials: D
authors.lastname: Taïeb
mesh_terms: D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D053858:Metabolic Networks and Pathways; D055442:Metabolome; D055432:Metabolomics / Q000379:methods; D008875:Middle Aged; D008958:Models, Molecular; D009154:Mutation; D019906:Nuclear Magnetic Resonance, Biomolecular; D010235:Paraganglioma / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D010673:Pheochromocytoma / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D049268:Positron-Emission Tomography; D017433:Protein Structure, Secondary; D012372:ROC Curve; D012680:Sensitivity and Specificity; D013385:Succinate Dehydrogenase / Q000737:chemistry / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D019802:Succinic Acid / Q000737:chemistry / Q000378:metabolism; D014057:Tomography, X-Ray Computed
chemical_list: D019802:Succinic Acid; D013385:Succinate Dehydrogenase