Metabolome Profiling by HRMAS NMR Spectroscopy of Pheochromocytomas and Paragangliomas Detects SDH Deficiency: Clinical and Pathophysiological Implications
Year: 2015
Type: article
Study design: Observational Study
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.
Source: Neoplasia
Institutions: Centre National de la Recherche Scientifique, Laboratoire des Sciences de l'Ingénieur, de l'Informatique et de l'Imagerie, Hôpitaux Universitaires de Strasbourg, Hôpital d'Hautepierre, Université de Strasbourg, Inserm, Aix-Marseille Université, Institut de Neurosciences de la Timone, Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, Biomedtech Facilities, Carnegie Mellon University, Hôpital de la Timone, Centre Hospitalier Régional et Universitaire de Nancy, Nutrition-Génétique et Exposition aux Risques Environnementaux, Université de Lorraine, Hôpital de la Conception, National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Centre Européen de Recherche en Imagerie Médicale
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,406
Funder: Conseil Régional d'Alsace
OpenAlex ID: W2015349680