A New Specific Succinate-Glutamate Metabolomic Hallmark in Sdhx-Related Paragangliomas

Alessio Imperiale (1, 2) , François-Marie Moussallieh (1, 2) , Frédéric Sebag (3) , Laurent Brunaud (4, 5) , Anne A. Barlier (6) , Karim Elbayed (1, 2) , Philippe Bachellier (7) , Bernard Goichot (8) , Karel Pacak (9) , Izzie-Jacques Namer (1, 2) , David Taieb (3)

1 ICube - Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie
2 FMTS - Fédération de Médecine Translationnelle de Strasbourg
3 Service de chirurgie générale et endocrinienne
4 Service de Chirurgie Digestive Hépatobiliaire et Endocrine [CHRU Nancy]
5 NGERE - Nutrition-Génétique et Exposition aux Risques Environnementaux
6 Laboratoire de Biochimie et de Biologie Moléculaire [Hôpital de la Conception - APHM]
7 Pôle des Pathologies Digestives Hépatiques et Transplantation [Hôpital Hautepierre-Strasbourg]
8 Département de Médecine Interne et Nutrition
9 NICHD - Eunice Kennedy Shriver National Institute of Child Health and Human Development

Paragangliomas (PGLs) are frequently associated with germline mutations in genes involved in energy metabolism. The purpose of the present study was to assess whether the tumor metabolomic profile of patients with hereditary and apparently sporadic PGLs enables the distinction of different subtypes of tumors. Twenty-eight unrelated patients with a histological diagnosis of PGLs were included in the present study. Twelve had germline mutations in SDHx genes (5 SDHB, 7 SDHD), 6 VHL, and 10 were apparently sporadic. Intact tumor samples from these patients (one per patient) were evaluated with 1H high-resolution magic angle spinning (HRMAS) NMR spectroscopy. SDHx-related tumors were characterized by an increase in succinate levels in comparison to other tumor subtypes (p = 0.0001 vs VHL and p = 0.000003 vs apparently sporadic). Furthermore, we found significantly lower values of glutamate in SDHx-related tumors compared to other subtypes (p = 0.0007 vs VHL and p = 0.003 vs apparently sporadic). Moreover, SDHx-tumors also exhibited lower values of ATP/ADP/AMP (p = 0.01) compared to VHL. VHL tumors were found to have the highest values of glutathione (GSH) compared to other tumors. Based on 4 metabolites (succinate, glutamate, GSH, and ATP/ADP/AMP), tumors were accurately distinguished from the other ones on both 3- and 2-class PLS-DA models. The present study shows that HRMAS NMR spectroscopy is a very promising method for investigating the metabolomic profile of various PGLs. The present data suggest the existence of a specific succinate-glutamate hallmark of SDHx PGLs. The relevance of such a metabolomic hallmark is expected to be very useful in designing novel treatment options as well as improving the diagnosis and follow-up of these tumors, including metastatic ones.

Domaines: Sciences du Vivant [q-bio]

Alessio Imperiale, François-Marie Moussallieh, Frédéric Sebag, Laurent Brunaud, Anne A. Barlier, et al.. A New Specific Succinate-Glutamate Metabolomic Hallmark in Sdhx-Related Paragangliomas. PLoS ONE, 2013, 8 (11), pp.e80539. ⟨10.1371/journal.pone.0080539⟩. ⟨hal-01699803⟩