A new specific succinate-glutamate metabolomic hallmark in SDHx-related paragangliomas

PLoS One. 2013 Nov 27;8(11):e80539. doi: 10.1371/journal.pone.0080539. eCollection 2013.

Abstract

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 (1)H 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Glutamic Acid / metabolism*
  • Humans
  • Metabolomics* / methods
  • Models, Biological
  • Paraganglioma / genetics
  • Paraganglioma / metabolism*
  • Succinate Dehydrogenase / genetics
  • Succinate Dehydrogenase / metabolism*
  • Succinic Acid / metabolism*

Substances

  • Glutamic Acid
  • Succinic Acid
  • Succinate Dehydrogenase

Grants and funding

This work is part of the CARMeN project and was supported by grants from Région Alsace, Oséo, Communauté Urbaine de Strasbourg, Conseil Départemental du Bas-Rhin, Bruker BioSpin, University of Strasbourg and Strasbourg University Hospital. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.