Krebs cycle metabolite profiling for identification and stratification of pheochromocytomas/paragangliomas due to succinate dehydrogenase deficiency

Susan Richter, Mirko Peitzsch, Elena Rapizzi, Jacques W. Lenders, Nan Qin, Aguirre A. De Cubas, Francesca Schiavi, Jyotsna U. Rao, Felix Beuschlein, Marcus Quinkler, Henri J. Timmers, Giuseppe Opocher, Massimo Mannelli, Karel Pacak, Mercedes Robledo, Graeme Eisenhofer

Research output: Contribution to journalArticle

Abstract

Design, Setting, and Patients: PPGL tumor specimens from 233 patients, including 45 with SDHx mutations, were provided from eight tertiary referral centers for mass spectrometric analyses of Krebs cycle metabolites.

Context: Mutations of succinate dehydrogenase A/B/C/D genes (SDHx) increase susceptibility to development of pheochromocytomas and paragangliomas (PPGLs), with particularly high rates of malignancy associated with SDHB mutations.

Objective: We assessed whether altered succinate dehydrogenase product-precursor relationships, manifested by differences in tumor ratios of succinate to fumarate or other metabolites, might aid in identifying and stratifying patients with SDHx mutations.

Main Outcome Measure: Diagnostic performance of the succinate:fumarate ratio for identification of pathogenic SDHx mutations.

Results: SDH-deficient PPGLs were characterized by 25-fold higher succinate and 80% lower fumarate, cis-aconitate, and isocitrate tissue levels than PPGLs without SDHx mutations. Receiveroperating characteristic curves for use of ratios of succinate to fumarate or to cis-aconitate and isocitrate to identify SDHx mutations indicated areas under curves of 0.94 to 0.96; an optimal cut-off of 97.7 for the succinate:fumarate ratio provided a diagnostic sensitivity of 93% at a specificityof 97% toidentify SDHX-mutated PPGLs. Succinate:fumarate ratios were higher in both SDHB-mutated and metastatic tumors than in those due to SDHD/C mutations or without metastases.

Conclusions: Mass spectrometric-based measurements of ratios of succinate:fumarate and other metabolites in PPGLs offer a useful method to identify patients for testing of SDHx mutations, with additional utility to quantitatively assess functionality of mutations and metabolic factors responsible for malignant risk.

Original languageEnglish
Pages (from-to)3903-3911
Number of pages9
JournalJournal of Clinical Endocrinology and Metabolism
Volume99
Issue number10
DOIs
Publication statusPublished - Oct 1 2014

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology
  • Biochemistry, medical
  • Endocrinology, Diabetes and Metabolism
  • Medicine(all)

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    Richter, S., Peitzsch, M., Rapizzi, E., Lenders, J. W., Qin, N., De Cubas, A. A., Schiavi, F., Rao, J. U., Beuschlein, F., Quinkler, M., Timmers, H. J., Opocher, G., Mannelli, M., Pacak, K., Robledo, M., & Eisenhofer, G. (2014). Krebs cycle metabolite profiling for identification and stratification of pheochromocytomas/paragangliomas due to succinate dehydrogenase deficiency. Journal of Clinical Endocrinology and Metabolism, 99(10), 3903-3911. https://doi.org/10.1210/jc.2014-2151