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J Clin Endocrinol Metab. 2014 Oct;99(10):3903-11. doi: 10.1210/jc.2014-2151. Epub 2014 Jul 11.

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

Author information

1
Institute of Clinical Chemistry and Laboratory Medicine (S.R., M.P., N.Q., G.E.), University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307 Dresden, Germany; Department of Experimental and Clinical Biomedical Sciences "Mario Serio" (E.R., M.M.), University of Florence and Istituto Toscano Tumori, Viale Pieraccini 6, 50139 Florence, Italy; Department of Medicine (J.W.L., J.U.R., H.J.T.), Radboud University Nijmegen Medical Centre, Geert Grooteplein Zuid 8, 6525GA, Nijmegen, The Netherlands; Department of Medicine III (J.W.L., G.E.), University Hospital Dresden, Fetscherstrasse 74, 01307 Dresden, Germany; Hereditary Endocrine Cancer Group (A.A.C., M.R.), CNIO, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (A.A.C., M.R.), C/Melchor Fernández Almagro 3, 28029 Madrid, Spain; Veneto Institute of Oncology IRCCS (F.S., G.O.), Via Gattamelata 64, 35128 Padova, Italy; Medizinische Klinik and Poliklinik IV (F.B.), Ludwig-Maximilians-Universität München, Ziemssenstrasse 1, D-80336 Munich, Germany; Clinical Endocrinology (M.Q.), Campus Mitte, University Hospital Charité, Charitéplatz 1, 10117, Berlin, Germany; Eunice Kennedy Shriver National Institute of Child Health and Human Development (K.P.), National Institutes of Health, 10 Center Drive, MSC-1109, Bethesda, Maryland 20892-1109.

Abstract

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.

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.

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. Receiver-operating 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 specificity of 97% to identify 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.

PMID:
25014000
PMCID:
PMC4184070
DOI:
10.1210/jc.2014-2151
[Indexed for MEDLINE]
Free PMC Article

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