Krebs cycle metabolite profiling for identification and stratification of pheochromocytomas/paragangliomas due to succinate dehydrogenase deficiency
Publication year
2014Source
Journal of Clinical Endocrinology and Metabolism, 99, 10, (2014), pp. 3903-11ISSN
Publication type
Article / Letter to editor
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Organization
Internal Medicine
Journal title
Journal of Clinical Endocrinology and Metabolism
Volume
vol. 99
Issue
iss. 10
Page start
p. 3903
Page end
p. 11
Subject
Radboudumc 16: Vascular damage RIHS: Radboud Institute for Health Sciences; Radboudumc 16: Vascular damage RIMLS: Radboud Institute for Molecular Life SciencesAbstract
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.
This item appears in the following Collection(s)
- Academic publications [238426]
- Faculty of Medical Sciences [90359]
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