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Krebs Cycle Metabolite Profiling for Identification and Stratification of Pheochromocytomas/Paragangliomas due to Succinate Dehydrogenase Deficiency
Open accessAbstract
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.
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“In 2008, mutation of SDH was discovered in cancers such as paraganglioma and pheochromocytoma cells124. Later, similar observations were made in gastrointestinal tumors, neuroblastomas, renal tumors, thyroid tumors, and testicular tumors125,126.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [124]
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Metadata
- Authors
- 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.
- Affiliations
- University Hospital Carl Gustav Carus (DE)
- University of Florence (IT)
- Radboud University Medical Center (NL)
- Hereditary Endocrine Cancer Group (A.A.C., M.R.), CNIO, Madrid, Spain
- Istituto Oncologico Veneto (IT)
- LMU Klinikum (DE)
- Charité – Universitätsmedizin Berlin (DE)
- 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
- Spanish National Cancer Research Centre (ES)
- Corresponding author
- Richter, Susan
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2014-10-01
- Volume
- 99
- Issue
- 10
- Pages
- 3903-3911
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC4184070
- OpenAlex
- W2116263600
- Cited by
- 135
- References
- 35
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 6 · 2023: 16 · 2022: 17 · 2021: 15 · 2020: 14 · 2019: 11 · 2018: 8 · 2017: 12 · 2016: 10 · 2015: 14 · 2014: 1
- FWCI
- 12.24
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Florence Research (University of Florence) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Padua Research Archive (University of Padova) (submittedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Health Sciences › Medicine › Oncology › Neuroblastoma Research and Treatments
- Keywords
- pheochromocytoma, paraganglioma, succinate dehydrogenase deficiency, SDHx mutations, Krebs cycle metabolites, SDHB mutation, metastasis, mutation detection, isocitrate, cis-aconitate
- MeSH terms
- Adolescent, Adrenal Gland Neoplasms, Adult, Aged, Citric Acid Cycle, Female, Follow-Up Studies, Fumarates, Humans, Male, Metabolic Diseases, Middle Aged, Paraganglioma, Pheochromocytoma, Sensitivity and Specificity, Succinate Dehydrogenase, Germ-Line Mutation, Succinic Acid, Young Adult
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