The DOI matches its Crossref record; 35 of the 35 references it cites were found in a registry or an index.
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]
Citations
Cites
Succinate is an inflammatory signal that induces IL-1β through HIF-1α
Tannahill, G. M., Curtis, A. M., Adamik, J., Palsson-McDermott, E. M., McGettrick, A. F., Goel, G., Frezza, C., Bernard, N. J., Kelly, B., Foley, N. H., et al. (2013) · Nature · doi:10.1038/nature11986 · Cited by 4,176
Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase
Selak, M. A., Armour, S. M., MacKenzie, E. D., Boulahbel, H., Watson, D. G., Mansfield, K. D., Pan, Y., Simon, M. C., Thompson, C. B., & Gottlieb, E. (2005) · Cancer Cell · doi:10.1016/j.ccr.2004.11.022 · Cited by 2,108
Pollard, P. J., Brière, J. J., Alam, N. A., Barwell, J., Barclay, E., Wortham, N. C., Hunt, T., Mitchell, M., Olpin, S., Moat, S. J., et al. (2005) · Human Molecular Genetics · doi:10.1093/hmg/ddi227 · Cited by 865
2-hydroxyglutarate detection by magnetic resonance spectroscopy in IDH-mutated patients with gliomas
Choi, C., Ganji, S. K., DeBerardinis, R. J., Hatanpaa, K. J., Rakheja, D., Kovacs, Z., Yang, X.-L., Mashimo, T., Raisanen, J. M., Marin-Valencia, I., et al. (2012) · Nature Medicine · doi:10.1038/nm.2682 · Cited by 839
SDH mutations establish a hypermethylator phenotype in paraganglioma
Letouzé, E., Martinelli, C., Loriot, C., Burnichon, N., Abermil, N., Ottolenghi, C., Janin, M., Menara, M., Nguyen, A. T., Benit, P., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.04.018 · Cited by 776
Janeway, K. A., Kim, S. Y., Lodish, M., Nosé, V., Rustin, P., Gaal, J., Dahia, P. L. M., Liegl, B., Ball, E. R., Raygada, M., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1009199108 · Cited by 628
Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas.
Gimenez‐Roqueplo, A., Favier, J., Rustin, P., Rieubland, C., Crespin, M., Nau, V., Kien, P. K. V., Corvol, P. L., Plouin, P., & Jeunemaı̂tre, X. (2003) · PubMed · Cited by 542
Eisenhofer, G., Lenders, J. W. M., Siegert, G., Bornstein, S. R., Friberg, P., Milosevic, D., Mannelli, M., Linehan, W. M., Adams, K. T., Timmers, H. J. L. M., et al. (2011) · European Journal of Cancer · doi:10.1016/j.ejca.2011.07.016 · Cited by 375
Self-citationGermline SDHB Mutations and Familial Renal Cell Carcinoma
Ricketts, C. J., Woodward, E. R., Killick, P., Morris, M. R., Astuti, D., Latif, F., & Maher, E. R. (2008) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djn254 · Cited by 354
An Update on the Genetics of Paraganglioma, Pheochromocytoma, and Associated Hereditary Syndromes
Gimenez‐Roqueplo, A., Dahia, P. L. M., & Robledo, M. (2012) · Hormone and Metabolic Research · doi:10.1055/s-0031-1301302 · Cited by 289
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Glutamine reliance in cell metabolism
Yoo, H. C., Yu, Y. C., Sung, Y., & Han, J. M. (2020) · Experimental & Molecular Medicine · doi:10.1038/s12276-020-00504-8 · Cited by 1,021
Papathomas, T. G., Oudijk, L., Persu, A., Gill, A. J., van Nederveen, F. H., Tischler, A. S., Tissier, F., Volante, M., Matías‐Guiu, X., Smid, M., et al. (2015) · Modern Pathology · doi:10.1038/modpathol.2015.41 · Cited by 228
Self-citationCurrent Approaches and Recent Developments in the Management of Head and Neck Paragangliomas
Taïeb, D., Kaliski, A., Boedeker, C. C., Martucci, V. L., Fojo, T., Adler, J. R., & Pacák, K. (2014) · Endocrine Reviews · doi:10.1210/er.2014-1026 · Cited by 169
New treatment strategies for advanced-stage gastrointestinal stromal tumours
Klug, L. R., Khosroyani, H. M., Kent, J. D., & Heinrich, M. C. (2022) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-022-00606-4 · Cited by 148
SDHB-Deficient Cancers: The Role of Mutations That Impair Iron Sulfur Cluster Delivery
Saxena, N., Maio, N., Crooks, D. R., Ricketts, C. J., Yang, Y., Wei, M.-H., Fan, T. W. ‐., Lane, A. N., Sourbier, C., Singh, A., et al. (2015) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djv287 · Cited by 125
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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