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Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers

Succinate dehydrogenase (SDH) mutations lead to the accumulation of succinate, which acts as an oncometabolite. Germline SDHx mutations predispose to paraganglioma (PGL) and pheochromocytoma (PCC), as well as to renal cell carcinoma and gastro‐intestinal stromal tumors. The SDHx genes were the first...

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Autores principales: Eijkelenkamp, Karin, Osinga, Thamara E., Links, Thera P., van der Horst‐Schrivers, Anouk N.A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Blackwell Publishing Ltd 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6972524/
https://www.ncbi.nlm.nih.gov/pubmed/30977114
http://dx.doi.org/10.1111/cge.13553
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author Eijkelenkamp, Karin
Osinga, Thamara E.
Links, Thera P.
van der Horst‐Schrivers, Anouk N.A.
author_facet Eijkelenkamp, Karin
Osinga, Thamara E.
Links, Thera P.
van der Horst‐Schrivers, Anouk N.A.
author_sort Eijkelenkamp, Karin
collection PubMed
description Succinate dehydrogenase (SDH) mutations lead to the accumulation of succinate, which acts as an oncometabolite. Germline SDHx mutations predispose to paraganglioma (PGL) and pheochromocytoma (PCC), as well as to renal cell carcinoma and gastro‐intestinal stromal tumors. The SDHx genes were the first tumor suppressor genes discovered which encode for a mitochondrial enzyme, thereby supporting Otto Warburg's hypothesis in 1926 that a direct link existed between mitochondrial dysfunction and cancer. Accumulation of succinate is the hallmark of tumorigenesis in PGL and PCC. Succinate accumulation inhibits several α‐ketoglutarate dioxygenases, thereby inducing the pseudohypoxia pathway and causing epigenetic changes. Moreover, SDH loss as a consequence of SDHx mutations can lead to reprogramming of cell metabolism. Metabolomics can be used as a diagnostic tool, as succinate and other metabolites can be measured in tumor tissue, plasma and urine with different techniques. Furthermore, these pathophysiological characteristics provide insight into therapeutic targets for metastatic disease. This review provides an overview of the pathophysiology and clinical implications of oncometabolite succinate in SDHx mutations.
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spelling pubmed-69725242020-01-27 Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers Eijkelenkamp, Karin Osinga, Thamara E. Links, Thera P. van der Horst‐Schrivers, Anouk N.A. Clin Genet Reviews Succinate dehydrogenase (SDH) mutations lead to the accumulation of succinate, which acts as an oncometabolite. Germline SDHx mutations predispose to paraganglioma (PGL) and pheochromocytoma (PCC), as well as to renal cell carcinoma and gastro‐intestinal stromal tumors. The SDHx genes were the first tumor suppressor genes discovered which encode for a mitochondrial enzyme, thereby supporting Otto Warburg's hypothesis in 1926 that a direct link existed between mitochondrial dysfunction and cancer. Accumulation of succinate is the hallmark of tumorigenesis in PGL and PCC. Succinate accumulation inhibits several α‐ketoglutarate dioxygenases, thereby inducing the pseudohypoxia pathway and causing epigenetic changes. Moreover, SDH loss as a consequence of SDHx mutations can lead to reprogramming of cell metabolism. Metabolomics can be used as a diagnostic tool, as succinate and other metabolites can be measured in tumor tissue, plasma and urine with different techniques. Furthermore, these pathophysiological characteristics provide insight into therapeutic targets for metastatic disease. This review provides an overview of the pathophysiology and clinical implications of oncometabolite succinate in SDHx mutations. Blackwell Publishing Ltd 2019-05-06 2020-01 /pmc/articles/PMC6972524/ /pubmed/30977114 http://dx.doi.org/10.1111/cge.13553 Text en © 2019 The Authors. Clinical Genetics published by John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Reviews
Eijkelenkamp, Karin
Osinga, Thamara E.
Links, Thera P.
van der Horst‐Schrivers, Anouk N.A.
Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers
title Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers
title_full Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers
title_fullStr Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers
title_full_unstemmed Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers
title_short Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers
title_sort clinical implications of the oncometabolite succinate in sdhx‐mutation carriers
topic Reviews
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6972524/
https://www.ncbi.nlm.nih.gov/pubmed/30977114
http://dx.doi.org/10.1111/cge.13553
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