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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...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Blackwell Publishing Ltd
2019
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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. |
format | Online Article Text |
id | pubmed-6972524 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Blackwell Publishing Ltd |
record_format | MEDLINE/PubMed |
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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