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Succinate dehydrogenase (SDH) and mitochondrial driven neoplasia
Abstract
The genes for the succinate dehydrogenase (SDH) subunits SDHA, SDHB, SDHC and SDHD are encoded in the autosome. The proteins are assembled in the mitochondria to form the mitochondrial complex 2, a key respiratory enzyme which links the Krebs cycle and the electron transport chain. Thirty percent of phaeochromocytoma and paraganglioma (PHEO/PGL) are hereditary and perhaps as many as half of these familial cases are caused by germline mutations of the SDH subunits. Negative immunohistochemical staining for the SDHB subunit identifies PHEO/PGL associated with germline mutation of any of the mitochondrial complex 2 components and can be used to triage formal genetic testing of all PHEO/PGL for SDH mutations. PHEO/PGL associated with SDHA mutation also show negative staining for SDHA as well as SDHB.A unique subgroup of gastrointestinal stromal tumours (GISTs) are driven by mitochondrial complex 2 dysfunction. These SDH deficient GISTs can also be definitively identified by negative staining for SDHB and show distinct clinical and morphological features including frequent onset in childhood and young adulthood, gastric location, a tendency to multifocality, absence of KIT and PDGFRA mutations, a prognosis not predicted by size and mitotic rate and a tendency to indolent behaviour of metastases. Some of these SDH deficient GISTs are driven by classical SDH mutations, but the precise mechanisms of tumourigenesis in many (including those associated with the Carney triad) remain unknown. Germline SDHB mutation is associated with a newly recognised type of renal carcinoma which commonly but not always demonstrates distinctive morphology and can also be recognised by negative staining for SDHB.Immunohistochemistry for SDHB therefore has emerged as a useful tool to recognise these distinct neoplasias driven by mitochondrial complex 2 dysfunction and to triage formal genetic testing for the associated syndromes.
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“Germ-line mutations in all Sdh subunit genes can cause mitochondrial disease and tumor susceptibility syndromes (Gill, 2012).”
From SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways (2013) · cites this paper as Gill, 2012
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“It was only after these first reports that germline mutation of SDHAF2 (previously called SDH5) and SDHA were shown to be associated with PHEO/PGL.(18,19) The PHEO/PGL associated with these mutations have now been shown to also demonstrate negative staining for SDHB.”
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Metadata
- Authors
- Gill, A. J.
- Affiliations
- The University of Sydney (AU)
- Corresponding author
- Gill, Anthony J.
- ORCID
- Gill, Anthony J.
- Venue
- Pathology
- Publisher
- Elsevier BV
- Published
- 2012-06
- Volume
- 44
- Issue
- 4
- Pages
- 285-292
- ISSN
- 0031-3025 (ISSN-L)
- OpenAlex
- W2156718948
- Cited by
- 215
- References
- 46
- Citations by year
- 2026: 9 · 2025: 15 · 2024: 11 · 2023: 13 · 2022: 15 · 2021: 22 · 2020: 14 · 2019: 11 · 2018: 16 · 2017: 21 · 2016: 17 · 2015: 19 · 2014: 18 · 2013: 11 · 2012: 3
- FWCI
- 3.15
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Pathology (publishedVersion)
- PubMed (publishedVersion)
- 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 › Gastroenterology › Gastrointestinal Tumor Research and Treatment
- Keywords
- succinate dehydrogenase, SDHB, SDHA, SDHC, SDHD, pheochromocytoma, paraganglioma, gastrointestinal stromal tumor, renal carcinoma, Carney triad, germline mutations, immunohistochemistry, tumourigenesis, hereditary cancer
- MeSH terms
- Gastrointestinal Neoplasms, Genetic Testing, Humans, Membrane Proteins, Neoplasms, Neoplastic Syndromes, Hereditary, Paraganglioma, Pheochromocytoma, Succinate Dehydrogenase, Gene Expression Regulation, Neoplastic, Germ-Line Mutation, Genetic Predisposition to Disease, Protein Subunits, Mitochondrial Proteins, Gastrointestinal Stromal Tumors
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