The enzyme succinate dehydrogenase (SDH) functions in the citric acid cycle and loss of function predisposes to the development of phaeochromocytoma/paraganglioma (PPGL), wild type gastrointestinal stromal tumour (wtGIST) and renal cell carcinoma. SDH-deficient tumours are most commonly associated with a germline SDH subunit gene (SDHA/B/C/D) mutation but can also be associated with epigenetic silencing of the SDHC gene. However, clinical diagnostic testing for an SDHC epimutation is not widely available. The objective of this study was to investigate the indications for and the optimum diagnostic pathways for the detection of SDHC epimutations in clinical practice. SDHC promoter methylation analysis of 32 paraffin embedded tumours (including 15 GIST and 17 PPGL) was performed using a pyrosequencing technique and correlated with SDHC gene expression. SDHC promoter methylation was identified in 6 (18.7%) tumours. All 6 SDHC epimutation cases presented with SDH deficient wtGIST and 3/6 cases had multiple primary tumours. No case of constitutional SDHC promoter hypermethylation was detected. Whole genome sequencing of germline DNA from three wtGIST cases with an SDHC epimutation, did not reveal any causative sequence anomalies. Herein, we recommend a diagnostic workflow for the detection of an SDHC epimutation in a service setting.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6629852 | PMC |
| http://dx.doi.org/10.1038/s41598-019-46124-9 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Germline Mutations in SDH-Deficient GISTs: A Current Update.
Genes (Basel)
March 2023
Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy.
Loss of function of the succinate dehydrogenase complex characterizes 20-40% of all -negative GIST. Approximately half of SDH-deficient GIST patients lack mutations and are caused by a hypermethylation of the promoter, which causes the repression of transcription and depletion of SDHC protein levels through a mechanism described as epimutation. The remaining 50% of SDH-deficient GISTs have mutations in one of the SDH subunits and mutations are the most common (30%), with consequent loss of SDHA and SDHB protein expression immunohistochemically.
View Article and Find Full Text PDFPreferential hypermethylation in SDH-deficient wild-type GIST.
J Clin Pathol
December 2023
Department of Medical Genetics and Cancer Research, University of Cambridge, Cambridge, UK.
Aims: Wild-type gastrointestinal stromal tumours (wtGIST) are frequently caused by inherited pathogenic variants, or somatic alterations in the succinate dehydrogenase subunit genes (). Succinate dehydrogenase is a key enzyme in the citric acid cycle. SDH deficiency caused by inactivation leads to an accumulation of succinate, which inhibits DNA and histone demethylase enzymes, resulting in global hypermethylation.
View Article and Find Full Text PDFAn exploration in pitfalls in interpreting SDHBÂ immunohistochemistry.
Histopathology
August 2022
Department of Pathology, University of California, San Francisco, CA, USA.
Aims: Mutations and epimutations in genes encoding the succinate dehydrogenase complex (SDHx) are associated with multiple tumour types in which identification of SDH-deficiency has significant management implications. Immunohistochemistry (IHC) for the succinate dehydrogenase B (SDHB) subunit can help to detect SDH-deficiency, which manifests as complete loss of staining in tumour cells. However, a subset of SDH-deficient tumours can show aberrant cytoplasmic SDHB-IHC staining patterns and be misinterpreted as 'retained', a diagnostic pitfall complicating interpretation.
View Article and Find Full Text PDFSDHC epi-mutation testing in gastrointestinal stromal tumours and related tumours in clinical practice.
Sci Rep
July 2019
Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre and Cancer Research UK Cambridge Centre, Cambridge, CB2 OQQ, United Kingdom.
The enzyme succinate dehydrogenase (SDH) functions in the citric acid cycle and loss of function predisposes to the development of phaeochromocytoma/paraganglioma (PPGL), wild type gastrointestinal stromal tumour (wtGIST) and renal cell carcinoma. SDH-deficient tumours are most commonly associated with a germline SDH subunit gene (SDHA/B/C/D) mutation but can also be associated with epigenetic silencing of the SDHC gene. However, clinical diagnostic testing for an SDHC epimutation is not widely available.
View Article and Find Full Text PDFTranslating metabolomic analysis of succinate dehydrogenase deficient tumours into clinical utility.
JCO Precis Oncol
March 2018
Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
Purpose: Mutations in the mitochondrial enzyme succinate dehydrogenase (SDH) subunit genes are associated with a wide spectrum of tumours including phaeochromocytoma and paraganglioma (PPGL) 1, 2, gastrointestinal stromal tumours (GIST) 3, renal cell carcinoma (RCC) 4 and pituitary adenomas5. SDH-related tumorigenesis is believed to be secondary to accumulation of the oncometabolite succinate. Our aim was to investigate the potential clinical applications of MRI spectroscopy (H-MRS) in a range of suspected SDH-related tumours.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!