Abstract
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.
Highlights
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 and renal cell carcinoma
Www.nature.com/scientificreports considered best practice for patients presenting with i) PPGL3, ii) wild type gastrointestinal stromal tumours[4] and iii) specific histopathological subtypes of renal cell carcinoma5. wtGIST are defined as GIST that are negative for KIT and PDGFRA somatic gene mutations and account for 15% of adult and 85% of paediatric GIST
Biallelic inactivation of any of the SDHx genes, most commonly results in destabilisation of the SDH enzyme complex, which can be detected by loss of staining for the SDHB protein on IH6 and wtGIST can be further classified based on the loss or preservation of SDHB protein expression on immunohistochemistry as a surrogate marker for loss of function of the SDH complex
Summary
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. All 6 SDHC epimutation cases presented with SDH deficient wtGIST and 3/6 cases had multiple primary tumours. Correspondence and requests for materials should be addressed to R.T.C. www.nature.com/scientificreports considered best practice for patients presenting with i) PPGL3, ii) wild type gastrointestinal stromal tumours (wtGIST)[4] and iii) specific histopathological subtypes of renal cell carcinoma. Biallelic inactivation of any of the SDHx genes, most commonly results in destabilisation of the SDH enzyme complex, which can be detected by loss of staining for the SDHB protein on IH6 and wtGIST can be further classified based on the loss or preservation of SDHB protein expression on immunohistochemistry as a surrogate marker for loss of function of the SDH complex. In addition to testing for germline SDHx variants, immunostaining for SDHB and SDHA is a valuable approach for identifying dSDH tumours[6]
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