SDHC epi-mutation testing in gastrointestinal stromal tumours and related tumours in clinical practice

Ruth T Casey, Rogier Ten Hoopen, Eguzkine Ochoa, Benjamin G Challis, James Whitworth, Philip S Smith, Jose Ezequiel Martin, Graeme R Clark, Fay Rodger, Mel Maranian, Kieren Allinson, Basetti Madhu, Thomas Roberts, Luis Campos, Joanne Anstee, Soo-Mi Park, Alison Marker, Colin Watts, Venkata R Bulusu, Olivier T GigerEamonn R Maher

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Article number10244
JournalScientific Reports
Issue number1
Publication statusPublished - 15 Jul 2019


  • Adolescent
  • Adrenal Gland Neoplasms/genetics
  • Adult
  • Aged
  • DNA Methylation/genetics
  • Epigenesis, Genetic/genetics
  • Epigenomics/methods
  • Female
  • Gastrointestinal Stromal Tumors/genetics
  • Genes, Regulator/genetics
  • Germ-Line Mutation
  • High-Throughput Nucleotide Sequencing/methods
  • Humans
  • Male
  • Membrane Proteins/genetics
  • Middle Aged
  • Mutation
  • Paraganglioma/genetics
  • Pheochromocytoma/genetics
  • Promoter Regions, Genetic/genetics
  • Succinate Dehydrogenase/genetics
  • Transcriptome/genetics


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