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

Accepted version
Peer-reviewed

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Article

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Authors

Casey, Ruth T 
Ten Hoopen, Rogier 
Ochoa, Eguzkine 
Challis, Benjamin G 
Whitworth, James 

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.

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Keywords

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

Journal Title

Sci Rep

Conference Name

Journal ISSN

2045-2322
2045-2322

Volume Title

9

Publisher

Springer Science and Business Media LLC

Rights

All rights reserved
Sponsorship
Cambridge University Hospitals NHS Foundation Trust (CUH) (BRC 2012-2017)
Cambridge University Hospitals NHS Foundation Trust (CUH) (BRC 2012-2017)
Cancer Research UK (C20/A20917)
Health Research Board Ireland and GIST Support UK (RTC), NIHR Senior Investigator Award (ERM), European Research Council Advanced Researcher Award (ERM), the British Heart Foundation (ERM). The University of Cambridge has received salary support in respect of ERM from the NHS in the East of England through the Clinical