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. Giger; Eamonn R. Maher

doi:10.1038/s41598-019-46124-9

Scientific Reports (Jul 2019)

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. Giger,
Eamonn R. Maher

Affiliations

Ruth T. Casey: Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre and Cancer Research UK Cambridge Centre
Rogier ten Hoopen: Department of Oncology, University of Cambridge, Addenbrooke’s Hospital
Eguzkine Ochoa: Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre and Cancer Research UK Cambridge Centre
Benjamin G. Challis: Department of Endocrinology, Cambridge University NHS Foundation Trust
James Whitworth: Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre and Cancer Research UK Cambridge Centre
Philip S. Smith: Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre and Cancer Research UK Cambridge Centre
Jose Ezequiel Martin: Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre and Cancer Research UK Cambridge Centre
Graeme R. Clark: Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre and Cancer Research UK Cambridge Centre
Fay Rodger: Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre and Cancer Research UK Cambridge Centre
Mel Maranian: Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre and Cancer Research UK Cambridge Centre
Kieren Allinson: Department of Histopathology Cambridge University NHS Foundation Trust and Cancer Research UK Cambridge Centre
Basetti Madhu: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre
Thomas Roberts: Haematology Oncology Diagnostic Service (HODS), Cambridge University NHS Foundation Trust
Luis Campos: Haematology Oncology Diagnostic Service (HODS), Cambridge University NHS Foundation Trust
Joanne Anstee: Department of Histopathology Cambridge University NHS Foundation Trust and Cancer Research UK Cambridge Centre
Soo-Mi Park: Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre and Cancer Research UK Cambridge Centre
Alison Marker: Department of Histopathology Cambridge University NHS Foundation Trust and Cancer Research UK Cambridge Centre
Colin Watts: Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham
Venkata R. Bulusu: Department of Medical Oncology, Cambridge University NHS Foundation Trust
Olivier T. Giger: Department of Histopathology Cambridge University NHS Foundation Trust and Cancer Research UK Cambridge Centre
Eamonn R. Maher: Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre and Cancer Research UK Cambridge Centre

DOI: https://doi.org/10.1038/s41598-019-46124-9
Journal volume & issue: Vol. 9, no. 1
pp. 1 – 10

Abstract

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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.

Published in Scientific Reports

ISSN: 2045-2322 (Online)
Publisher: Nature Portfolio
Country of publisher: United Kingdom
LCC subjects: Medicine; Science
Website: https://www.nature.com/srep/

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