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

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 journal › Article › peer-review

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.

Original language	English
Article number	10244
Journal	Scientific Reports
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41598-019-46124-9
Publication status	Published - 15 Jul 2019

Keywords

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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Casey, R. T., Ten Hoopen, R., Ochoa, E., Challis, B. G., Whitworth, J., Smith, P. S., Martin, J. E., Clark, G. R., Rodger, F., Maranian, M., Allinson, K., Madhu, B., Roberts, T., Campos, L., Anstee, J., Park, S.-M., Marker, A., Watts, C., Bulusu, V. R., ... Maher, E. R. (2019). SDHC epi-mutation testing in gastrointestinal stromal tumours and related tumours in clinical practice. Scientific Reports, 9(1), Article 10244. https://doi.org/10.1038/s41598-019-46124-9

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title = "SDHC epi-mutation testing in gastrointestinal stromal tumours and related tumours in clinical practice",

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.",

keywords = "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",

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

year = "2019",

month = jul,

day = "15",

doi = "10.1038/s41598-019-46124-9",

language = "English",

volume = "9",

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Casey, RT, Ten Hoopen, R, Ochoa, E, Challis, BG, Whitworth, J, Smith, PS, Martin, JE, Clark, GR, Rodger, F, Maranian, M, Allinson, K, Madhu, B, Roberts, T, Campos, L, Anstee, J, Park, S-M, Marker, A, Watts, C, Bulusu, VR, Giger, OT & Maher, ER 2019, 'SDHC epi-mutation testing in gastrointestinal stromal tumours and related tumours in clinical practice', Scientific Reports, vol. 9, no. 1, 10244. https://doi.org/10.1038/s41598-019-46124-9

TY - JOUR

T1 - SDHC epi-mutation testing in gastrointestinal stromal tumours and related tumours in clinical practice

AU - Casey, Ruth T

AU - Ten Hoopen, Rogier

AU - Ochoa, Eguzkine

AU - Challis, Benjamin G

AU - Whitworth, James

AU - Smith, Philip S

AU - Martin, Jose Ezequiel

AU - Clark, Graeme R

AU - Rodger, Fay

AU - Maranian, Mel

AU - Allinson, Kieren

AU - Madhu, Basetti

AU - Roberts, Thomas

AU - Campos, Luis

AU - Anstee, Joanne

AU - Park, Soo-Mi

AU - Marker, Alison

AU - Watts, Colin

AU - Bulusu, Venkata R

AU - Giger, Olivier T

AU - Maher, Eamonn R

PY - 2019/7/15

Y1 - 2019/7/15

N2 - 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.

AB - 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.

KW - Adolescent

KW - Adrenal Gland Neoplasms/genetics

KW - Adult

KW - Aged

KW - DNA Methylation/genetics

KW - Epigenesis, Genetic/genetics

KW - Epigenomics/methods

KW - Female

KW - Gastrointestinal Stromal Tumors/genetics

KW - Genes, Regulator/genetics

KW - Germ-Line Mutation

KW - High-Throughput Nucleotide Sequencing/methods

KW - Humans

KW - Male

KW - Membrane Proteins/genetics

KW - Middle Aged

KW - Mutation

KW - Paraganglioma/genetics

KW - Pheochromocytoma/genetics

KW - Promoter Regions, Genetic/genetics

KW - Succinate Dehydrogenase/genetics

KW - Transcriptome/genetics

UR - https://www.nature.com/articles/s41598-019-46124-9

U2 - 10.1038/s41598-019-46124-9

DO - 10.1038/s41598-019-46124-9

M3 - Article

C2 - 31308404

SN - 2045-2322

VL - 9

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 10244

ER -

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

Abstract

Keywords

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