Translating in vivo metabolomic analysis of succinate dehydrogenase deficient tumours into clinical utility

Ruth T Casey; Mary A McLean; Basetti Madhu; Benjamin G Challis; Rogier Ten Hoopen; Thomas Roberts; Graeme R Clark; Deborah Pittfield; Helen L Simpson; Venkata R Bulusu; Kieran Allinson; Lisa Happerfield; Soo-Mi Park; Alison Marker; Olivier Giger; Eamonn R Maher; Ferdia A Gallagher

doi:10.1200/PO.17.00191

Translating in vivo metabolomic analysis of succinate dehydrogenase deficient tumours into clinical utility

Ruth T Casey, Mary A McLean, Basetti Madhu, Benjamin G Challis, Rogier Ten Hoopen, Thomas Roberts, Graeme R Clark, Deborah Pittfield, Helen L Simpson, Venkata R Bulusu, Kieran Allinson, Lisa Happerfield, Soo-Mi Park, Alison Marker, Olivier Giger, Eamonn R Maher, Ferdia A Gallagher

Research output: Contribution to journal › Article › peer-review

Abstract

PURPOSE: Mutations in the mitochondrial enzyme succinate dehydrogenase (SDH) subunit genes are associated with a wide spectrum of tumours including phaeochromocytoma and paraganglioma (PPGL) 1, 2, gastrointestinal stromal tumours (GIST) 3, renal cell carcinoma (RCC) 4 and pituitary adenomas5. SDH-related tumorigenesis is believed to be secondary to accumulation of the oncometabolite succinate. Our aim was to investigate the potential clinical applications of MRI spectroscopy (1H-MRS) in a range of suspected SDH-related tumours.

PATIENTS AND METHODS: Fifteen patients were recruited to this study. Respiratory-gated single-voxel 1H-MRS was performed at 3T to quantify the content of succinate at 2.4 ppm and choline at 3.22 ppm.

RESULTS: A succinate peak was seen in six patients, all of whom had a germline SDHx mutation or loss of SDHB by immunohistochemistry. A succinate peak was also detected in two patients with a metastatic wild-type GIST (wtGIST) and no detectable germline SDHx mutation but a somatic epimutation in SDHC. Three patients without a tumour succinate peak retained SDHB expression, consistent with SDH functionality. In six cases with a borderline or absent peak, technical difficulties such as motion artefact rendered 1H-MRS difficult to interpret. Sequential imaging in a patient with a metastatic abdominal paraganglioma demonstrated loss of the succinate peak after four cycles of [177Lu]-DOTATATE, with a corresponding biochemical response in normetanephrine.

CONCLUSIONS: This study has demonstrated the translation into clinical practice of in vivo metabolomic analysis using 1H-MRS in patients with SDH-deficient tumours. Potential applications include non-invasive diagnosis and disease stratification, as well as monitoring of tumour response to targeted treatments.

Original language	English
Pages (from-to)	1-12
Number of pages	12
Journal	JCO precision oncology
Volume	2
DOIs	https://doi.org/10.1200/PO.17.00191
Publication status	Published - 29 Mar 2018

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Casey, R. T., McLean, M. A., Madhu, B., Challis, B. G., Ten Hoopen, R., Roberts, T., Clark, G. R., Pittfield, D., Simpson, H. L., Bulusu, V. R., Allinson, K., Happerfield, L., Park, S.-M., Marker, A., Giger, O., Maher, E. R., & Gallagher, F. A. (2018). Translating in vivo metabolomic analysis of succinate dehydrogenase deficient tumours into clinical utility. JCO precision oncology, 2, 1-12. https://doi.org/10.1200/PO.17.00191

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title = "Translating in vivo metabolomic analysis of succinate dehydrogenase deficient tumours into clinical utility",

abstract = "PURPOSE: Mutations in the mitochondrial enzyme succinate dehydrogenase (SDH) subunit genes are associated with a wide spectrum of tumours including phaeochromocytoma and paraganglioma (PPGL) 1, 2, gastrointestinal stromal tumours (GIST) 3, renal cell carcinoma (RCC) 4 and pituitary adenomas5. SDH-related tumorigenesis is believed to be secondary to accumulation of the oncometabolite succinate. Our aim was to investigate the potential clinical applications of MRI spectroscopy (1H-MRS) in a range of suspected SDH-related tumours.PATIENTS AND METHODS: Fifteen patients were recruited to this study. Respiratory-gated single-voxel 1H-MRS was performed at 3T to quantify the content of succinate at 2.4 ppm and choline at 3.22 ppm.RESULTS: A succinate peak was seen in six patients, all of whom had a germline SDHx mutation or loss of SDHB by immunohistochemistry. A succinate peak was also detected in two patients with a metastatic wild-type GIST (wtGIST) and no detectable germline SDHx mutation but a somatic epimutation in SDHC. Three patients without a tumour succinate peak retained SDHB expression, consistent with SDH functionality. In six cases with a borderline or absent peak, technical difficulties such as motion artefact rendered 1H-MRS difficult to interpret. Sequential imaging in a patient with a metastatic abdominal paraganglioma demonstrated loss of the succinate peak after four cycles of [177Lu]-DOTATATE, with a corresponding biochemical response in normetanephrine.CONCLUSIONS: This study has demonstrated the translation into clinical practice of in vivo metabolomic analysis using 1H-MRS in patients with SDH-deficient tumours. Potential applications include non-invasive diagnosis and disease stratification, as well as monitoring of tumour response to targeted treatments.",

author = "Casey, {Ruth T} and McLean, {Mary A} and Basetti Madhu and Challis, {Benjamin G} and {Ten Hoopen}, Rogier and Thomas Roberts and Clark, {Graeme R} and Deborah Pittfield and Simpson, {Helen L} and Bulusu, {Venkata R} and Kieran Allinson and Lisa Happerfield and Soo-Mi Park and Alison Marker and Olivier Giger and Maher, {Eamonn R} and Gallagher, {Ferdia A}",

year = "2018",

month = mar,

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doi = "10.1200/PO.17.00191",

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Casey, RT, McLean, MA, Madhu, B, Challis, BG, Ten Hoopen, R, Roberts, T, Clark, GR, Pittfield, D, Simpson, HL, Bulusu, VR, Allinson, K, Happerfield, L, Park, S-M, Marker, A, Giger, O, Maher, ER & Gallagher, FA 2018, 'Translating in vivo metabolomic analysis of succinate dehydrogenase deficient tumours into clinical utility', JCO precision oncology, vol. 2, pp. 1-12. https://doi.org/10.1200/PO.17.00191

TY - JOUR

T1 - Translating in vivo metabolomic analysis of succinate dehydrogenase deficient tumours into clinical utility

AU - Casey, Ruth T

AU - McLean, Mary A

AU - Madhu, Basetti

AU - Challis, Benjamin G

AU - Ten Hoopen, Rogier

AU - Roberts, Thomas

AU - Clark, Graeme R

AU - Pittfield, Deborah

AU - Simpson, Helen L

AU - Bulusu, Venkata R

AU - Allinson, Kieran

AU - Happerfield, Lisa

AU - Park, Soo-Mi

AU - Marker, Alison

AU - Giger, Olivier

AU - Maher, Eamonn R

AU - Gallagher, Ferdia A

PY - 2018/3/29

Y1 - 2018/3/29

N2 - PURPOSE: Mutations in the mitochondrial enzyme succinate dehydrogenase (SDH) subunit genes are associated with a wide spectrum of tumours including phaeochromocytoma and paraganglioma (PPGL) 1, 2, gastrointestinal stromal tumours (GIST) 3, renal cell carcinoma (RCC) 4 and pituitary adenomas5. SDH-related tumorigenesis is believed to be secondary to accumulation of the oncometabolite succinate. Our aim was to investigate the potential clinical applications of MRI spectroscopy (1H-MRS) in a range of suspected SDH-related tumours.PATIENTS AND METHODS: Fifteen patients were recruited to this study. Respiratory-gated single-voxel 1H-MRS was performed at 3T to quantify the content of succinate at 2.4 ppm and choline at 3.22 ppm.RESULTS: A succinate peak was seen in six patients, all of whom had a germline SDHx mutation or loss of SDHB by immunohistochemistry. A succinate peak was also detected in two patients with a metastatic wild-type GIST (wtGIST) and no detectable germline SDHx mutation but a somatic epimutation in SDHC. Three patients without a tumour succinate peak retained SDHB expression, consistent with SDH functionality. In six cases with a borderline or absent peak, technical difficulties such as motion artefact rendered 1H-MRS difficult to interpret. Sequential imaging in a patient with a metastatic abdominal paraganglioma demonstrated loss of the succinate peak after four cycles of [177Lu]-DOTATATE, with a corresponding biochemical response in normetanephrine.CONCLUSIONS: This study has demonstrated the translation into clinical practice of in vivo metabolomic analysis using 1H-MRS in patients with SDH-deficient tumours. Potential applications include non-invasive diagnosis and disease stratification, as well as monitoring of tumour response to targeted treatments.

AB - PURPOSE: Mutations in the mitochondrial enzyme succinate dehydrogenase (SDH) subunit genes are associated with a wide spectrum of tumours including phaeochromocytoma and paraganglioma (PPGL) 1, 2, gastrointestinal stromal tumours (GIST) 3, renal cell carcinoma (RCC) 4 and pituitary adenomas5. SDH-related tumorigenesis is believed to be secondary to accumulation of the oncometabolite succinate. Our aim was to investigate the potential clinical applications of MRI spectroscopy (1H-MRS) in a range of suspected SDH-related tumours.PATIENTS AND METHODS: Fifteen patients were recruited to this study. Respiratory-gated single-voxel 1H-MRS was performed at 3T to quantify the content of succinate at 2.4 ppm and choline at 3.22 ppm.RESULTS: A succinate peak was seen in six patients, all of whom had a germline SDHx mutation or loss of SDHB by immunohistochemistry. A succinate peak was also detected in two patients with a metastatic wild-type GIST (wtGIST) and no detectable germline SDHx mutation but a somatic epimutation in SDHC. Three patients without a tumour succinate peak retained SDHB expression, consistent with SDH functionality. In six cases with a borderline or absent peak, technical difficulties such as motion artefact rendered 1H-MRS difficult to interpret. Sequential imaging in a patient with a metastatic abdominal paraganglioma demonstrated loss of the succinate peak after four cycles of [177Lu]-DOTATATE, with a corresponding biochemical response in normetanephrine.CONCLUSIONS: This study has demonstrated the translation into clinical practice of in vivo metabolomic analysis using 1H-MRS in patients with SDH-deficient tumours. Potential applications include non-invasive diagnosis and disease stratification, as well as monitoring of tumour response to targeted treatments.

UR - https://ascopubs.org/doi/10.1200/PO.17.00191

U2 - 10.1200/PO.17.00191

DO - 10.1200/PO.17.00191

M3 - Article

C2 - 30949620

SN - 2473-4284

VL - 2

SP - 1

EP - 12

JO - JCO precision oncology

JF - JCO precision oncology

ER -

Translating in vivo metabolomic analysis of succinate dehydrogenase deficient tumours into clinical utility

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