Ruth T Casey1,2, Mary A McLean3, Basetti Madhu3, Benjamin G Challis2, Rogier Ten Hoopen4, Thomas Roberts5, Graeme R Clark1, Deborah Pittfield2, Helen L Simpson6, Venkata R Bulusu7, Kieran Allinson8, Lisa Happerfield9, Soo-Mi Park1, Alison Marker8, Olivier Giger4, Eamonn R Maher1, Ferdia A Gallagher3,10. 1. Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre and Cancer Research UK Cambridge Centre, CB2 OQQ, United Kingdom. 2. Department of Endocrinology, Cambridge University NHS Foundation Trust, Cambridge, CB2 OQQ, United Kingdom. 3. Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK. 4. Department of Pathology, University of Cambridge, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK. 5. Haematology Oncology Diagnostic Service (HODS), Cambridge University NHS Foundation Trust, Cambridge, CB2 OQQ, United Kingdom. 6. Department of Diabetes and Endocrinology, University College London Hospitals, NHS Foundation Trust, London, NW1 2PG UK. 7. Department of Medical Oncology, Cambridge University NHS Foundation Trust, Cambridge, CB2 OQQ, United Kingdom. 8. Department of Histopathology Cambridge University NHS Foundation Trust and Cancer Research UK Cambridge Centre Cambridge, CB2 0QQ, United Kingdom. 9. Department of Immunohistochemistry, Cambridge University NHS Foundation Trust, Cambridge, CB2 OQQ, United Kingdom. 10. Department of Radiology, Cambridge University NHS Foundation Trust, CB2 OQQ, United Kingdom.
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.
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.
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