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Translating In Vivo Metabolomic Analysis of Succinate Dehydrogenase–Deficient Tumors Into Clinical Utility

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Casey, Ruth T 
McLean, Mary A 
Madhu, Basetti 
Challis, Benjamin G 
ten Hoopen, Rogier 


jats:secjats:titlePurpose</jats:title>jats:p Mutations in the mitochondrial enzyme succinate dehydrogenase (SDH) subunit genes are associated with a wide spectrum of tumors, including pheochromocytomas and paragangliomas, GI stromal tumors, renal cell carcinomas, and pituitary adenomas. SDH-related tumorigenesis is believed to be secondary to accumulation of the oncometabolite succinate. Our aim was to investigate the potential clinical applications of proton-1 magnetic resonance spectroscopy (jats:sup1</jats:sup>H-MRS) in a range of suspected SDH-related tumors. </jats:p></jats:sec>jats:secjats:titlePatients and Methods</jats:title>jats:p Fifteen patients were recruited to this study. Respiratory-gated single-voxel jats:sup1</jats:sup>H-MRS was performed at 3T to quantify the content of succinate at 2.4 ppm and choline at 3.22 ppm. </jats:p></jats:sec>jats:secjats:titleResults</jats:title>jats:p A succinate peak was seen in six patients, all of whom had germ line SDHx mutations or loss of SDHB by immunohistochemistry. Succinate peaks were also detected in two patients with metastatic wild-type GI stromal tumors and no detectable germ line SDHx mutations but with somatic epimutations in SDHC. Three patients without tumor succinate peaks retained SDHB expression, consistent with SDH functionality. In six patients with borderline or absent peaks, technical difficulties such as motion artifact rendered jats:sup1</jats:sup>H-MRS difficult to interpret. Sequential imaging in a patient with a metastatic abdominal paraganglioma demonstrated loss of the succinate peak after four cycles of [jats:sup177</jats:sup>Lu]DOTATATE, with a corresponding biochemical response in normetanephrine. </jats:p></jats:sec>jats:secjats:titleConclusion</jats:title>jats:p This study has demonstrated the translation into clinical practice of in vivo metabolomic analysis using jats:sup1</jats:sup>H-MRS in patients with SDH-deficient tumors. Potential applications include noninvasive diagnosis and disease stratification, as well as monitoring of tumor response to targeted treatments. </jats:p></jats:sec>



Journal Title

JCO Precision Oncology

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American Society of Clinical Oncology (ASCO)
Cambridge University Hospitals NHS Foundation Trust (CUH) (unknown)
Cambridge University Hospitals NHS Foundation Trust (CUH) (BRC 2012-2017)
Health Research Board (via National University of Ireland, Galway) (unknown)
European Research Council (323004)
GIST Support UK (GSUKRC01)
Department of Health (via National Institute for Health Research (NIHR)) (NF-SI-0616-10035)
Cancer Research UK (unknown)
Cancer Research UK (C14303/A17197)