Translating <i>in vivo</i> metabolomic analysis of succinate dehydrogenase deficient tumours into clinical utility.

Abstract

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. 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. A succinate peak was seen in six patients, all of whom had a germline <i>SDHx</i> 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 <i>SDHx</i> mutation but a somatic epimutation in <i>SDHC.</i> 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. This study has demonstrated the translation into clinical practice of <i>in vivo</i> 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.