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 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. 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.
Highlights
The succinate dehydrogenase (SDH) enzyme is composed of four subunits (A-D) and has a key role in the Krebs cycle and oxidative phosphorylation[6]
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 detected in two patients with a metastatic wild-type gastrointestinal stromal tumours (GISTs) and no detectable germline SDHx mutation but a somatic epimutation in SDHC
Summary
The succinate dehydrogenase (SDH) enzyme is composed of four subunits (A-D) and has a key role in the Krebs cycle and oxidative phosphorylation[6]. In the past two decades germline mutations in the genes encoding the four SDH subunits (SDHA/SDHB/SDHC/ SDHD), collectively known as SDHx have emerged as an important cause of human neoplasia and a paradigm for the role of disordered cellular metabolism in oncogenesis 1–5, 7. Germline SDHB mutations are associated with a high risk of malignancy in PPGL9. Other tumour types associated with SDHx mutations include gastrointestinal stromal tumours (GISTs) and renal cell carcinomas (RCCs)[10,11,12,13]. GISTs are mesenchymal tumours of the gastrointestinal tract and in adults usually associated with somatic activating mutations in the KIT or PDGFRA genes[3, 11].
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