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

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

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

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.

Description

Keywords

Translational, hereditary, imaging technique, metabolic cancer, metabolomics

Journal Title

JCO Precis Oncol

Conference Name

Journal ISSN

2473-4284
2473-4284

Volume Title

2

Publisher

American Society of Clinical Oncology (ASCO)
Sponsorship
Cancer Research Uk (None)
Cambridge University Hospitals NHS Foundation Trust (CUH) (BRC 2012-2017)
Cancer Research UK (unknown)
Cancer Research UK (C14303/A17197)
Cancer Research UK (11562)