Genetic mutations in genes encoding enzymes involved in cellular metabolism such as the citric acid cycle genes, have recently been implicated in a wide spectrum of tumour development. These genetic aberrations can disrupt the normal function of the metabolic enzymes they encode and result in a pathological accumulation of specific metabolites. The abnormal accumulation of specific metabolites can drive tumourigenesis and in such cases the metabolites are referred to as ‘oncometabolites’. One such oncometabolite is succinate; a citric acid cycle metabolite which accumulates in the presence of a mutation affecting the succinate dehydrogenase enzyme (SDH) complex. Mutations in the genes (SDHA/SDHB/SDHC/SDHD) encoding the (SDH) enzyme complex can predispose to the development of a rare tumour type called phaeochromocytoma as well as other tumours including; renal tumours, gastrointestinal stromal tumours and rarely pituitary tumours.
The detection of oncometabolite accumulation has a number of potential translational applications including; i) early detection of a genetic abnormality, ii) deciphering the pathological consequence of a genetic variant of uncertain clinical significance and ii) potentially as a biomarker to help us follow biological tumour response to therapy. In this study we combined the study of a rare hereditary disease with new technology and collaborated with colleagues in CRUK and the Department of Radiology. Our aim was to investigate the clinical utility of a radiological modality; MRI spectroscopy as a tool for detecting succinate accumulation in vivo in the tumours of patients with suspected or confirmed mutations in the SDH genes and to identify the possible translational applications of this tool.
Fifteen subjects (6 females, 9 males; mean age 40 years (range 21-80 years) were studied and this is the largest study to date to evaluate MRI spectroscopy in patients with SDH enzyme deficiency. This proof-of-principle study demonstrated that detection of a succinate peak was specific for a variety of SDH mutated tumour types. We have demonstrated for the first time that MRI spectroscopy can also be used to determine the SDH status of GISTs and pituitary adenomas and that a succinate peak can be detected in tumours with epigenetic inactivation of the SDHC gene. Importantly this study also demonstrated that MRI spectroscopy could be a valuable tool for the assessment of tumour response in the context of radionuclide and other therapies as alterations in succinate levels were detected despite stable appearances of the tumour diameter on conventional cross sectional imaging.