Utility of the succinate: Fumarate ratio for assessing SDH dysfunction in different tumor types.

ABSTRACT

OBJECTIVE: Mutations of genes encoding the four subunits of succinate dehydrogenase (SDH) have been associated with pheochromocytoma and paraganglioma (PPGLs), gastrointestinal stromal tumors (GISTs) and renal cell carcinomas (RCCs). These tumors have not been characterized in a way that reflects severity of SDH dysfunction. Mass spectrometric analysis now allows measurement of metabolites extracted from formalin fixed paraffin embedded (FFPE) specimens. We assess whether SDH deficiency in various tumor types characterized by loss of SDHB protein expression correlates with SDH dysfunction as assessed by the ratio of succinatefumarate in FFPE specimens. PATIENTS AND METHODS: Sections of FFPE tumor specimens from 18 PPGL, 10 GIST and 11 RCC patients with known SDHx mutation status for SDH deficiency were collected for mass spectrometric analysis of succinate and fumarate. RESULTS: FFPE samples showed higher succinatefumarate ratios in SDH-deficient PPGLs compared to SDH-sufficient PPGLs. Similarly, a higher succinatefumarate ratio was able to distinguish SDH-deficient GISTs and RCCs from their SDH-sufficient counterparts with great selectivity. Interestingly, the cut-off value of the succinatefumarate ratio was two-folds greater in RCCs than GISTs. CONCLUSION: Analyzing biochemical imbalances preserved in FFPE specimens with mass spectrometry expands the method and sample type repertoire available for characterisation of multiple neoplasias associated with SDH deficiency.