Endocrine Abstracts

SDHA, B, C, and D (SDHx) genes encode the four subunits of succinate dehydrogenase (SDH), a mitochondrial enzyme of the tricarboxylic acid (TCA) cycle that oxidizes succinate into fumarate. They were the first genes encoding a mitochondrial enzyme demonstrated to act as tumor suppressors, an important finding supporting the hypothesis of a direct link between mitochondrial dysfunction and cancer proposed by Otto Warburg in the 1920’s. It is estimated that germline mutations in SDHx genes represent around half of inherited pheochromocytoma and paraganglioma (PPGL), which are referred to as Cluster 1 tumors. In PPGL, SDH loss-of-function results in the accumulation of succinate, which acts as an oncometabolite, by inhibiting 2-oxoglutarate-dependent dioxygenases among which HIF prolyl-hydroxylases drive a pseudohypoxic response and promote angiogenesis and DNA demethylases cause a hypermethylator phenotype. This presentation will show how our team uses genetic and OMICs analyses on the large series of human PPGL gathered by the French COMETE network, combined with experimental studies on Sdhb knockout cells and xenografts to decipher these mechanisms and develop tools to evaluate the response to anti-angiogenic or demethylating therapies. It will also show how we used OMICS analyses combined with whole-exome sequencing to identify new PPGL susceptibility genes within the cluster 1 group of PPGL. Using such an approach, we previously identified the first PPGL case harboring a germline FH gene mutation and now discovered a new mitochondrial tumor suppressor gene encoding an unsuspected carrier. These finding demonstrate the central role of mitochondrial deficiencies in the predisposition to paragangliomas.