Endocrine Abstracts (2017) 49 S17.2 | DOI: 10.1530/endoabs.49.S17.2

Clinical implications of SDHx mutations

Anne-Paule Gimenez-Roqueplo


Paragangliomas and pheochromocytomas (PPGL) are neuroendocrine tumors with a very strong genetic component. A germline mutation in one of the different susceptibility genes identified so far explains about 40% of all cases. Genetic testing is recommended in every affected patient and next-generation sequencing (NGS) is the ideal technology to screen the high number of PPGL susceptibility genes (1). The interpretation of genetic variants identified by NGS can be guided by the clinical presentation as well as by the secretory phenotype and by the immunohistochemical analysis of tumors (2). The diagnosis of an inherited form drives clinical management and tumor surveillance of the patient and relatives (1). While whole-exome sequencing studies showed that PPGL is characterized by a low mutation rate of 0.3 mutations per megabase similar to other neural crest-derived tumors, the first integrative genomic analysis of a large collection of 202 PPGL, carried out by the French COMETE network, demonstrated that mutation status in PPGL susceptibility genes is strongly correlated with multi-omics data and revealed the crucial role of predisposing mutations as being the main drivers of PPGL (3). PPGL subtypes can be defined by a set of unique genomic alterations that represent different molecular entities. Transcriptomic studies identified two main molecular pathways, activating either the hypoxic pathway (cluster C1) or the MAPkinase/mTOR signalling (cluster C2). This comprehensive analysis illustrated the functional interdependence between genomic and epigenomic dysregulations. Indeed, DNA methylation profiling uncovered a hypermethylator phenotype specific to the tumors related to a mutation in one of the PPGL susceptibility genes encoding for a protein of the tricarboxylic cycle. Besides, we demonstrated that succinate is acting as an oncometabolite, inhibiting 2-oxoglutarate-dependent dioxygenases, such as HIF prolyl-hydroxylases and histone/DNA demethylases, explaining noradrenergic secretory and metastatic phenotypes of PPGL classified in cluster 1A (4). A recently published novel comprehensive multi-platform analysis of 173 PPGLs led by TCGA has confirmed the COMETE data and identified recurrent fusions genes by RNA sequencing. Altogether those data suggested new therapeutic targets for patients with a metastatic PPGL as well as novel diagnostic and prognostic biomarkers. New ‘omics’-based tests for PPGL are likely to be transferred from research laboratories to clinical practice in order to give the access to a precise molecular classification of every PPGL, after surgery, to practicing clinicians with the goal of establishing a personalized medical management.


1. Favier, Nat Rev Endocrinol, 2015.

2. Toledo, Nat Rev Endocrinol, 2017.

3. Castro-Vega, Nat Commun, 2015.

4. Letouzé, Cancer Cell, 2013.

5. Fishbein, Cancer Cell, 2017.

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