Paragangliomas and pheochromocytomas (PPGL) are neuroendocrine tumors with a very strong genetic component. A germline mutation in one of the 13 different susceptibility genes identified so far explains about 40% of all cases. Genetic testing, which is indicated in every patient, can be guided by the clinical presentation as well as by the secretory phenotype and by the immunohistochemical analysis of the tumors. The diagnosis of an inherited form drives clinical management and tumor surveillance1.
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 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 PPGL2. 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 or the MAPkinase/mTOR signalling. This comprehensive analysis further illustrated the functional interdependence between genomic and epigenomic dysregulations. Indeed, DNA methylation profiling uncovered a hypermethylator phenotype in SDH-related tumors and revealed that succinate is acting as an oncometabolite, inhibiting 2-oxoglutarate-dependent dioxygenases, such as HIF prolyl-hydroxylases and histone/DNA demethylases3. miRNA sequencing identified miRNA expression clusters strongly associated with mRNA expression profiling. Omics data suggested new therapeutic targets for patients with a metastatic PPGL and new diagnosis and prognostic biomarkers. The knowledge of specific genomic alterations should provide a real help for individual patient management and should guide the choice of targeted therapy for malignant cases. New omics-based tests are likely to be transferred from research laboratories to clinical practice to offer the access to a precise molecular classification of PPGL to practicing clinicians with the goal of establishing a personalized medical management of affected patients.
1. Favier, Nat Rev Endocrinol, 2015.
2. Castro-Vega, Nat Commun, 2015.
3. Letouzé, Cancer Cell 2013.