Genetics of paragangliomas and pheochromocytomas

Pheochromocytomas and paragangliomas are rare tumors that arise from chromaffin tissues of the adrenal medulla and from sympathetic and parasympathetic ganglia. Ten susceptibility genes (VHL, RET, NF1, SDHA, B, C and D, SDHAF2, TMEM127 and finally MAX) are responsible for at least 30% of the cases. These patients can either have a familial history of the disease, a syndromic presentation, but can also emerge as apparently sporadic forms. Moreover, recent transcriptomic studies have led to the identification of somatic mutations in VHL and RET genes in 15% of sporadic cases, thus bringing a molecular explanation for nearly half of all cases. These findings have had a major impact on the understanding of the molecular mechanisms of tumorigenesis in pheochromocytomas and paragangliomas. It was shown that the genetic status of tumors is associated with particular transcription signatures, such as the activation of the pseudohypoxic response or the activation of MAPK or mTOR signalling. From nowadays to a close future, these advances will have important consequences on the monitoring of patients, from genetic counseling to a personalized clinical management.