Molecular genetics of pheochromocytoma/paraganglioma

Abstract

Pheochromocytomas and paragangliomas (PPGL) are neuroendocrine tumors which secrete catecholamines, causing cardiovascular compromise. While isolated tumors and locoregional disease can be treated surgically, treatment options for metastatic disease are limited, and no targeted therapies exist. Approximately 25% of PPGL are causatively associated with germline pathogenic variants, which are known risk factors for multifocal and metastatic PPGL. Knowledge of somatic driver mutations continues to evolve. Molecular classification of PPGL has identified three genomic subtypes: Cluster 1 (pseudohypoxia), Cluster 2 (kinase signaling) and Cluster 3 (Wnt-altered). This review summaries recent studies characterizing the tumor microenvironment, genomic drivers of tumorigenesis and progression, and current research on molecular targets for novel diagnostic and therapeutic strategies in PPGL.