Genetics of pheochromocytoma and paraganglioma

Purpose of review This review summarizes our current understanding of germline and somatic genetics and genomics of pheochromocytomas and paragangliomas (PCC/PGL), describes existing knowledge gaps, and discusses future research directions. Recent findings Germline pathogenic variants (PVs) are found in up to 40% of those with PCC/PGL. Tumors with germline PVs are broadly categorized as Cluster 1 (pseudohypoxia), including those with SDH , VHL , FH , and EPAS1 PVs, or Cluster 2 (kinase signaling) including those with NF1 , RET , TMEM127 , and MAX PVs. Somatic driver mutations exist in some of the same genes ( RET, VHL, NF1, EPAS1 ) as well as in additional genes including HRAS , CSDE1 and genes involved in cell immortalization ( ATRX and TERT ). Other somatic driver events include recurrent fusion genes involving MAML3 . Summary PCC/PGL have the highest association with germline PVs of all human solid tumors. Expanding our understanding of the molecular pathogenesis of PCC/PGL is essential to advancements in diagnosis and surveillance and the development of novel therapies for these unique tumors.