Rethinking pheochromocytomas and paragangliomas from a genomic perspective

Pheochromocytomas (PCC) and paragangliomas (PGL) are rare neuroendocrine tumors of neural crest origin. These tumors are caused by germline or somatic mutations in known susceptibility genes in up to 70% of cases. Over the past few years, the emergence of high-throughput technologies has enabled the unprecedented characterization of genomic alterations in PCC/PGL, and has improved our understanding of the molecular mechanisms that distinguish the different tumor subtypes. Integrated genomic analyses have shown that the mutation status of PCC/PGL susceptibility genes strongly correlates with multi-omics data. These observations not only emphasize the role of the long-standing susceptibility genes as the main drivers of PCC/PGL tumorigenesis, but also illustrate the functional interdependence between genomic and epigenomic alterations. In this review, we discuss the genomic landscape underlying PCC/PGL, its functional consequences for tumorigenesis and tumor progression, and the potential clinical relevance of this knowledge for the application of precision medicine for patients with PCC/PGL.