Genetics of Pheochromocytoma

Abstract Pheochromocytoma (PHEO) and paraganglioma (PGL) are closely related neuroendocrine tumours of the chromaffin tissues of the sympathetic and parasympathetic nervous system. These rare tumours have a strong genetic component, with underlying germline and somatic mutations in one of 17 genes found in approximately 50%. Clinical presentations of PHEO/PGL vary based on the affected gene, and understanding these differences can help guide genetic testing, an important part of PHEO/PGL patient management. Despite the differences in presentation and gene function, all 17 genes may affect a single pathway. Particularly, recent proposals have focused on hypoxia‐inducible factors (HIFs) as key players in PHEO/PGL, due to the known pseudohypoxic environment found in these tumours and the central role played by HIFs in cellular processes. By linking the susceptibility genes to a central potential therapeutic target like HIF, new treatment methods could soon be introduced to improve the outcomes of PHEO/PGL patients. Key Concepts: Pheochromocytomas and paragangliomas have the strongest genetic component of any endocrine tumour; half or more are linked to germline and somatic mutations in 17 genes. The clinical presentations associated with each gene vary, particularly with regard to tumour location, multiplicity, biochemical phenotype, average patient age at diagnosis and risk of metastases. Genetic testing is an essential component of PHEO/PGL management, but can be costly and time‐consuming; newer techniques to resolve these limitations are being explored. Messenger RNA expression profiles can help broadly classify PHEO/PGL into two well‐established clusters based on their broader mechanistic errors. Additional clustering mechanisms are being proposed based on other analyses, including miRNA, transcriptomic, metabolomic and proteomic studies. Beyond clustering, unifying theories to link PHEO/PGL susceptibility genes have been proposed to link all 17 genes to a common signalling pathway, focusing particularly on the processes of apoptosis and hypoxia response. Identifying common targets between the genes could aid in the identification of novel treatment strategies for patients with these rare neuroendocrine tumours.