Genetics of Pheochromocytoma


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.

Keywords: genetics; pheochromocytoma; paraganglioma; hypoxia; hypoxia‐inducible factors; succinate dehydrogenase

Figure 1.

Recommended genetic testing algorithm for patients with PHEO/PGL. *If both normetanephrine and methoxytyramine are elevated, follow the algorithm for methoxytyramine. If both normetanephrine and metanephrine are elevated, follow the algorithm for metanephrine. **In patients with elevated normetanephrine with clinical features that do not clearly indicate which gene to test, perform immunohistochemistry for SDHB and SDHA. +If tumour is adrenal, TMEM127 testing may be considered. Abbreviations: DA, dopamine; HIF2A, hypoxia‐inducible factor 2‐alpha; HNP, head and neck PGL; h/o, history of; MAX, myc‐associated factor X; MEN2, multiple endocrine neoplasia type 2; MTY, methoxytyramine; NF1, neurofibromatosis type 1; RET, rearranged during transfection; SDHA, succinate dehydrogenase subunit A; SDHB, succinate dehydrogenase subunit B; SDHC, succinate dehydrogenase subunit C; SDHD, succinate dehydrogenase subunit D; TMEM127, transmembrane protein 127; VHL, von Hippel–Lindau. Adapted from Karasek et al. (). © US Government.

Figure 2.

Regulation of hypoxia‐inducible factors (HIFs) under normoxia and hypoxia. Multiple PHEO and PGL susceptibility genes are involved in HIF regulation, suggesting a common role for HIF in the pathogenesis of PHEO/PGL. Reproduced from Jochmanová et al. (). © US Government.



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Further Reading

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Eisenhofer G, Pacak K, Huynh TT et al. (2011) Catecholamine metabolomic and secretory phenotypes in phaeochromocytoma. Endocrine‐Related Cancer 18(1): 97–111.

Fishbein L, Merrill S, Fraker DL, Cohen DL and Nathanson KL (2013) Inherited mutations in pheochromocytoma and paraganglioma: why all patients should be offered genetic testing. Annals of Surgical Oncology 20(5): 1444–1450.

Ni Y, Zbuk KM, Sadler T et al. (2008) Germline mutations and variants in the succinate dehydrogenase genes in Cowden and Cowden‐like syndromes. American Journal of Human Genetics 83(2): 261–268.

Vicha A, Musil Z and Pacak K (2013) Genetics of pheochromocytoma and paraganglioma syndromes: new advances and future treatment options. Current Opinion in Endocrinology & Diabetes and Obesity 20(3): 186–191.

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Martucci, Victoria L, and Pacak, Karel(Apr 2014) Genetics of Pheochromocytoma. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0025302]