Isocitrate Dehydrogenase Mutations Are Rare in Pheochromocytomas and Paragangliomas

Paragangliomas and pheochromocytomas are neuroendocrine tumors that occur sporadically and in the context of inherited tumor syndromes including hereditary paraganglioma-pheochromocytoma syndrome and von Hippel-Lindau disease (VHL). The paraganglioma-pheochromocytoma syndrome is caused by germline-inactivating mutations in the mitochondrial succinate dehydrogenase (SDH) genes SDHB, SDHC, SDHD, or SDHAF2, and VHL is the result of inactivating VHL gene mutations. In SDH- and VHL-related paraganglioma and pheochromocytoma, hypoxia-inducible factor (HIF) stabilization has been described as the causal oncogenic event. Recently, HIF activation has also been found in glioblastoma multiforme, as the result of somatic mutational inactivation of the isocitrate dehydrogenase (IDH) type 1 or type 2 enzymes. These findings suggest that inactivating IDH1 and IDH2 mutations might also play a role in paraganglioma and pheochromocytoma tumorigenesis, especially in non-SDH- or non-VHL-related tumors.