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.

We investigated 365 pheochromocytomas and paragangliomas, including 269 sporadic tumors without SDH or VHL gene mutations, for mutations in IDH1 and IDH2. Only codons 132 and 172 were screened because these are the ones exclusively involved.

In one of 131 paragangliomas, a somatic heterozygous IDH1 p.Arg132Cys mutation was detected in a sporadic carotid paraganglioma diagnosed in a 61-yr-old woman. No mutations were found in 234 pheochromocytomas.

IDH mutations are very rare in paragangliomas and pheochromocytomas and do not appear to play an important role in oncogenic HIF activation known to be present in these tumors.