Mutations of the metabolic genes IDH1, IDH2, and SDHAF2 are not major determinants of the pseudohypoxic phenotype of sporadic pheochromocytomas and paragangliomas

Context: Pheochromocytomas and paragangliomas are genetically heterogeneous tumors of neural crest origin. Approximately half of these tumors activate a pseudohypoxic transcription response, which is due in a minority of the cases to germline mutations of the VHL gene or the genes encoding subunits of the metabolicenzymesuccinate dehydrogenase (SDH),SDHB,SDHC,orSDHD. However, the genetic basis of the hypoxic-like profile of the remaining tumors is undetermined. Mutations in genes involved in the energy metabolism, isocitrate dehydrogenase 1 (IDH1) and -2 (IDH2) and SDHAF2, a component of SDH, can mimic a pseudohypoxic state. Design:Weexamined the sequence spanning the mutation-susceptible codons 132 ofIDH1and172 of IDH2,andthe entire coding region ofSDHAF2, in 104 pheochromocytomasandparagangliomas, including tumors with a pseudohypoxic expression profile. Results: We did not find mutations in IDH1, IDH2, or SDHAF2 in any of the tumors in this cohort. Conclusion: Conserved residues of IDH1 and IDH2 or the SDHAF2 gene are not frequently mutated in pheochromocytomas and paragangliomas. The molecular basis for activation of a hypoxic response in the majority of tumors without VHL or SDH mutations remains to be defined.