Mutations of the Metabolic Genes IDH1, IDH2, and SDHAF2 are not major determinants of the Pseudohypoxic Phenotype of Sporadic Pheochromocytomas and Paragangliomas

YAO L, ; BARONTINI M, ; NIEDERLE B, ; JECH M, ; PFRAGNER R, ; DAHIA PL

JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM

ENDOCRINE SOC

Lugar: Springfield; Año: 2010 vol. 95 p. 1469 - 1472

0021-972X

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.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.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.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. (J Clin Endocrinol Metab 95: 1469–1472, 2010)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. (J Clin Endocrinol Metab 95: 1469–1472, 2010)