Mutations of the metabolic genes IDH1, IDH2, and SDHAF2 are not major determinants of the pseudohypoxic phenotype of sporadic pheochromocytomas and paragangliomas.
BACKGROUND
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 metabolic enzyme succinate dehydrogenase (SDH), SDHB, SDHC, or SDHD. 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.


METHODS
We examined the sequence spanning the mutation-susceptible codons 132 of IDH1 and 172 of IDH2, and the entire coding region of SDHAF2, in 104 pheochromocytomas and paragangliomas, 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.


CONCLUSIONS
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.
Yao
Li
L
Division of Hematology and Molecular Oncology, Department of Medicine and Cellular, Structural Biology, University of Texas Health Science Center, 7703 Floyd Curl Drive, MC7880, San Antonio, Texas 78229, USA.
Barontini
Marta
M
Niederle
Bruno
B
Jech
Marion
M
Pfragner
Roswitha
R
Dahia
Patricia L M
PL
D000008:Abdominal Neoplasms / Q000235:genetics; D000310:Adrenal Gland Neoplasms / Q000235:genetics; D015687:Cell Hypoxia / Q000235:genetics*; D020869:Gene Expression Profiling; D006258:Head and Neck Neoplasms / Q000235:genetics; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D024101:Mitochondrial Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D010235:Paraganglioma / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
D024101:Mitochondrial Proteins; C543341:SDHAF2 protein, human; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human