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.
J Clin Endocrinol Metab. 2010 Mar;95(3):1469-72. doi: 10.1210/jc.2009-2245. Epub 2010 Feb 3.
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.
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.
We did not find mutations in IDH1, IDH2, or SDHAF2 in any of the tumors in this cohort.
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.
嗜铬细胞瘤和副神经节瘤是起源于神经嵴的具有遗传异质性的肿瘤。这些肿瘤中约有一半会激活假缺氧转录反应，少数情况下是由于 VHL 基因或编码代谢酶琥珀酸脱氢酶（SDH）亚基的基因的种系突变，SDHB、SDHC 或 SDHD。然而，其余肿瘤缺氧样特征的遗传基础尚未确定。参与能量代谢的基因（异柠檬酸脱氢酶 1（IDH1）和 2（IDH2）以及 SDH 的组成部分 SDHAF2）中的突变可以模拟假缺氧状态。
我们检查了 IDH1 的易突变密码子 132 和 IDH2 的 172 以及 SDHAF2 的整个编码区的序列，在 104 例嗜铬细胞瘤和副神经节瘤中，包括具有假缺氧表达谱的肿瘤。
在该队列的任何肿瘤中均未发现 IDH1、IDH2 或 SDHAF2 突变。
IDH1 和 IDH2 或 SDHAF2 基因的保守残基在嗜铬细胞瘤和副神经节瘤中很少发生突变。大多数没有 VHL 或 SDH 突变的肿瘤中激活缺氧反应的分子基础仍有待确定。
