Department of Pathology, Josephine Nefkens Institute, Room Ae304, Erasmus MC, University Medical Center Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.
J Clin Endocrinol Metab. 2010 Mar;95(3):1274-8. doi: 10.1210/jc.2009-2170. Epub 2009 Nov 13.
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.
副神经节瘤和嗜铬细胞瘤是神经内分泌肿瘤，它们可以偶发出现，也可以出现在遗传肿瘤综合征的背景下，包括遗传性副神经节瘤-嗜铬细胞瘤综合征和 von Hippel-Lindau 病（VHL）。副神经节瘤-嗜铬细胞瘤综合征是由线粒体琥珀酸脱氢酶（SDH）基因 SDHB、SDHC、SDHD 或 SDHAF2 的种系失活突变引起的，而 VHL 是 VHL 基因突变失活的结果。在 SDH 和 VHL 相关的副神经节瘤和嗜铬细胞瘤中，缺氧诱导因子（HIF）的稳定已被描述为因果致癌事件。最近，在多形性胶质母细胞瘤中也发现了 HIF 的激活，这是由于异柠檬酸脱氢酶（IDH）1 型或 2 型酶的体细胞突变失活所致。这些发现表明，IDH1 和 IDH2 突变也可能在副神经节瘤和嗜铬细胞瘤的肿瘤发生中发挥作用，尤其是在非 SDH 或非 VHL 相关的肿瘤中。
我们研究了 365 例嗜铬细胞瘤和副神经节瘤，包括 269 例无 SDH 或 VHL 基因突变的散发性肿瘤，以检测 IDH1 和 IDH2 的突变。仅筛选了 132 和 172 号密码子，因为这两个密码子是唯一涉及的。
在一名 61 岁女性诊断的散发性颈动脉副神经节瘤中发现了一个 IDH1 p.Arg132Cys 点突变，这是一个体细胞杂合突变。在 234 例嗜铬细胞瘤中未发现突变。
IDH 突变在副神经节瘤和嗜铬细胞瘤中非常罕见，似乎在已知存在于这些肿瘤中的致瘤 HIF 激活中不起重要作用。
