Casar-Borota Olivera, Øystese Kristin Astrid Berland, Sundström Magnus, Melchior Linea, Popovic Vera
Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, Dag Hammarskjölds väg 20, 751 85, Uppsala, Sweden.
Department of Clinical Pathology and Cytology, Uppsala University Hospital, Rudbeck Laboratory, Dag Hammarskjölds väg 20, 751 85, Uppsala, Sweden.
Pituitary. 2016 Aug;19(4):407-14. doi: 10.1007/s11102-016-0720-7.
Inactivating mutations of isocitrate dehydrogenase (IDH) 1 and 2, mitochondrial enzymes participating in the Krebs tricarboxylic acid cycle play a role in the tumorigenesis of gliomas and also less frequently in acute myeloid leukemia and other malignancies. Inhibitors of mutant IDH1 and IDH2 may potentially be effective in the treatment of the IDH mutation driven tumors. Mutations in the succinate dehydrogenase, the other enzyme complex participating in the Krebs cycle and electron transfer of oxidative phosphorylation occur in the paragangliomas, gastrointestinal stromal tumors, and occasionally in the pituitary adenomas. We aimed to determine whether the IDH1(R132H) mutation, the most frequent IDH mutation in human malignancies, occurs in pituitary adenomas.
We performed immunohistochemical analysis by using a monoclonal anti-IDH1(R132H) antibody on the tissue microarrays containing specimens from the pituitary adenomas of different hormonal types from 246 patients. In positive samples, the status of the IDH1 gene was further examined by molecular genetic analyses.
In all but one patient, there was no expression of mutated IDH1(R132H) protein in the tumor cells by immunohistochemistry. Only one patient with a recurring clinically non-functioning gonadotroph adenoma demonstrated IDH1(R132H)-immunostaining in both the primary tumor and the recurrence. However, no mutation in the IDH1 gene was detected using different molecular genetic analyses.
IDH1(R132H) mutation occurs only exceptionally in pituitary adenomas and does not play a role in their pathogenesis. Patients with pituitary adenomas do not seem to be candidates for treatment with the inhibitors of mutant IDH1.
异柠檬酸脱氢酶（IDH）1和2是参与三羧酸循环的线粒体酶，其失活突变在胶质瘤的肿瘤发生中起作用，在急性髓系白血病和其他恶性肿瘤中出现的频率较低。突变型IDH1和IDH2的抑制剂可能对治疗IDH突变驱动的肿瘤有效。琥珀酸脱氢酶是参与三羧酸循环和氧化磷酸化电子传递的另一种酶复合物，其突变发生在副神经节瘤、胃肠道间质瘤中，偶尔也出现在垂体腺瘤中。我们旨在确定人类恶性肿瘤中最常见的IDH突变即IDH1（R132H）突变是否存在于垂体腺瘤中。
我们使用单克隆抗IDH1（R132H）抗体对包含246例不同激素类型垂体腺瘤标本的组织芯片进行免疫组化分析。在阳性样本中，通过分子遗传学分析进一步检测IDH1基因的状态。
除1例患者外，免疫组化显示肿瘤细胞中均无突变型IDH1（R132H）蛋白表达。仅1例复发性临床无功能促性腺激素瘤患者在原发性肿瘤和复发病灶中均表现出IDH1（R132H）免疫染色。然而，使用不同的分子遗传学分析未检测到IDH1基因的突变。
IDH1（R132H）突变仅在垂体腺瘤中罕见发生，且在其发病机制中不起作用。垂体腺瘤患者似乎不是突变型IDH1抑制剂治疗的候选对象。
