Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China.
Fudan Institute for Metabolic Diseases, Fudan University, Shanghai, China.
Endocrine. 2018 Aug;61(2):216-223. doi: 10.1007/s12020-018-1617-1. Epub 2018 May 30.
Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors of neural crest origin. Germline or somatic mutations of numerous genes have been implicated in the pathogenesis of PPGLs, including the isocitrate dehydrogenase 1 (IDH1) gene and alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene. Although concurrent IDH1 and ATRX mutations are frequently seen in gliomas, they have never been reported together in PPGLs. The aim of this study was to characterize one paraganglioma with concurrent IDH1 and ATRX mutations identified by whole exome sequencing.
Leukocyte and tumor DNA were used for whole exome sequencing and Sanger sequencing. 2-hydroxyglurarate level and the global DNA methylation status in the tumor were measured. ATRX's cDNA transcripts were analyzed. Tyrosine hydroxylase (TH), HIF1α and ATRX staining, as well as telomere-specific FISH was also performed.
The presence of a somatic IDH1 (c.394C>T, p.R132C) mutation and a concurrent somatic ATRX splicing mutation (c.4318-2A>G) in the current case was confirmed. Dramatic accumulation of 2-hydroxyglutarate was detected in the paraganglioma without the global DNA hypermethylation, and pseudohypoxia was also activated. Importantly, immunohistochemistry revealed negative TH staining in the tumor and the first exon region of TH gene was hypermethylated resulting in normal plasma metanephrines. The splicing ATRX mutation resulted in two transcripts, causing frameshifts. Immunohistochemistry revealed scarce ATRX staining in the tumor. Alternative lengthening of telomeres (ALT) was detected by FISH.
This case represents the first concurrence of IDH1 and ATRX mutations in PPGLs. Although relatively rare, a somatic R132C mutation of IDH1 might play a role in a small subset of sporadic PPGLs.
嗜铬细胞瘤和副神经节瘤（PPGLs）是起源于神经嵴的神经内分泌肿瘤。许多基因的种系或体细胞突变与 PPGLs 的发病机制有关，包括异柠檬酸脱氢酶 1（IDH1）基因和α地中海贫血/智力迟钝综合征 X 连锁（ATRX）基因。虽然 IDH1 和 ATRX 突变在神经胶质瘤中经常同时发生，但它们从未在 PPGLs 中同时报道过。本研究的目的是通过全外显子组测序来描述一个同时存在 IDH1 和 ATRX 突变的副神经节瘤。
白细胞和肿瘤 DNA 用于全外显子组测序和 Sanger 测序。测量肿瘤中的 2-羟基戊二酸水平和全基因组 DNA 甲基化状态。分析 ATRX 的 cDNA 转录物。还进行了酪氨酸羟化酶（TH）、HIF1α 和 ATRX 染色以及端粒特异性 FISH。
本病例证实存在体细胞 IDH1（c.394C>T，p.R132C）突变和同时存在的体细胞 ATRX 剪接突变（c.4318-2A>G）。在没有全基因组 DNA 过度甲基化的情况下，副神经节瘤中检测到 2-羟基戊二酸的显著积累，并且假性缺氧也被激活。重要的是，免疫组织化学显示肿瘤中 TH 染色阴性，TH 基因的第一外显子区域发生高甲基化，导致正常的血浆代谢物。剪接 ATRX 突变导致两个转录本，导致移码。免疫组织化学显示肿瘤中 ATRX 染色稀少。通过 FISH 检测端粒的替代延长（ALT）。
本病例代表了 PPGLs 中 IDH1 和 ATRX 突变的首次同时发生。虽然相对罕见，但 IDH1 的体细胞 R132C 突变可能在一小部分散发性 PPGLs 中发挥作用。
