Wang Hao-Yuan, Tang Kai, Liang Ting-Yu, Zhang Wei-Zhong, Li Ji-Ye, Wang Wen, Hu Hui-Min, Li Ming-Yang, Wang Hui-Qing, He Xiao-Zheng, Zhu Zhi-Yuan, Liu Yan-Wei, Zhang Shi-Zhong
Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, 253# Gongye Road, Guangzhou, China.
The National Key Clinical Specialty. The Engineering Technology Research Center of Education Ministry of China Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
J Exp Clin Cancer Res. 2016 May 31;35:86. doi: 10.1186/s13046-016-0362-7.
Mutations in isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) are frequent in low-grade gliomas and secondary glioblastomas (sGBM). Because they yield the same oncometabolite, D-2-hydroxyglutarate, they are often treated as equivalent and pooled. The objective of this study was to provide insight into the differences between IDH1 and IDH2 mutant gliomas.
To investigate the different clinical and molecular characterization between IDH1 mutant and IDH2 mutant gliomas, we studied 811 patients with IDH1 mutations, IDH2 mutations and IDH1/2 wild-type. In addition, whole-transcriptome sequencing and DNA methylation data were used to assess the distribution of genetic changes in IDH1 and IDH2 mutant gliomas in a Chinese population-based cohort.
Among 811 gliomas in our cohort, 448 cases (55.2%) harbored an IDH1 mutation, 18 cases (2.2%) harbored an IDH2 mutation and 345 cases (42.6%) harbored an IDH1/2 wild-type. We found that IDH1 and IDH2 are mutually exclusive in gliomas, and IDH2 mutations are mutually exclusive with PTEN, P53 and ATRX mutations. Patients with IDH2 mutations had a higher frequency of 1p/19q co-deletion (p < 0.05) than IDH1 mutant patients. In addition, a Gene Set Enrichment Analysis (GSEA) showed that IDH2 mutant gliomas were associated with the oxidative phosphorylation gene set, and the four most representative biological processes for genes commonly altered by hypermethylation in IDH2 mutant gliomas were the regulation of cell proliferation, cell motion, cell migration and response to hypoxia. Patients with IDH2 mutant gliomas exhibited longer Overall survival (OS) (p < 0.05) and longer Progression-free survival (PFS) (p < 0.05) than patients with IDH1/2 wild-type gliomas. However, their OS and PFS did not differ from that of IDH1 mutant patients.
Our study revealed an intrinsic distinction between IDH1 and IDH2 mutant gliomas, and these mutations should be considered separately because their differences could have implications for the diagnosis and treatment of IDH1/2 mutant gliomas.
异柠檬酸脱氢酶1（IDH1）和异柠檬酸脱氢酶2（IDH2）突变在低级别胶质瘤和继发性胶质母细胞瘤（sGBM）中很常见。由于它们产生相同的致癌代谢物D-2-羟基戊二酸，因此常被视为等效并合并处理。本研究的目的是深入了解IDH1和IDH2突变型胶质瘤之间的差异。
为了研究IDH1突变型和IDH2突变型胶质瘤之间不同的临床和分子特征，我们研究了811例IDH1突变、IDH2突变及IDH1/2野生型的患者。此外，利用全转录组测序和DNA甲基化数据评估了基于中国人群队列中IDH1和IDH2突变型胶质瘤的基因变化分布。
在我们队列的811例胶质瘤中，448例（55.2%）存在IDH1突变，18例（2.2%）存在IDH2突变，345例（42.6%）为IDH1/2野生型。我们发现IDH1和IDH2在胶质瘤中相互排斥，且IDH2突变与PTEN、P53和ATRX突变相互排斥。IDH2突变患者的1p/19q共缺失频率高于IDH1突变患者（p < 0.05）。此外，基因集富集分析（GSEA）显示IDH2突变型胶质瘤与氧化磷酸化基因集相关，IDH2突变型胶质瘤中因高甲基化而常见改变的基因的四个最具代表性的生物学过程是细胞增殖调控、细胞运动、细胞迁移和低氧反应。与IDH1/2野生型胶质瘤患者相比，IDH2突变型胶质瘤患者的总生存期（OS）更长（p < 0.05），无进展生存期（PFS）也更长（p < 0.05）。然而，其OS和PFS与IDH1突变患者并无差异。
我们的研究揭示了IDH1和IDH2突变型胶质瘤之间的内在差异，这些突变应分别考虑，因为它们的差异可能对IDH1/2突变型胶质瘤的诊断和治疗产生影响。
