title: The comparison of clinical and biological characteristics between IDH1 and IDH2 mutations in gliomas.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.|Chinese Glioma Cooperative Group (CGCG), Beijing, China.
authors.forename: Hao-Yuan
authors.initials: HY
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, No. 6 TiantanXili, Dongcheng District, Beijing, 100050, China.|Chinese Glioma Cooperative Group (CGCG), Beijing, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Tang
authors.affiliation: Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.|Chinese Glioma Cooperative Group (CGCG), Beijing, China.
authors.forename: Ting-Yu
authors.initials: TY
authors.lastname: Liang
authors.affiliation: 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.
authors.forename: Wei-Zhong
authors.initials: WZ
authors.lastname: Zhang
authors.affiliation: Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.|Center for Brain Disorders Research, Capital Medical University, Beijing, 100069, China.
authors.forename: Ji-Ye
authors.initials: JY
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, No. 6 TiantanXili, Dongcheng District, Beijing, 100050, China.|Chinese Glioma Cooperative Group (CGCG), Beijing, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Wang
authors.affiliation: Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.|Chinese Glioma Cooperative Group (CGCG), Beijing, China.
authors.forename: Hui-Min
authors.initials: HM
authors.lastname: Hu
authors.affiliation: Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.|Chinese Glioma Cooperative Group (CGCG), Beijing, China.
authors.forename: Ming-Yang
authors.initials: MY
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Hui-Qing
authors.initials: HQ
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Xiao-Zheng
authors.initials: XZ
authors.lastname: He
authors.affiliation: 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.
authors.forename: Zhi-Yuan
authors.initials: ZY
authors.lastname: Zhu
authors.affiliation: Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, No. 6 TiantanXili, Dongcheng District, Beijing, 100050, China. liuyanwei_tiantan@163.com.|Beijing Neurosurgical Institute, Capital Medical University, Beijing, China. liuyanwei_tiantan@163.com.|Chinese Glioma Cooperative Group (CGCG), Beijing, China. liuyanwei_tiantan@163.com.
authors.forename: Yan-Wei
authors.initials: YW
authors.lastname: Liu
authors.affiliation: Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, 253# Gongye Road, Guangzhou, China. shizhong_zh@163.com.|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. shizhong_zh@163.com.
authors.forename: Shi-Zhong
authors.initials: SZ
authors.lastname: Zhang
mesh_terms: D044466:Asian People; D002465:Cell Movement; D049109:Cell Proliferation; D002681:China; D019175:DNA Methylation; D005260:Female; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D005910:Glioma / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D008297:Male; D009154:Mutation; D011379:Prognosis; D017423:Sequence Analysis, RNA; D016019:Survival Analysis
chemical_list: C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human
keywords: DNA methylation analyzes; Glioma; IDH mutation; Whole transcriptome sequencing