title: Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas.
abstract: Mutations in the genes encoding isocitrate dehydrogenase, IDH1 and IDH2, have been reported in gliomas, myeloid leukemias, chondrosarcomas and thyroid cancer. We discovered IDH1 and IDH2 mutations in 34 of 326 (10%) intrahepatic cholangiocarcinomas. Tumor with mutations in IDH1 or IDH2 had lower 5-hydroxymethylcytosine and higher 5-methylcytosine levels, as well as increased dimethylation of histone H3 lysine 79 (H3K79). Mutations in IDH1 or IDH2 were associated with longer overall survival (P=0.028) and were independently associated with a longer time to tumor recurrence after intrahepatic cholangiocarcinoma resection in multivariate analysis (P=0.021). IDH1 and IDH2 mutations were significantly associated with increased levels of p53 in intrahepatic cholangiocarcinomas, but no mutations in the p53 gene were found, suggesting that mutations in IDH1 and IDH2 may cause a stress that leads to p53 activation. We identified 2309 genes that were significantly hypermethylated in 19 cholangiocarcinomas with mutations in IDH1 or IDH2, compared with cholangiocarcinomas without these mutations. Hypermethylated CpG sites were significantly enriched in CpG shores and upstream of transcription start sites, suggesting a global regulation of transcriptional potential. Half of the hypermethylated genes overlapped with DNA hypermethylation in IDH1-mutant gliobastomas, suggesting the existence of a common set of genes whose expression may be affected by mutations in IDH1 or IDH2 in different types of tumors.
authors: State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China.
authors: P
authors: P
authors: Wang
authors: Q
authors: Q
authors: Dong
authors: C
authors: C
authors: Zhang
authors: P-F
authors: PF
authors: Kuan
authors: Y
authors: Y
authors: Liu
authors: W R
authors: WR
authors: Jeck
authors: J B
authors: JB
authors: Andersen
authors: W
authors: W
authors: Jiang
authors: G L
authors: GL
authors: Savich
authors: T-X
authors: TX
authors: Tan
authors: J T
authors: JT
authors: Auman
authors: J M
authors: JM
authors: Hoskins
authors: A D
authors: AD
authors: Misher
authors: C D
authors: CD
authors: Moser
authors: S M
authors: SM
authors: Yourstone
authors: J W
authors: JW
authors: Kim
authors: K
authors: K
authors: Cibulskis
authors: G
authors: G
authors: Getz
authors: H V
authors: HV
authors: Hunt
authors: S S
authors: SS
authors: Thorgeirsson
authors: L R
authors: LR
authors: Roberts
authors: D
authors: D
authors: Ye
authors: K-L
authors: KL
authors: Guan
authors: Y
authors: Y
authors: Xiong
authors: L-X
authors: LX
authors: Qin
authors: D Y
authors: DY
authors: Chiang
mesh_terms: D001483:Base Sequence; D001650:Bile Duct Neoplasms / Q000235:genetics / Q000378:metabolism; D001653:Bile Ducts, Intrahepatic / Q000473:pathology; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism; D018281:Cholangiocarcinoma / Q000235:genetics* / Q000378:metabolism; D018899:CpG Islands; D019175:DNA Methylation; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism; D006657:Histones / Q000235:genetics; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D017422:Sequence Analysis, DNA; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D006657:Histones; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human