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.
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Acknowledgements
The UNC Biospecimen Core Facility, Mammalian Genotyping Core Facility and Translational Pathology Laboratory provided technical assistance for this study. Funding for this research was provided by: the 985 Program from the Chinese Ministry of Education (KLG, YX), MOST 973 (No. 2009CB918401, No. 2011CB910600, No. 2012CB910300, No. 2012CB910101; DY, YX and KLG); the NSFC Program of International Cooperation and Exchanges (No. 81120108016; LXQ, YX) and the China National Key Projects for Infectious Disease (2008ZX10002-021, 2012ZX10002-012; LZQ), the National Institutes of Health (KLG, YX, SST, LRR), the James S McDonnell Foundation (YX), the Samuel Waxman Cancer Research Foundation (YX), the American Gastroenterological Association Foundation for Digestive Health and Nutrition (LRR), the Alfred P Sloan Foundation fellowship (DYC), the Nancy Stegman Cancer Research Fund (DYC) and the University Cancer Research Fund (DYC, YX).
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DYC is a consultant for Aveo Pharmaceuticals and Entremed, and held minor stock ownership in Illumina, which did not have any role in the study design, data collection and analysis, decision to publish or preparation of the manuscript.
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Wang, P., Dong, Q., Zhang, C. et al. Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas. Oncogene 32, 3091–3100 (2013). https://doi.org/10.1038/onc.2012.315
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DOI: https://doi.org/10.1038/onc.2012.315
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