Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2013-06

AUTHORS

Pu Wang, Qiongzhu Dong, Chong Zhang, Pei-Fen Kuan, Yufeng Liu, William R. Jeck, Jesper B. Andersen, Wenqing Jiang, Gleb L. Savich, Ting-Xu Tan, J. Todd Auman, Janelle M. Hoskins, Anne D. Misher, Catherine D. Moser, Scott M. Yourstone, Jin Woo Kim, Kristian Cibulskis, Gad Getz, Heike V. Hunt, Snorri S. Thorgeirsson, Lewis R. Roberts, Dan Ye, Kun-Liang Guan, Yue Xiong, Lun-Xiu Qin, Derek Y. Chiang

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. More... »

PAGES

3091

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/onc.2012.315

DOI

http://dx.doi.org/10.1038/onc.2012.315

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1046269452

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/22824796


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