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Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas
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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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“Like TH17 cells, CD8+ T cells are highly dependent on the activation of HIF-1α and glycolysis, which is responsible for mediating trafficking into hypoxic tumour environments and inflamed tissue147,148.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [148]
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Metadata
- Authors
- Wang, P., Dong, Q., Zhang, C., Kuan, P.-F., Liu, Y., Jeck, W. R., Andersen, J. B., Jiang, W., Savich, G. L., Tan, T.-X., Auman, J. T., Hoskins, J. M., Misher, A. D., Moser, C. D., Yourstone, S. M., Kim, J. W., Cibulskis, K., Getz, G., Hunt, H. V., Thorgeirsson, S. S., Roberts, L. R., Ye, D., Guan, K.-L., Xiong, Y., Qin, L.-X., & Chiang, D. Y.
- Affiliations
- Fudan University (CN)
- Shanghai Medical College of Fudan University (CN)
- University of North Carolina at Chapel Hill (US)
- National Institutes of Health (US)
- Mayo Clinic (US)
- Atrium Health Wake Forest Baptist (US)
- Broad Institute (US)
- Corresponding author
- Xiong, Y
- Qin, L-X
- Chiang, D Y
- ORCID
- Venue
- Oncogene
- Published
- 2012-07-23
- Volume
- 32
- Issue
- 25
- Pages
- 3091-3100
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- PMC
- PMC3500578
- OpenAlex
- W2018041848
- Cited by
- 399
- References
- 48
- Citations by year
- 2026: 20 · 2025: 19 · 2024: 26 · 2023: 22 · 2022: 19 · 2021: 38 · 2020: 38 · 2019: 31 · 2018: 27 · 2017: 38 · 2016: 29 · 2015: 37 · 2014: 30 · 2013: 22 · 2012: 3
- FWCI
- 29.96
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- Fudan University
- National Institutes of Health (5r01ca149569-05)
- National Human Genome Research Institute (R01HG006272)
- National Cancer Institute (R01-CA149569, R01CA163834)
- Topics
- Health Sciences › Medicine › Surgery › Cholangiocarcinoma and Gallbladder Cancer Studies
- Health Sciences › Medicine › Surgery › Pediatric Hepatobiliary Diseases and Treatments
- Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
- Keywords
- IDH mutation, IDH1, IDH2, intrahepatic cholangiocarcinoma, DNA hypermethylation, 5-hydroxymethylcytosine, 5-methylcytosine, p53 activation, overall survival, tumor recurrence, glioblastoma, transcriptional regulation, tumor resection
- MeSH terms
- Base Sequence, Bile Duct Neoplasms, Bile Ducts, Intrahepatic, Brain Neoplasms, Glioblastoma, Histones, Humans, Isocitrate Dehydrogenase, Liver Neoplasms, Mutation, Neoplasm Recurrence, Local, Tumor Suppressor Protein p53, Sequence Analysis, DNA, Cholangiocarcinoma, CpG Islands, DNA Methylation
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