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

Oncogene volume 32, pages 3091–3100 (2013)Cite this article

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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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References

  1. Yan H, Parsons DW, Jin GL, McLendon R, Rasheed BA, Yuan WS et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med 2009; 360: 765–773.

    Article  CAS  Google Scholar 

  2. Marcucci G, Maharry K, Wu YZ, Radmacher MD, Mrozek K, Margeson D et al. IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B Study. J Clin Oncol 2010; 28: 2348–2355.

    Article  CAS  Google Scholar 

  3. Amary MF, Bacsi K, Maggiani F, Damato S, Halai D, Berisha F et al. IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J Pathol 2011; 224: 334–343.

    Article  CAS  Google Scholar 

  4. Shibata T, Kokubu A, Miyamoto M, Sasajima Y, Yamazaki N . Mutant IDH1 confers an in vivo growth in a melanoma cell line with BRAF mutation. Am J Pathol 2011; 178: 1395–1402.

    Article  CAS  Google Scholar 

  5. Amary MF, Damato S, Halai D, Eskandarpour M, Berisha F, Bonar F et al. Ollier disease and Maffucci syndrome are caused by somatic mosaic mutations of IDH1 and IDH2. Nat Genet 2011; 43: 1262–1265.

    Article  CAS  Google Scholar 

  6. Pansuriya TC, van Eijk R, d'Adamo P, van Ruler MA, Kuijjer ML, Oosting J et al. Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome. Nat Genet 2011; 43: 1256–1261.

    Article  CAS  Google Scholar 

  7. Zhao SM, Lin Y, Xu W, Jiang WQ, Zha ZY, Wang P et al. Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1 alpha. Science 2009; 324: 261–265.

    Article  CAS  Google Scholar 

  8. Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 2009; 462: 739–744.

    Article  CAS  Google Scholar 

  9. Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell 2011; 19: 17–30.

    Article  CAS  Google Scholar 

  10. Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoeitic differentiation. Cancer Cell 2010; 18: 553–567.

    Article  CAS  Google Scholar 

  11. Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 2009; 324: 930–935.

    Article  CAS  Google Scholar 

  12. Ito S, D'Alessio AC, Taranova OV, Hong K, Sowers LC, Zhang Y . Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature 2010; 466: 1129–1133.

    Article  CAS  Google Scholar 

  13. Ito S, Shen L, Dai Q, Wu SC, Collins LB, Swenberg JA et al. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 2011; 333: 1300–1303.

    Article  CAS  Google Scholar 

  14. He YF, Li BZ, Li Z, Liu P, Wang Y, Tang Q et al. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science 2011; 333: 1303–1307.

    Article  CAS  Google Scholar 

  15. Noushmehr H, Weisenberger DJ, Diefes K, Phillips HS, Pujara K, Berman BP et al. Identification of a CpG Island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 2010; 17: 510–522.

    Article  CAS  Google Scholar 

  16. Verhaak RGW, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 2009; 17: 98–110.

    Article  Google Scholar 

  17. Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P et al. An integrated genomic analysis of human glioblastoma multiforme. Science 2008; 321: 1807–1812.

    Article  CAS  Google Scholar 

  18. Toyota M, Ahuja N, Ohe-Toyota M, Herman JG, Baylin SB, Issa JP . CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci USA 1999; 96: 8681–8686.

    Article  CAS  Google Scholar 

  19. Nagasaka T, Sasamoto H, Notohara K, Cullings HM, Takeda M, Kimura K et al. Colorectal cancer with mutation in BRAF, KRAS, and wild-type with respect to both oncogenes showing different patterns of DNA methylation. J Clin Oncol 2004; 22: 4584–4594.

    Article  CAS  Google Scholar 

  20. Jones PA, Baylin SB . The epigenomics of cancer. Cell 2007; 128: 683–692.

    Article  CAS  Google Scholar 

  21. Widschwendter M, Fiegl H, Egle D, Mueller-Holzner E, Spizzo G, Marth C et al. Epigenetic stem cell signature in cancer. Nature Genet 2007; 39: 157–158.

    Article  CAS  Google Scholar 

  22. Ohm JE, McGarvey KM, Yu X, Cheng LZ, Schuebel KE, Cope L et al. A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing. Nat Genet 2007; 39: 237–242.

    Article  CAS  Google Scholar 

  23. Schlesinger Y, Straussman R, Keshet I, Farkash S, Hecht M, Zimmerman J et al. Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer. Nat Genet 2007; 39: 232–236.

    Article  CAS  Google Scholar 

  24. Fang F, Turcan S, Rimner A, Kaufman A, Giri D, Morris LG et al. Breast cancer methylomes establish an epigenomic foundation for metastasis. Sci Transl Med 2011; 3: 75ra25.

    Article  Google Scholar 

  25. Blechacz B, Gores GJ . Cholangiocarcinoma: advances in pathogenesis, diagnosis, and treatment. Hepatology 2008; 48: 308–321.

    Article  CAS  Google Scholar 

  26. Hezel AF, Deshpande V, Zhu AX . Genetics of biliary tract cancers and emerging targeted therapies. J Clin Oncol 2010; 28: 3531–3540.

    Article  CAS  Google Scholar 

  27. Yang B, Zhong C, Peng YJ, Lai Z, Ding JP . Molecular mechanisms of ‘off-on switch’ of activities of human IDH1 by tumor-associated mutation R132H. Cell Res 2010; 20: 1188–1200.

    Article  CAS  Google Scholar 

  28. Xu Y, Wu F, Tan L, Kong L, Xiong L, Deng J et al. Genome-wide regulation of 5hmC, 5mC, and gene expression by Tet1 hydroxylase in mouse embryonic stem cells. Mol Cell 2011; 42: 451–464.

    Article  CAS  Google Scholar 

  29. Dunn GP, Rinne ML, Wykosky J, Genovese G, Quayle SN, Dunn IF et al. Emerging insights into the molecular and cellular basis of glioblastoma. Genes Dev 2012; 26: 756–784.

    Article  CAS  Google Scholar 

  30. Watanabe T, Nobusawa S, Kleihues P, Ohgaki H . IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas. Am J Pathol 2009; 174: 1149–1153.

    Article  CAS  Google Scholar 

  31. Aishima S, Kuroda Y, Nishihara Y, Taguchi K, Taketomi A, Maehara Y et al. Gastric mucin phenotype defines tumour progression and prognosis of intrahepatic cholangiocarcinoma: gastric foveolar type is associated with aggressive tumour behaviour. Histopathology 2006; 49: 35–44.

    Article  CAS  Google Scholar 

  32. Andersen JB, Spee B, Bechacz BR, Avital I, Komuta M, Barbour A et al. Genomic and genetic characterization of cholangiocarcinoma identifies therapeutic targets for tyrosine kinase inhibitors. Gastroenterology 2012; 142: 1021–1031.

    Article  CAS  Google Scholar 

  33. Borger DR, Tanabe KK, Fan KC, Lopez HU, Fantin VR, Straley KS et al. Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping. Oncologis 2012; 17: 72–79.

    Article  CAS  Google Scholar 

  34. Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 2010; 17: 225–234.

    Article  CAS  Google Scholar 

  35. Kipp BR, Voss JS, Kerr SE, Barr Fritcher EG, Graham RP, Zhang L et al. Isocitrate dehydrogenase 1 and 2 mutations in cholangiocarcinoma. Hum Pathol 2012.

  36. Moran-Crusio K, Reavie L, Shih A, Abdel-Wahab O, Ndiaye-Lobry D, Lobry C et al. Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell 2011; 20: 11–24.

    Article  CAS  Google Scholar 

  37. Abdel-Wahab O, Manshouri T, Patel J, Harris K, Yao JJ, Hedvat C et al. Genetic analysis of transforming events that convert chronic myeloproliferative neoplasms to leukemias. Cancer Res 2010; 70: 447–452.

    Article  CAS  Google Scholar 

  38. Turner R, Lozoya O, Wang Y, Cardinale V, Gaudio E, Alpini G et al. Human hepatic stem cell and maturational liver lineage biology. Hepatology 2011; 53: 1035–1045.

    Article  CAS  Google Scholar 

  39. Cardinale V, Wang Y, Carpino G, Mendel G, Alpini G, Gaudio E et al. The biliary tree-a reservoir of multipotent stem cells. Nat Rev Gastroenterol Hepatol 2012; 9: 231–240.

    Article  CAS  Google Scholar 

  40. Hinoue T, Weisenberger DJ, Lange CP, Shen H, Byun HM, Van Den Berg D et al. Genome-scale analysis of aberrant DNA methylation in colorectal cancer. Genome Res 2012; 22: 271–282.

    Article  CAS  Google Scholar 

  41. Brenet F, Moh M, Funk P, Feierstein E, Viale AJ, Socci ND et al. DNA methylation of the first exon is tightly linked to transcriptional silencing. PLoS One 2011; 6: e14524.

    Article  CAS  Google Scholar 

  42. Chapman MA, Lawrence MS, Keats JJ, Cibulskis K, Sougnez C, Schinzel AC et al. Initial genome sequencing and analysis of multiple myeloma. Nature 2011; 471: 467–472.

    Article  CAS  Google Scholar 

  43. Llovet JM, Di Bisceglie AM, Bruix J, Kramer BS, Lencioni R, Zhu AX et al. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst 2008; 100: 698–711.

    Article  Google Scholar 

  44. Andersen JB, Factor VM, Marquardt JU, Raggi C, Lee YH, Seo D et al. An integrated genomic and epigenomic approach predicts therapeutic response to zebularine in human liver cancer. Sci Transl Med 2010; 2: 54ra77.

    PubMed  PubMed Central  Google Scholar 

  45. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 2005; 102: 15545–15550.

    Article  CAS  Google Scholar 

  46. Merico D, Isserlin R, Stueker O, Emili A, Bader GD . Enrichment map: a network-based method for gene-set enrichment visualization and interpretation. PLoS One 2010; 5: e13984.

    Article  Google Scholar 

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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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Author notes

  1. P Wang and Q Dong: These authors contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China

    P Wang, W Jiang, K-L Guan & Y Xiong

  2. Molecular and Cell Biology Laboratory, Institute of Biomedical Sciences, Fudan University, Shanghai, China

    P Wang, W Jiang, D Ye, K-L Guan & Y Xiong

  3. Liver Cancer Institute and Zhongshan Hospital, Institute of Biomedical Sciences, Fudan University, Shanghai, China

    Q Dong & L-X Qin

  4. Department of Statistics and Operations Research, Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, NC, USA

    C Zhang & Y Liu

  5. Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA

    P-F Kuan

  6. Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA

    P-F Kuan, W R Jeck, G L Savich, T-X Tan, J T Auman, J M Hoskins, A D Misher, S M Yourstone, Y Xiong & D Y Chiang

  7. Department of Genetics, University of North Carolina, Chapel Hill, NC, USA

    W R Jeck, G L Savich, T-X Tan, S M Yourstone & D Y Chiang

  8. Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    J B Andersen & S S Thorgeirsson

  9. Institute of Pharmacogenomics and Individualized Medicine, University of North Carolina, Chapel Hill, NC, USA

    J T Auman, J M Hoskins & A D Misher

  10. Division of Gastroenterology and Hepatology, Mayo Clinic Center for Cell Signaling in Gastroenterology, Mayo Clinic Cancer Center, Mayo Clinic, Rochester, MN, USA

    C D Moser & L R Roberts

  11. Center for Cancer Genomics, Wake Forest University Baptist Medical Center, Winston-Salem, NC, USA

    J W Kim

  12. Genome Sequencing Analysis Program and Platform, Broad Institute, 7 Cambridge Center, Cambridge, MA, USA

    K Cibulskis & G Getz

  13. Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA

    H V Hunt

  14. Department of Biochemistry, Shanghai Medical College, Fudan University, Shanghai, China

    K-L Guan

  15. Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA

    K-L Guan

  16. Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC, USA

    Y Xiong

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  1. P Wang
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Correspondence to Y Xiong, L-X Qin or D Y Chiang.

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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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