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@ARTICLE{Goeppert:120090,
      author       = {B. Goeppert and C. Konermann$^*$ and C. R. Schmidt$^*$ and
                      O. Bogatyrova$^*$ and L. Geiselhart$^*$ and C. Ernst$^*$ and
                      L. Gu$^*$ and N. Becker$^*$ and M. Zucknick$^*$ and A.
                      Mehrabi and M. Hafezi and F. Klauschen and A. Stenzinger and
                      A. Warth and K. Breuhahn and M. Renner and W. Weichert and
                      P. Schirmacher and C. Plass$^*$ and D. Weichenhan$^*$},
      title        = {{G}lobal alterations of {DNA} methylation in
                      cholangiocarcinoma target the {W}nt signaling pathway.},
      journal      = {Hepatology},
      volume       = {59},
      number       = {2},
      issn         = {0270-9139},
      address      = {New York [u.a.]},
      publisher    = {Wiley Interscience},
      reportid     = {DKFZ-2017-00677},
      pages        = {544 - 554},
      year         = {2014},
      abstract     = {The molecular mechanisms underlying the genesis of
                      cholangiocarcinomas (CCs) are poorly understood. Epigenetic
                      changes such as aberrant hypermethylation and subsequent
                      atypical gene expression are characteristic features of most
                      human cancers. In CC, data regarding global methylation
                      changes are lacking so far. We performed a genome-wide
                      analysis for aberrant promoter methylation in human CCs. We
                      profiled 10 intrahepatic and 8 extrahepatic CCs in
                      comparison to non-neoplastic biliary tissue specimens, using
                      methyl-CpG immunoprecipitation (MCIp) combined with
                      whole-genome CpG island arrays. DNA methylation was
                      confirmed by quantitative mass spectrometric analysis and
                      functional relevance of promoter hypermethylation was shown
                      in demethylation experiments of two CC cell lines using
                      5-aza-2'deoxycytidine (DAC) treatment. Immunohistochemical
                      staining of tissue microarrays (TMAs) from 223 biliary tract
                      cancers (BTCs) was used to analyze candidate gene expression
                      at the protein level. Differentially methylated,
                      promoter-associated regions were nonrandomly distributed and
                      enriched for genes involved in cancer-related pathways
                      including Wnt, transforming growth factor beta (TGF-β), and
                      PI3K signaling pathways. In CC cell lines, silencing of
                      genes involved in Wnt signaling, such as SOX17, WNT3A, DKK2,
                      SFRP1, SFRP2, and SFRP4 was reversed after DAC
                      administration. Candidate protein SFRP2 was substantially
                      down-regulated in neoplastic tissues of all BTC subtypes as
                      compared to normal tissues. A significant inverse
                      correlation of SFRP2 protein expression and pT status was
                      found in BTC patients.We provide a comprehensive analysis to
                      define the genome-wide methylation landscape of human CC.
                      Several candidate genes of cancer-relevant signaling
                      pathways were identified, and closer analysis of selected
                      Wnt pathway genes confirmed the relevance of this pathway in
                      CC. The presented global methylation data are the basis for
                      future studies on epigenetic changes in
                      cholangiocarcinogenesis.},
      keywords     = {DNA, Neoplasm (NLM Chemicals) / Membrane Proteins (NLM
                      Chemicals) / SFRP2 protein, human (NLM Chemicals) / Wnt
                      Proteins (NLM Chemicals)},
      cin          = {C010 / C060},
      ddc          = {610},
      cid          = {I:(DE-He78)C010-20160331 / I:(DE-He78)C060-20160331},
      pnm          = {313 - Cancer risk factors and prevention (POF3-313)},
      pid          = {G:(DE-HGF)POF3-313},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:24002901},
      doi          = {10.1002/hep.26721},
      url          = {https://inrepo02.dkfz.de/record/120090},
}