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@ARTICLE{Goeppert:143591,
      author       = {B. Goeppert and R. Toth$^*$ and S. Singer and T. Albrecht
                      and D. B. Lipka$^*$ and P. Lutsik$^*$ and D. Brocks$^*$ and
                      M. Baehr$^*$ and O. Muecke$^*$ and Y. Assenov$^*$ and L.
                      Gu$^*$ and V. Endris and A. Stenzinger and A. Mehrabi and P.
                      Schirmacher$^*$ and C. Plass$^*$ and D. Weichenhan$^*$ and
                      S. Roessler},
      title        = {{I}ntegrative {A}nalysis {D}efines {D}istinct {P}rognostic
                      {S}ubgroups of {I}ntrahepatic {C}holangiocarcinoma.},
      journal      = {Hepatology},
      volume       = {69},
      number       = {5},
      issn         = {1527-3350},
      address      = {New York [u.a.]},
      publisher    = {Wiley Interscience},
      reportid     = {DKFZ-2019-01171},
      pages        = {2091 - 2106},
      year         = {2019},
      abstract     = {Intrahepatic cholangiocarcinoma (iCCA) is the second most
                      common primary liver cancer. It is defined by cholangiocytic
                      differentiation and has poor prognosis. Recently, epigenetic
                      processes have been shown to play an important role in
                      cholangiocarcinogenesis. We performed an integrative
                      analysis on 52 iCCAs using both genetic and epigenetic data
                      with a specific focus on DNA methylation components. We
                      found recurrent isocitrate dehydrogenase 1 (IDH1) and IDH2
                      $(28\%)$ gene mutations, recurrent arm-length copy number
                      alterations (CNAs), and focal alterations such as deletion
                      of 3p21 or amplification of 12q15, which affect BRCA1
                      Associated Protein 1, polybromo 1, and mouse double minute 2
                      homolog. DNA methylome analysis revealed excessive
                      hypermethylation of iCCA, affecting primarily the bivalent
                      genomic regions marked with both active and repressive
                      histone modifications. Integrative clustering of genetic and
                      epigenetic data identified four iCCA subgroups with
                      prognostic relevance further designated as IDH, high (H),
                      medium (M), and low (L) alteration groups. The IDH group
                      consisted of all samples with IDH1 or IDH2 mutations and
                      showed, together with the H group, a highly disrupted
                      genome, characterized by frequent deletions of chromosome
                      arms 3p and 6q. Both groups showed excessive
                      hypermethylation with distinct patterns. The M group showed
                      intermediate characteristics regarding both genetic and
                      epigenetic marks, whereas the L group exhibited few
                      methylation changes and mutations and a lack of CNAs.
                      Methylation-based latent component analysis of cell-type
                      composition identified differences among these four groups.
                      Prognosis of the H and M groups was significantly worse than
                      that of the L group. Conclusion: Using an integrative
                      genomic and epigenomic analysis approach, we identified four
                      major iCCA subgroups with widespread genomic and epigenomic
                      differences and prognostic implications. Furthermore, our
                      data suggest differences in the cell-of-origin of the iCCA
                      subtypes.},
      cin          = {B370 / L101 / C010},
      ddc          = {610},
      cid          = {I:(DE-He78)B370-20160331 / I:(DE-He78)L101-20160331 /
                      I:(DE-He78)C010-20160331},
      pnm          = {312 - Functional and structural genomics (POF3-312)},
      pid          = {G:(DE-HGF)POF3-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:30615206},
      doi          = {10.1002/hep.30493},
      url          = {https://inrepo02.dkfz.de/record/143591},
}