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@ARTICLE{Klett:137604,
      author       = {H. Klett$^*$ and Y. Balavarca$^*$ and R. Toth$^*$ and B.
                      Gigic$^*$ and N. Habermann$^*$ and D. Scherer$^*$ and P.
                      Schrotz-King$^*$ and A. Ulrich and P. Schirmacher and E.
                      Herpel and H. Brenner$^*$ and C. M. Ulrich and K. B. Michels
                      and H. Busch and M. Boerries$^*$},
      title        = {{R}obust prediction of gene regulation in colorectal cancer
                      tissues from {DNA} methylation profiles.},
      journal      = {Epigenetics},
      volume       = {13},
      number       = {4},
      issn         = {1559-2308},
      address      = {Austin, Tex.},
      publisher    = {Landes Bioscience},
      reportid     = {DKFZ-2018-01484},
      pages        = {386 - 397},
      year         = {2018},
      abstract     = {DNA methylation is recognized as one of several epigenetic
                      regulators of gene expression and as potential driver of
                      carcinogenesis through gene-silencing of tumor suppressors
                      and activation of oncogenes. However, abnormal methylation,
                      even of promoter regions, does not necessarily alter gene
                      expression levels, especially if the gene is already
                      silenced, leaving the exact mechanisms of methylation
                      unanswered. Using a large cohort of matching DNA methylation
                      and gene expression samples of colorectal cancer (CRC; n =
                      77) and normal adjacent mucosa tissues (n = 108), we
                      investigated the regulatory role of methylation on gene
                      expression. We show that on a subset of genes enriched in
                      common cancer pathways, methylation is significantly
                      associated with gene regulation through gene-specific
                      mechanisms. We built two classification models to infer gene
                      regulation in CRC from methylation differences of tumor and
                      normal tissues, taking into account both gene-silencing and
                      gene-activation effects through hyper- and hypo-methylation
                      of CpGs. The classification models result in high prediction
                      performances in both training and independent CRC testing
                      cohorts (0.92<AUC<0.97) as well as in individual patient
                      data (average AUC = 0.82), suggesting a robust interplay
                      between methylation and gene regulation. Validation analysis
                      in other cancerous tissues resulted in lower prediction
                      performances (0.69<AUC<0.90); however, it identified genes
                      that share robust dependencies across cancerous tissues. In
                      conclusion, we present a robust classification approach that
                      predicts the gene-specific regulation through DNA
                      methylation in CRC tissues with possible transition to
                      different cancer entities. Furthermore, we present HMGA1 as
                      consistently associated with methylation across cancers,
                      suggesting a potential candidate for DNA methylation
                      targeting cancer therapy.},
      cin          = {L601 / G110 / C070 / L101},
      ddc          = {610},
      cid          = {I:(DE-He78)L601-20160331 / I:(DE-He78)G110-20160331 /
                      I:(DE-He78)C070-20160331 / I:(DE-He78)L101-20160331},
      pnm          = {313 - Cancer risk factors and prevention (POF3-313)},
      pid          = {G:(DE-HGF)POF3-313},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:29697014},
      pmc          = {pmc:PMC6140810},
      doi          = {10.1080/15592294.2018.1460034},
      url          = {https://inrepo02.dkfz.de/record/137604},
}