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@ARTICLE{Kuhmann:127757,
      author       = {C. Kuhmann$^*$ and C. Li and M. Kloor$^*$ and M. Salou$^*$
                      and C. Weigel$^*$ and C. R. Schmidt and L. W. C. Ng and W.
                      W. Y. Tsui and S. Y. Leung and S. T. Yuen and N. Becker$^*$
                      and D. Weichenhan$^*$ and C. Plass$^*$ and P. Schmezer$^*$
                      and T. L. Chan and O. Popanda$^*$},
      title        = {{A}ltered regulation of {DNA} ligase {IV} activity by
                      aberrant promoter {DNA} methylation and gene amplification
                      in colorectal cancer.},
      journal      = {Human molecular genetics},
      volume       = {23},
      number       = {8},
      issn         = {1460-2083},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {DKFZ-2017-03779},
      pages        = {2043 - 2054},
      year         = {2014},
      abstract     = {Colorectal cancer (CRC) presents as a very heterogeneous
                      disease which cannot sufficiently be characterized with the
                      currently known genetic and epigenetic markers. To identify
                      new markers for CRC we scrutinized the methylation status of
                      231 DNA repair-related genes by methyl-CpG
                      immunoprecipitation followed by global methylation profiling
                      on a CpG island microarray, as altered expression of these
                      genes could drive genomic and chromosomal instability
                      observed in these tumors. We show for the first time
                      hypermethylation of MMP9, DNMT3A and LIG4 in CRC which was
                      confirmed in two CRC patient groups with different
                      ethnicity. DNA ligase IV (LIG4) showed strong differential
                      promoter methylation (up to $60\%)$ which coincided with
                      downregulation of mRNA in $51\%$ of cases. This functional
                      association of LIG4 methylation and gene expression was
                      supported by LIG4 re-expression in
                      5-aza-2'-deoxycytidine-treated colon cancer cell lines, and
                      reduced ligase IV amounts and end-joining activity in
                      extracts of tumors with hypermethylation. Methylation of
                      LIG4 was not associated with other genetic and epigenetic
                      markers of CRC in our study. As LIG4 is located on
                      chromosome 13 which is frequently amplified in CRC, two loci
                      were tested for gene amplification in a subset of 47 cases.
                      Comparison of amplification, methylation and expression data
                      revealed that, in $30\%$ of samples, the LIG4 gene was
                      amplified and methylated, but expression was not changed. In
                      conclusion, hypermethylation of the LIG4 promoter is a new
                      mechanism to control ligase IV expression. It may represent
                      a new epigenetic marker for CRC independent of known
                      markers.},
      keywords     = {Biomarkers, Tumor (NLM Chemicals) / LIG4 protein, human
                      (NLM Chemicals) / RNA, Messenger (NLM Chemicals) / DNA
                      (Cytosine-5-)-Methyltransferase (NLM Chemicals) / DNA
                      methyltransferase 3A (NLM Chemicals) / MMP9 protein, human
                      (NLM Chemicals) / Matrix Metalloproteinase 9 (NLM Chemicals)
                      / DNA Ligases (NLM Chemicals) / DNA Ligase ATP (NLM
                      Chemicals)},
      cin          = {C010 / C060 / G105},
      ddc          = {570},
      cid          = {I:(DE-He78)C010-20160331 / I:(DE-He78)C060-20160331 /
                      I:(DE-He78)G105-20160331},
      pnm          = {313 - Cancer risk factors and prevention (POF3-313)},
      pid          = {G:(DE-HGF)POF3-313},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:24282031},
      doi          = {10.1093/hmg/ddt599},
      url          = {https://inrepo02.dkfz.de/record/127757},
}