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@ARTICLE{Yang:127820,
      author       = {R. Yang$^*$ and K. Pfütze$^*$ and M. Zucknick$^*$ and C.
                      Sutter and B. Wappenschmidt and F. Marme and B. Qu and K.
                      Cuk$^*$ and C. Engel and S. Schott and A. Schneeweiss and H.
                      Brenner$^*$ and R. Claus$^*$ and C. Plass$^*$ and P. Bugert
                      and M. Hoth and C. Sohn and R. Schmutzler and C. R. Bartram
                      and B. Burwinkel$^*$},
      title        = {{DNA} methylation array analyses identified breast
                      cancer-associated {HYAL}2 methylation in peripheral blood.},
      journal      = {International journal of cancer},
      volume       = {136},
      number       = {8},
      issn         = {0020-7136},
      address      = {Bognor Regis},
      publisher    = {Wiley-Liss},
      reportid     = {DKFZ-2017-03842},
      pages        = {1845 - 1855},
      year         = {2015},
      abstract     = {Breast cancer (BC) is the leading cause of cancer-related
                      mortality in women worldwide. Changes in DNA methylation in
                      peripheral blood could be associated with malignancy at
                      early stage. However, the BC-associated DNA methylation
                      signatures in peripheral blood were largely unknown. Here,
                      we performed a genome-wide methylation screening and
                      identified a BC-associated differentially methylated CpG
                      site cg27091787 in the hyaluronoglucosaminidase 2 gene
                      (HYAL2) (discovery round with 72 BC case and 24 controls: p
                      = 2.61 × 10(-9) adjusted for cell-type proportions). The
                      substantially decreased methylation of cg27091787 in BC
                      cases was confirmed in two validation rounds (first
                      validation round with 338 BC case and 507 controls: p <
                      0.0001; second validation round with 189 BC case and 189
                      controls: p < 0.0001). In addition to cg27091787, the
                      decreased methylation of a 650-bp CpG island shore of HYAL2
                      was also associated with increased risk of BC. Moreover, the
                      expression and methylation of HYAL2 were inversely
                      correlated with a p-value of 0.006. To note, the
                      BC-associated decreased HYAL2 methylation was replicated in
                      the T-cell fraction (p = 0.034). The cg27091787 methylation
                      level enabled a powerful discrimination of early-stage BC
                      cases (stages 0 and I) from healthy controls [area under
                      curve (AUC) = 0.89], and was robust for the detection of BC
                      in younger women as well (age < 50, AUC = 0.87). Our study
                      reveals a strong association between decreased HYAL2
                      methylation in peripheral blood and BC, and provides a
                      promising blood-based marker for the detection of early BC.},
      keywords     = {Biomarkers, Tumor (NLM Chemicals) / Cell Adhesion Molecules
                      (NLM Chemicals) / GPI-Linked Proteins (NLM Chemicals) /
                      Hyal2 protein, human (NLM Chemicals) /
                      Hyaluronoglucosaminidase (NLM Chemicals)},
      cin          = {C080 / C070 / G110 / C060 / C010},
      ddc          = {610},
      cid          = {I:(DE-He78)C080-20160331 / I:(DE-He78)C070-20160331 /
                      I:(DE-He78)G110-20160331 / I:(DE-He78)C060-20160331 /
                      I:(DE-He78)C010-20160331},
      pnm          = {313 - Cancer risk factors and prevention (POF3-313)},
      pid          = {G:(DE-HGF)POF3-313},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:25213452},
      doi          = {10.1002/ijc.29205},
      url          = {https://inrepo02.dkfz.de/record/127820},
}