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@ARTICLE{Schmitt:143882,
      author       = {K. Schmitt and B. Molfenter and N. Koerich Laureano$^*$ and
                      B. Tawk$^*$ and M. Bieg$^*$ and X. Pastor Hostench$^*$ and
                      D. Weichenhan$^*$ and N. D. Ullrich and V. Shang and D.
                      Richter$^*$ and F. Stögbauer and L. Schroeder$^*$ and B. de
                      Bem Prunes and F. Visioli and P. Varvaki Rados and A. Jou
                      and M. Plath and P. A. Federspil and J. Thierauf and J.
                      Döscher and S. E. Weissinger and T. K. Hoffmann and S.
                      Wagner and C. Wittekindt and N. Ishaque$^*$ and R. Eils$^*$
                      and J. P. Klussmann and D. Holzinger$^*$ and C. Plass$^*$
                      and A. Abdollahi$^*$ and K. Freier and W. Weichert$^*$ and
                      K. Zaoui and J. Hess$^*$},
      title        = {{S}omatic mutations and promotor methylation of the
                      ryanodine receptor 2 is a common event in the pathogenesis
                      of head and neck cancer.},
      journal      = {International journal of cancer},
      volume       = {145},
      number       = {12},
      issn         = {1097-0215},
      address      = {Bognor Regis},
      publisher    = {Wiley-Liss},
      reportid     = {DKFZ-2019-01444},
      pages        = {3299-3310},
      year         = {2019},
      abstract     = {Genomic sequencing projects unraveled the mutational
                      landscape of head and neck squamous cell carcinoma (HNSCC)
                      and provided a comprehensive catalogue of somatic mutations.
                      However, the limited number of significant cancer-related
                      genes obtained so far only partially explains the biological
                      complexity of HNSCC and hampers the development of novel
                      diagnostic biomarkers and therapeutic targets. We pursued a
                      multi-scale omics approach based on whole-exome sequencing,
                      global DNA methylation and gene expression profiling data
                      derived from tumor samples of the HIPO-HNC cohort (n=87),
                      and confirmed new findings with datasets from The Cancer
                      Genome Atlas (TCGA). Promoter methylation was confirmed by
                      MassARRAY analysis and protein expression was assessed by
                      immunohistochemistry and immunofluorescence staining. We
                      discovered a set of cancer-related genes with frequent
                      somatic mutations and high frequency of promoter
                      methylation. This included the ryanodine receptor 2 (RYR2),
                      which showed variable promoter methylation and expression in
                      both tumor samples and cell lines. Immunohistochemical
                      staining of tissue sections unraveled a gradual loss of RYR2
                      expression from normal mucosa via dysplastic lesion to
                      invasive cancer, and indicated that reduced RYR2 expression
                      in adjacent tissue and precancerous lesions might serve as
                      risk factor for unfavorable prognosis and upcoming malignant
                      conversion. In summary, our data indicate that impaired RYR2
                      function by either somatic mutation or epigenetic silencing
                      is a common event in HNSCC pathogenesis. Detection of RYR2
                      expression and/or promoter methylation might enable risk
                      assessment for malignant conversion of dysplastic lesions.
                      This article is protected by copyright. All rights
                      reserved.},
      cin          = {A102 / E210 / L101 / B080 / B370 / B340 / F022 / F020 /
                      L701 / E221},
      ddc          = {610},
      cid          = {I:(DE-He78)A102-20160331 / I:(DE-He78)E210-20160331 /
                      I:(DE-He78)L101-20160331 / I:(DE-He78)B080-20160331 /
                      I:(DE-He78)B370-20160331 / I:(DE-He78)B340-20160331 /
                      I:(DE-He78)F022-20160331 / I:(DE-He78)F020-20160331 /
                      I:(DE-He78)L701-20160331 / I:(DE-He78)E221-20160331},
      pnm          = {315 - Imaging and radiooncology (POF3-315)},
      pid          = {G:(DE-HGF)POF3-315},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:31135957},
      doi          = {10.1002/ijc.32481},
      url          = {https://inrepo02.dkfz.de/record/143882},
}