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@ARTICLE{Ahadova:134800,
      author       = {A. Ahadova$^*$ and R. Gallon and J. Gebert$^*$ and A.
                      Ballhausen$^*$ and V. Endris and M. Kirchner and A.
                      Stenzinger and J. Burn and M. von Knebel Doeberitz$^*$ and
                      H. Bläker and M. Kloor$^*$},
      title        = {{T}hree molecular pathways model colorectal carcinogenesis
                      in {L}ynch syndrome.},
      journal      = {International journal of cancer},
      volume       = {143},
      number       = {1},
      issn         = {0020-7136},
      address      = {Bognor Regis},
      publisher    = {Wiley-Liss},
      reportid     = {DKFZ-2018-00593},
      pages        = {139 - 150},
      year         = {2018},
      abstract     = {Lynch syndrome is caused by germline mutations of DNA
                      mismatch repair (MMR) genes. MMR deficiency has long been
                      regarded as a secondary event in the pathogenesis of Lynch
                      syndrome colorectal cancers. Recently, this concept has been
                      challenged by the discovery of MMR-deficient crypt foci in
                      the normal mucosa. We aimed to reconstruct colorectal
                      carcinogenesis in Lynch syndrome by collecting molecular and
                      histology evidence from Lynch syndrome adenomas and
                      carcinomas. We determined the frequency of MMR deficiency in
                      adenomas from Lynch syndrome mutation carriers by
                      immunohistochemistry and by systematic literature analysis.
                      To trace back the pathways of pathogenesis, histological
                      growth patterns and mutational signatures were analyzed in
                      Lynch syndrome colorectal cancers. Literature and
                      immunohistochemistry analysis demonstrated MMR deficiency in
                      491 $(76.7\%)$ out of 640 adenomas $(95\%$ CI: $73.3\%$ to
                      $79.8\%)$ from Lynch syndrome mutation carriers.
                      Histologically normal MMR-deficient crypts were found
                      directly adjacent to dysplastic adenoma tissue, proving
                      their role as tumor precursors in Lynch syndrome.
                      Accordingly, mutation signature analysis in Lynch colorectal
                      cancers revealed that KRAS and APC mutations commonly occur
                      after the onset of MMR deficiency. Tumors lacking evidence
                      of polypous growth frequently presented with CTNNB1 and TP53
                      mutations. Our findings demonstrate that Lynch syndrome
                      colorectal cancers can develop through three pathways, with
                      MMR deficiency commonly representing an early and possibly
                      initiating event. This underlines that targeting
                      MMR-deficient cells by chemoprevention or vaccines against
                      MMR deficiency-induced frameshift peptide neoantigens holds
                      promise for tumor prevention in Lynch syndrome.},
      cin          = {G105},
      ddc          = {610},
      cid          = {I:(DE-He78)G105-20160331},
      pnm          = {317 - Translational cancer research (POF3-317)},
      pid          = {G:(DE-HGF)POF3-317},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:29424427},
      doi          = {10.1002/ijc.31300},
      url          = {https://inrepo02.dkfz.de/record/134800},
}