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@ARTICLE{Schuler:839969,
      author       = {Schuler, Nadine and Palm, Jan and Schmitz, Sabine and
                      Lorat, Yvonne and Rübe, Claudia E.},
      title        = {{I}ncreasing genomic instability during cancer therapy in a
                      patient with {L}i-{F}raumeni syndrome},
      journal      = {Clinical and translational radiation oncology},
      volume       = {7},
      issn         = {2405-6308},
      address      = {Amsterdam},
      publisher    = {Elsevier},
      reportid     = {FZJ-2017-07543},
      pages        = {71 - 78},
      year         = {2017},
      abstract     = {Background: Li-Fraumeni syndrome (LFS) is a cancer
                      predisposition disorder characterized by germlinemutations
                      of the p53 tumor-suppressor gene. In response to DNA damage,
                      p53 stimulates protective cellularprocesses including
                      cell-cycle arrest and apoptosis to prevent aberrant cell
                      proliferation. Currentcancer therapies involve agents that
                      damage DNA, which also affect non-cancerous
                      hematopoieticstem/progenitor cells. Here, we report on a
                      child with LFS who developed genomic instability
                      duringcraniospinal irradiation for metastatic choroid plexus
                      carcinoma (CPC).Case presentation: This previously healthy
                      4-year-old boy presented with parieto-temporal brain
                      tumor,diagnosed as CPC grade-3. Screening for
                      cancer-predisposing syndrome revealed heterozygous p53
                      germlinemutation, leading to LFS diagnosis. After tumour
                      resection and systemic chemotherapy, entire craniospinalaxis
                      was irradiated due to leptomeningeal seeding, resulting in
                      disease stabilization for nearly12 months. Blood lymphocytes
                      of LFS patient (p53-deficient) and age-matched
                      tumor-children (p53-proficient) were collected before,
                      during and after craniospinal irradiation and compared with
                      asymptomaticcarriers for identical p53 mutation, not exposed
                      to DNA-damaging treatment. In p53-deficientlymphocytes of
                      LFS patient radiation-induced DNA damage failed to induce
                      cell-cycle arrest or apoptosis.Although DNA repair capacity
                      was not impaired, p53-deficient blood lymphocytes of LFS
                      patient showedsignificant accumulation of 53BP1-foci during
                      and even several months after irradiation, reflecting
                      persistentDNA damage. Electron microscopy revealed DNA
                      abnormalities ranging from simple unrepairedlesions to
                      chromosomal abnormalities. Metaphase spreads of
                      p53-deficient lymphocytes explored bymFISH revealed high
                      amounts of complex chromosomal aberrations after
                      craniospinal irradiation.Conclusions: Tumor suppressor p53
                      plays a central role in maintaining genomic stability by
                      promotingcell-cycle checkpoints and apoptosis. Here, we
                      demonstrate that a patient with LFS receiving
                      craniospinalirradiation including large volumes of bone
                      marrow developed progressive genomic instability of
                      thehematopoietic system. During DNA-damaging radiotherapy,
                      genome-stabilizing mechanisms in
                      proliferatingstem/progenitor cells are perturbed by p53
                      deficiency, increasing the risk of cancer initiation
                      andprogression.},
      cin          = {S-US},
      ddc          = {610},
      cid          = {I:(DE-Juel1)S-US-20090406},
      pnm          = {899 - ohne Topic (POF3-899)},
      pid          = {G:(DE-HGF)POF3-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:29594232},
      UT           = {WOS:000458475000011},
      doi          = {10.1016/j.ctro.2017.10.004},
      url          = {https://juser.fz-juelich.de/record/839969},
}