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@ARTICLE{Bochtler:119318,
      author       = {T. Bochtler$^*$ and M. Granzow and F. Stölzel and C.
                      Kunz$^*$ and B. Mohr and M. Kartal-Kaess$^*$ and K.
                      Hinderhofer and C. Heilig$^*$ and M. Kramer and C. Thiede
                      and V. Endris and M. Kirchner$^*$ and A. Stenzinger and A.
                      Benner$^*$ and M. Bornhäuser and G. Ehninger and A. D. Ho
                      and A. Jauch and A. Krämer$^*$},
      title        = {{M}arker chromosomes can arise from chromothripsis and
                      predict adverse prognosis in acute myeloid leukemia.},
      journal      = {Blood},
      volume       = {129},
      number       = {10},
      issn         = {1528-0020},
      address      = {Stanford, Calif.},
      publisher    = {HighWire Press},
      reportid     = {DKFZ-2017-00073},
      pages        = {1333-1342},
      year         = {2017},
      abstract     = {Metaphase karyotyping is an established diagnostic standard
                      in acute myeloid leukemia (AML) for risk stratification. One
                      of the cytogenetic findings in AML are structurally highly
                      abnormal marker chromosomes. In this study we have assessed
                      frequency, cytogenetic characteristics, prognostic impact
                      and underlying biological origin of marker chromosomes.
                      Given their inherent gross structural chromosomal damage, we
                      speculated that they may arise from chromothripsis, a
                      recently described phenomenon of chromosome fragmentation in
                      a single catastrophic event. In 2 large consecutive
                      prospective, randomized, multicenter, intensive chemotherapy
                      trials (AML96, AML2003) from the Study Alliance Leukemia
                      (SAL) marker chromosomes were detectable in 165/1026
                      $(16.1\%)$ of aberrant non-core-binding-factor (CBF)
                      karyotype patients. Adverse-risk karyotypes displayed a
                      higher frequency of marker chromosomes $(26.5\%$ in
                      adverse-risk, $40.3\%$ in complex aberrant and $41.2\%$ in
                      abnormality(17p) karyotypes, p<.0001 each). Marker
                      chromosomes were associated with a poorer prognosis compared
                      to other non-CBF aberrant karyotypes and led to lower
                      remission rates (CR+CRi), inferior event-free survival as
                      well as overall survival in both trials. In multivariate
                      analysis, marker chromosomes independently predicted poor
                      prognosis in the AML96 trial ≤60 years. As detected by
                      array-CGH, about one third of marker chromosomes (18/49) had
                      arisen from chromothripsis, whereas this phenomenon was
                      virtually undetectable in a control group of marker
                      chromosome-negative complex aberrant karyotypes (1/34). The
                      chromothripsis-positive cases were characterized by a
                      particularly high degree of karyotype complexity, TP53
                      mutations and dismal prognosis. In conclusion, marker
                      chromosomes are indicative of chromothripsis and associated
                      with poor prognosis per se and not merely by association
                      with other adverse cytogenetic features.},
      cin          = {G330 / C060},
      ddc          = {610},
      cid          = {I:(DE-He78)G330-20160331 / I:(DE-He78)C060-20160331},
      pnm          = {317 - Translational cancer research (POF3-317)},
      pid          = {G:(DE-HGF)POF3-317},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:28119329},
      doi          = {10.1182/blood-2016-09-738161},
      url          = {https://inrepo02.dkfz.de/record/119318},
}