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@ARTICLE{Claus:119761,
      author       = {R. Claus$^*$ and D. M. Lucas and A. S. Ruppert and K. E.
                      Williams and D. Weng and K. Patterson and M. Zucknick$^*$
                      and C. C. Oakes$^*$ and L. Z. Rassenti and A. W. Greaves and
                      S. Geyer and W. G. Wierda and J. R. Brown and J. G. Gribben
                      and J. C. Barrientos and K. R. Rai and N. E. Kay and T. J.
                      Kipps and P. Shields and W. Zhao and M. R. Grever and C.
                      Plass$^*$ and J. C. Byrd},
      title        = {{V}alidation of {ZAP}-70 methylation and its relative
                      significance in predicting outcome in chronic lymphocytic
                      leukemia.},
      journal      = {Blood},
      volume       = {124},
      number       = {1},
      issn         = {1528-0020},
      address      = {Stanford, Calif.},
      publisher    = {HighWire Press},
      reportid     = {DKFZ-2017-00388},
      pages        = {42 - 48},
      year         = {2014},
      abstract     = {ZAP-70 methylation 223 nucleotides downstream of
                      transcription start (CpG+223) predicts outcome in chronic
                      lymphocytic leukemia (CLL), but its impact relative to CD38
                      and ZAP-70 expression or immunoglobulin heavy chain variable
                      region (IGHV) status is uncertain. Additionally,
                      standardizing ZAP-70 expression analysis has been
                      unsuccessful. CpG+223 methylation was quantitatively
                      determined in 295 untreated CLL cases using MassARRAY.
                      Impact on clinical outcome vs CD38 and ZAP-70 expression and
                      IGHV status was evaluated. Cases with low methylation
                      $(<20\%)$ had significantly shortened time to first
                      treatment (TT) and overall survival (OS) (P < .0001). For
                      TT, low methylation defined a large subset of ZAP-70
                      protein-negative cases with significantly shortened TT
                      (median, 8.0 vs 3.9 years for high vs low methylation;
                      hazard ratio [HR] = 0.43; $95\%$ confidence interval [CI],
                      0.25-0.74). Conversely, 16 ZAP-70 protein-positive cases
                      with high methylation had poor outcome (median, 1.1 vs 2.3
                      years for high vs low methylation; HR = 1.62; $95\%$ CI,
                      0.87-3.03). For OS, ZAP-70 methylation was the strongest
                      risk factor; CD38 and ZAP-70 expression or IGHV status did
                      not significantly improve OS prediction. A pyrosequencing
                      assay was established that reproduced the MassARRAY data (κ
                      coefficient > 0.90). Thus, ZAP-70 CpG+223 methylation
                      represents a superior biomarker for TT and OS that can be
                      feasibly measured, supporting its use in risk-stratifying
                      CLL.},
      keywords     = {Biomarkers, Tumor (NLM Chemicals) / Immunoglobulin Variable
                      Region (NLM Chemicals) / ZAP-70 Protein-Tyrosine Kinase (NLM
                      Chemicals) / ZAP70 protein, human (NLM Chemicals)},
      cin          = {C010 / C060},
      ddc          = {610},
      cid          = {I:(DE-He78)C010-20160331 / I:(DE-He78)C060-20160331},
      pnm          = {313 - Cancer risk factors and prevention (POF3-313)},
      pid          = {G:(DE-HGF)POF3-313},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:24868078},
      pmc          = {pmc:PMC4125353},
      doi          = {10.1182/blood-2014-02-555722},
      url          = {https://inrepo02.dkfz.de/record/119761},
}