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@ARTICLE{Leeksma:142962,
      author       = {A. C. Leeksma and J. Taylor and B. Wu$^*$ and J. R. Gardner
                      and J. He and M. Nahas and M. Gonen and W. G. Alemayehu and
                      D. Te Raa and T. Walther$^*$ and J. Hüllein$^*$ and S.
                      Dietrich and R. Claus and F. de Boer and K. de Heer and J.
                      Dubois and M. Dampmann and J. Dürig and M. H. J. van Oers
                      and C. H. Geisler and E. Eldering and R. L. Levine and V.
                      Miller and T. Mughal and N. Lamanna and M. G. Frattini and
                      M. L. Heaney and A. Zelenetz and T. Zenz$^*$ and O.
                      Abdel-Wahab and A. P. Kater},
      title        = {{C}lonal diversity predicts adverse outcome in chronic
                      lymphocytic leukemia.},
      journal      = {Leukemia},
      volume       = {33},
      number       = {2},
      issn         = {1476-5551},
      address      = {London},
      publisher    = {Springer Nature},
      reportid     = {DKFZ-2019-00590},
      pages        = {390 - 402},
      year         = {2019},
      abstract     = {Genomic analyses of chronic lymphocytic leukemia (CLL)
                      identified somatic mutations and associations of clonal
                      diversity with adverse outcomes. Clonal evolution likely has
                      therapeutic implications but its dynamic is less well
                      studied. We studied clonal composition and prognostic value
                      of seven recurrently mutated driver genes using targeted
                      next-generation sequencing in 643 CLL patients and found
                      higher frequencies of mutations in TP53 (35 vs. $12\%,$
                      p < 0.001) and SF3B1 (20 vs. $11\%,$ p < 0.05) and
                      increased number of (sub)clonal (p < 0.0001) mutations
                      in treated patients. We next performed an in-depth
                      evaluation of clonal evolution on untreated CLL patients (50
                      'progressors' and 17 matched 'non-progressors') using a 404
                      gene-sequencing panel and identified novel mutated genes
                      such as AXIN1, SDHA, SUZ12, and FOXO3. Progressors carried
                      more mutations at initial presentation (2.5 vs. 1,
                      p < 0.0001). Mutations in specific genes were associated
                      with increased (SF3B1, ATM, and FBXW7) or decreased
                      progression risk (AXIN1 and MYD88). Mutations affecting
                      specific signaling pathways, such as Notch and MAP kinase
                      pathway were enriched in progressive relative to
                      non-progressive patients. These data extend earlier findings
                      that specific genomic alterations and diversity of subclones
                      are associated with disease progression and persistence of
                      disease in CLL and identify novel recurrently mutated genes
                      and associated outcomes.},
      cin          = {G250},
      ddc          = {610},
      cid          = {I:(DE-He78)G250-20160331},
      pnm          = {312 - Functional and structural genomics (POF3-312)},
      pid          = {G:(DE-HGF)POF3-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:30038380},
      doi          = {10.1038/s41375-018-0215-9},
      url          = {https://inrepo02.dkfz.de/record/142962},
}