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@ARTICLE{Homan:277354,
      author       = {C. C. Homan and M. W. Drazer and K. Yu and D. M. Lawrence
                      and J. Feng and L. A. Arriola-Martinez and M. J. Pozsgai and
                      K. E. McNeely and T. T. Ha and P. Venugopal and P. Arts and
                      S. King-Smith and J. J. Cheah and M. Armstrong and P. Wang
                      and C. Bödör and A. B. Cantor and M. Cazzola and E. S.
                      Degelman and C. D. DiNardo and N. Duployez and R. Favier and
                      S. Fröhling$^*$ and A. Rio-Machin and J. M. Klco and A.
                      Krämer$^*$ and M. Kurokawa and J. Lee and L. Malcovati and
                      N. V. Morgan and N. Georges and C. Owen and K. P. Patel and
                      C. Preudhomme and H. Raslova and H. Y. Rienhoff and T.
                      Ripperger and R. R. Schulte and K. Tawana and E. Velloso and
                      Y. Benedict and E. M. K. Kim and R. Sood and A. P. Hsu and
                      S. M. Holland and K. Phillips and N. Poplawski and M. Babic
                      and A. H. Wei and C. J. Forsyth and H. Mar Fan and I. Lewis
                      and J. P. Cooney and R. Susman and L. C. Fox and P. Blombery
                      and D. Singhal and D. K. Hiwase and B. Phipson and A. W.
                      Schreiber and C. N. Hahn and H. S. Scott and P. P. Liu and
                      L. A. Godley and A. L. Brown},
      title        = {{S}omatic mutational landscape of hereditary hematopoietic
                      malignancies caused by germ line {RUNX}1, {GATA}2, and
                      {DDX}41 variants.},
      journal      = {Blood advances},
      volume       = {7},
      number       = {20},
      issn         = {2473-9529},
      address      = {Washington, DC},
      publisher    = {American Society of Hematology},
      reportid     = {DKFZ-2023-01360},
      pages        = {6092-6107},
      year         = {2023},
      note         = {2023 Oct 24;7(20):6092-6107},
      abstract     = {Individuals with germline variants associated with
                      hereditary hematopoietic malignancies (HHMs) have a highly
                      variable risk for leukemogenesis. Gaps in our understanding
                      of pre-malignant states in HHMs have hampered efforts to
                      design effective clinical surveillance programs, provide
                      personalized pre-emptive treatments and inform appropriate
                      counselling for patients. We used the largest known
                      comparative international cohort of germline RUNX1, GATA2,
                      or DDX41 variant carriers without and with hematopoietic
                      malignancies (HMs) to identify patterns of genetic drivers
                      that are unique to each HHM syndrome before and after
                      leukemogenesis. These patterns included striking
                      heterogeneity in rates of early-onset clonal hematopoiesis
                      (CH), with a high prevalence of CH in RUNX1 and GATA2
                      variant carriers who did not have malignancies
                      ('carriers-without HM'). We observed a paucity of CH in
                      DDX41 carriers-without HM. In RUNX1 carriers-without HM with
                      CH, we detected variants in TET2, PHF6, and, most
                      frequently, BCOR. These genes were recurrently mutated in
                      RUNX1-driven malignancies, suggesting CH is a direct
                      precursor to malignancy in RUNX1-driven HHMs. Leukemogenesis
                      in RUNX1 and DDX41 carriers was often driven by second-hits
                      in RUNX1 and DDX41, respectively. This study may inform the
                      development of HHM-specific clinical trials and
                      gene-specific approaches to clinical monitoring. For
                      example, trials investigating the potential benefits of
                      monitoring DDX41 carriers-without HM for low-frequency
                      second hits in DDX41 may now be beneficial. Similarly,
                      trials monitoring carriers-without HM with RUNX1 germline
                      variants for the acquisition of somatic variants in BCOR,
                      PHF6, TET2, and second hits in RUNX1 are warranted.},
      cin          = {A360 / B340 / HD01},
      ddc          = {610},
      cid          = {I:(DE-He78)A360-20160331 / I:(DE-He78)B340-20160331 /
                      I:(DE-He78)HD01-20160331},
      pnm          = {311 - Zellbiologie und Tumorbiologie (POF4-311)},
      pid          = {G:(DE-HGF)POF4-311},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37406166},
      doi          = {10.1182/bloodadvances.2023010045},
      url          = {https://inrepo02.dkfz.de/record/277354},
}