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Somatic mutational landscape of hereditary hematopoietic malignancies caused by germline variants in RUNX1, GATA2, and DDX41

Individuals with germ line variants associated with hereditary hematopoietic malignancies (HHMs) have a highly variable risk for leukemogenesis. Gaps in our understanding of premalignant states in HHMs have hampered efforts to design effective clinical surveillance programs, provide personalized pre...

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Main Authors: Homan, Claire C. (Author) , Drazer, Michael W. (Author) , Yu, Kai (Author) , Lawrence, David M. (Author) , Feng, Jinghua (Author) , Arriola-Martinez, Luis (Author) , Pozsgai, Matthew J. (Author) , McNeely, Kelsey E. (Author) , Ha, Thuong (Author) , Venugopal, Parvathy (Author) , Arts, Peer (Author) , King-Smith, Sarah L. (Author) , Cheah, Jesse (Author) , Armstrong, Mark (Author) , Wang, Paul (Author) , Bödör, Csaba (Author) , Cantor, Alan B. (Author) , Cazzola, Mario (Author) , Degelman, Erin (Author) , DiNardo, Courtney D. (Author) , Duployez, Nicolas (Author) , Favier, Remi (Author) , Fröhling, Stefan (Author) , Rio-Machin, Ana (Author) , Klco, Jeffery M. (Author) , Krämer, Alwin (Author) , Kurokawa, Mineo (Author) , Lee, Joanne (Author) , Malcovati, Luca (Author) , Morgan, Neil V. (Author) , Natsoulis, Georges (Author) , Owen, Carolyn (Author) , Patel, Keyur P. (Author) , Preudhomme, Claude (Author) , Raslova, Hana (Author) , Rienhoff, Hugh (Author) , Ripperger, Tim (Author) , Schulte, Rachael (Author) , Tawana, Kiran (Author) , Velloso, Elvira (Author) , Yan, Benedict (Author) , Kim, Erika (Author) , Sood, Raman (Author) , Hsu, Amy P. (Author) , Holland, Steven M. (Author) , Phillips, Kerry (Author) , Poplawski, Nicola K. (Author) , Babic, Milena (Author) , Wei, Andrew H. (Author) , Forsyth, Cecily (Author) , Mar Fan, Helen (Author) , Lewis, Ian D. (Author) , Cooney, Julian (Author) , Susman, Rachel (Author) , Fox, Lucy C. (Author) , Blombery, Piers (Author) , Singhal, Deepak (Author) , Hiwase, Devendra (Author) , Phipson, Belinda (Author) , Schreiber, Andreas W. (Author) , Hahn, Christopher N. (Author) , Scott, Hamish S. (Author) , Liu, Paul (Author) , Godley, Lucy A. (Author) , Brown, Anna L. (Author)
Format: Article (Journal)
Language:English
Published: October 12, 2023
In: Blood advances
Year: 2023, Volume: 7, Issue: 20, Pages: 6092-6107
ISSN:2473-9537
DOI:10.1182/bloodadvances.2023010045
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1182/bloodadvances.2023010045
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Author Notes:Claire C. Homan, Michael W. Drazer, Kai Yu, David M. Lawrence, Jinghua Feng, Luis Arriola-Martinez, Matthew J. Pozsgai, Kelsey E. McNeely, Thuong Ha, Parvathy Venugopal, Peer Arts, Sarah L. King-Smith, Jesse Cheah, Mark Armstrong, Paul Wang, Csaba Bödör, Alan B. Cantor, Mario Cazzola, Erin Degelman, Courtney D. DiNardo, Nicolas Duployez, Remi Favier, Stefan Fröhling, Ana Rio-Machin, Jeffery M. Klco, Alwin Krämer, Mineo Kurokawa, Joanne Lee, Luca Malcovati, Neil V. Morgan, Georges Natsoulis, Carolyn Owen, Keyur P. Patel, Claude Preudhomme, Hana Raslova, Hugh Rienhoff, Tim Ripperger, Rachael Schulte, Kiran Tawana, Elvira Velloso, Benedict Yan, Erika Kim, Raman Sood, Amy P. Hsu, Steven M. Holland, Kerry Phillips, Nicola K. Poplawski, Milena Babic, Andrew H. Wei, Cecily Forsyth, Helen Mar Fan, Ian D. Lewis, Julian Cooney, Rachel Susman, Lucy C. Fox, Piers Blombery, Deepak Singhal, Devendra Hiwase, Belinda Phipson, Andreas W. Schreiber, Christopher N. Hahn, Hamish S. Scott, Paul Liu, Lucy A. Godley, and Anna L. Brown
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Summary:Individuals with germ line variants associated with hereditary hematopoietic malignancies (HHMs) have a highly variable risk for leukemogenesis. Gaps in our understanding of premalignant states in HHMs have hampered efforts to design effective clinical surveillance programs, provide personalized preemptive treatments, and inform appropriate counseling 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 germ line variants for the acquisition of somatic variants in BCOR, PHF6, and TET2 and second hits in RUNX1 are warranted.
Item Description:Gesehen am 11.12.2023
Physical Description:Online Resource
ISSN:2473-9537
DOI:10.1182/bloodadvances.2023010045

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