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

  • Claire C. Homan
    1Department of Genetics and Molecular Pathology, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, Australia
  • Michael W. Drazer
    3Departments of Medicine and Human Genetics, Section of Hematology/Oncology, Center for Clinical Cancer Genetics, and The University of Chicago Comprehensive Cancer Center, The University of Chicago, Chicago, IL
  • Kai Yu
    4Division of Intramural Research, Oncogenesis and Development Section, Translational and Functional Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD
  • David M. Lawrence
    1Department of Genetics and Molecular Pathology, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, Australia
  • Jinghua Feng
    2UniSA Clinical and Health Sciences, University of South Australia, Adelaide, Australia
  • Luis Arriola-Martinez
    1Department of Genetics and Molecular Pathology, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, Australia
  • Matthew J. Pozsgai
    3Departments of Medicine and Human Genetics, Section of Hematology/Oncology, Center for Clinical Cancer Genetics, and The University of Chicago Comprehensive Cancer Center, The University of Chicago, Chicago, IL
  • Kelsey E. McNeely
    3Departments of Medicine and Human Genetics, Section of Hematology/Oncology, Center for Clinical Cancer Genetics, and The University of Chicago Comprehensive Cancer Center, The University of Chicago, Chicago, IL
  • Thuong Ha
    1Department of Genetics and Molecular Pathology, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, Australia
  • Parvathy Venugopal
    1Department of Genetics and Molecular Pathology, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, Australia
  • Peer Arts
    1Department of Genetics and Molecular Pathology, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, Australia
  • Sarah L. King-Smith
    1Department of Genetics and Molecular Pathology, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, Australia
  • Jesse Cheah
    1Department of Genetics and Molecular Pathology, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, Australia
  • Mark Armstrong
    1Department of Genetics and Molecular Pathology, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, Australia
  • Paul Wang
    2UniSA Clinical and Health Sciences, University of South Australia, Adelaide, Australia
  • Csaba Bödör
    6HCEMM-SE Molecular Oncohematology Research Group, 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
  • Alan B. Cantor
    7Division of Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
  • Mario Cazzola
    8Department of Molecular Medicine, University of Pavia, Pavia, Italy
  • Erin Degelman
    10Alberta Children’s Hospital, Calgary, Alberta, Canada
  • Courtney D. DiNardo
    11Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
  • Nicolas Duployez
    12Laboratory of Hematology, Biology and Pathology Center, Centre Hospitalier Regional Universitaire de Lille, Lille, France
  • Remi Favier
    14Assistance Publique-Hôpitaux de Paris, Armand Trousseau Children's Hospital, Paris, France
  • Stefan Fröhling
    15Department of Translational Medical Oncology, National Center for Tumor Diseases and German Cancer Research Center (DKFZ), Heidelberg, Germany
  • Ana Rio-Machin
    17Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
  • Jeffery M. Klco
    18St Jude Children's Research Hospital, Memphis, TN
  • Alwin Krämer
    19Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany
  • Mineo Kurokawa
    20Department of Hematology & Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
  • Joanne Lee
    21Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore
  • Luca Malcovati
    8Department of Molecular Medicine, University of Pavia, Pavia, Italy
  • Neil V. Morgan
    22Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
  • Georges Natsoulis
    23Imago Biosciences, Inc, San Francisco, CA
  • Carolyn Owen
    24Division of Hematology and Hematological Malignancies, Foothills Medical Centre, Calgary, AB, Canada
  • Keyur P. Patel
    11Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
  • Claude Preudhomme
    12Laboratory of Hematology, Biology and Pathology Center, Centre Hospitalier Regional Universitaire de Lille, Lille, France
  • Hana Raslova
    25Institut Gustave Roussy, Université Paris Sud, Equipe Labellisée par la Ligue Nationale Contre le Cancer, Villejuif, France
  • Hugh Rienhoff
    23Imago Biosciences, Inc, San Francisco, CA
  • Tim Ripperger
    26Department of Human Genetics, Hannover Medical School, Hannover, Germany
  • Rachael Schulte
    27Division of Pediatric Hematology and Oncology, Riley Children’s Hospital, Indiana University School of Medicine, Indianapolis, IN
  • Kiran Tawana
    28Department of Haematology, Addenbrooke’s Hospital, Cambridge, United Kingdom
  • Elvira Velloso
    29Service of Hematology, Transfusion and Cell Therapy and Laboratory of Medical Investigation in Pathogenesis and Directed Therapy in Onco-Immuno-Hematology (LIM-31) HCFMUSP, University of Sao Paulo Medical School, Sao Paulo, Brazil
  • Benedict Yan
    21Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore
  • Erika Kim
    31National Cancer Institute, National Institutes of Health, Rockville, MD
  • Raman Sood
    4Division of Intramural Research, Oncogenesis and Development Section, Translational and Functional Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD
  • Amy P. Hsu
    33National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
  • Steven M. Holland
    33National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
  • Kerry Phillips
    34Adult Genetics Unit, Royal Adelaide Hospital, Adelaide, SA, Australia
  • Nicola K. Poplawski
    34Adult Genetics Unit, Royal Adelaide Hospital, Adelaide, SA, Australia
  • Milena Babic
    1Department of Genetics and Molecular Pathology, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, Australia
  • Andrew H. Wei
    36Department of Haematology, Peter McCallum Cancer Centre, Royal Melbourne Hospital, Walter and Eliza Hall Institute of Medical Research, The University of Melbourne, Melbourne, VIC, Australia
  • Cecily Forsyth
    37Central Coast Haematology, North Gosford, NSW, Australia
  • Helen Mar Fan
    38Department of Medicine, The University of Queensland, Brisbane, QLD, Australia
  • Ian D. Lewis
    39Adelaide Oncology & Haematology, North Adelaide, SA, Australia
  • Julian Cooney
    40Department of Haematology, Fiona Stanley Hospital, Murdoch, WA, Australia
  • Rachel Susman
    41Genetic Health Queensland, Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia
  • Lucy C. Fox
    42Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  • Piers Blombery
    42Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  • Deepak Singhal
    43Department of Haematology, SA Pathology, Adelaide, SA, Australia
  • Devendra Hiwase
    35Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia
  • Belinda Phipson
    44Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
  • Andreas W. Schreiber
    2UniSA Clinical and Health Sciences, University of South Australia, Adelaide, Australia
  • Christopher N. Hahn
    1Department of Genetics and Molecular Pathology, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, Australia
  • Hamish S. Scott
    1Department of Genetics and Molecular Pathology, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, Australia
  • Paul Liu
    4Division of Intramural Research, Oncogenesis and Development Section, Translational and Functional Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD
  • Lucy A. Godley
    3Departments of Medicine and Human Genetics, Section of Hematology/Oncology, Center for Clinical Cancer Genetics, and The University of Chicago Comprehensive Cancer Center, The University of Chicago, Chicago, IL
  • Anna L. Brown
    1Department of Genetics and Molecular Pathology, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, Australia

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説明

<jats:title>Abstract</jats:title> <jats:p>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.</jats:p>

収録刊行物

  • Blood Advances

    Blood Advances 7 (20), 6092-6107, 2023-10-12

    American Society of Hematology

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