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Somatic mutational landscape of hereditary hematopoietic malignancies caused by germline variants in <i>RUNX1</i>, <i>GATA2</i>, and <i>DDX41</i>
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- 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
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- 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
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- 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
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- 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
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- Jinghua Feng
- 2UniSA Clinical and Health Sciences, University of South Australia, Adelaide, Australia
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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
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- Paul Wang
- 2UniSA Clinical and Health Sciences, University of South Australia, Adelaide, Australia
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- Csaba Bödör
- 6HCEMM-SE Molecular Oncohematology Research Group, 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
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- Alan B. Cantor
- 7Division of Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
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- Mario Cazzola
- 8Department of Molecular Medicine, University of Pavia, Pavia, Italy
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- Erin Degelman
- 10Alberta Children’s Hospital, Calgary, Alberta, Canada
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- Courtney D. DiNardo
- 11Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
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- Nicolas Duployez
- 12Laboratory of Hematology, Biology and Pathology Center, Centre Hospitalier Regional Universitaire de Lille, Lille, France
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- Remi Favier
- 14Assistance Publique-Hôpitaux de Paris, Armand Trousseau Children's Hospital, Paris, France
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- Stefan Fröhling
- 15Department of Translational Medical Oncology, National Center for Tumor Diseases and German Cancer Research Center (DKFZ), Heidelberg, Germany
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- Ana Rio-Machin
- 17Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
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- Jeffery M. Klco
- 18St Jude Children's Research Hospital, Memphis, TN
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- Alwin Krämer
- 19Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany
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- Mineo Kurokawa
- 20Department of Hematology & Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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- Joanne Lee
- 21Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore
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- Luca Malcovati
- 8Department of Molecular Medicine, University of Pavia, Pavia, Italy
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- Neil V. Morgan
- 22Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
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- Georges Natsoulis
- 23Imago Biosciences, Inc, San Francisco, CA
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- Carolyn Owen
- 24Division of Hematology and Hematological Malignancies, Foothills Medical Centre, Calgary, AB, Canada
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- Keyur P. Patel
- 11Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
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- Claude Preudhomme
- 12Laboratory of Hematology, Biology and Pathology Center, Centre Hospitalier Regional Universitaire de Lille, Lille, France
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- Hana Raslova
- 25Institut Gustave Roussy, Université Paris Sud, Equipe Labellisée par la Ligue Nationale Contre le Cancer, Villejuif, France
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- Hugh Rienhoff
- 23Imago Biosciences, Inc, San Francisco, CA
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- Tim Ripperger
- 26Department of Human Genetics, Hannover Medical School, Hannover, Germany
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- Rachael Schulte
- 27Division of Pediatric Hematology and Oncology, Riley Children’s Hospital, Indiana University School of Medicine, Indianapolis, IN
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- Kiran Tawana
- 28Department of Haematology, Addenbrooke’s Hospital, Cambridge, United Kingdom
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- 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
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- Benedict Yan
- 21Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore
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- Erika Kim
- 31National Cancer Institute, National Institutes of Health, Rockville, MD
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- 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
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- Amy P. Hsu
- 33National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
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- Steven M. Holland
- 33National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
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- Kerry Phillips
- 34Adult Genetics Unit, Royal Adelaide Hospital, Adelaide, SA, Australia
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- Nicola K. Poplawski
- 34Adult Genetics Unit, Royal Adelaide Hospital, Adelaide, SA, Australia
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- 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
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- 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
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- Cecily Forsyth
- 37Central Coast Haematology, North Gosford, NSW, Australia
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- Helen Mar Fan
- 38Department of Medicine, The University of Queensland, Brisbane, QLD, Australia
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- Ian D. Lewis
- 39Adelaide Oncology & Haematology, North Adelaide, SA, Australia
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- Julian Cooney
- 40Department of Haematology, Fiona Stanley Hospital, Murdoch, WA, Australia
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- Rachel Susman
- 41Genetic Health Queensland, Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia
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- Lucy C. Fox
- 42Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
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- Piers Blombery
- 42Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
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- Deepak Singhal
- 43Department of Haematology, SA Pathology, Adelaide, SA, Australia
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- Devendra Hiwase
- 35Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia
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- Belinda Phipson
- 44Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
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- Andreas W. Schreiber
- 2UniSA Clinical and Health Sciences, University of South Australia, Adelaide, Australia
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- 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
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- 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
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- 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
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- 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
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- 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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Description
<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>
Journal
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- Blood Advances
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Blood Advances 7 (20), 6092-6107, 2023-10-12
American Society of Hematology