0
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

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

      research-article
      1 , 2 , 3 , 4 , 1 , 2 , 5 , 2 , 5 , 1 , 2 , 3 , 3 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 2 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 8 , 9 , 22 , 23 , 24 , 11 , 12 , 13 , 25 , 23 , 26 , 27 , 28 , 29 , 30 , 21 , 31 , 4 , NISC Comparative Sequencing Program 32 , 33 , 33 , 34 , 34 , 35 , 1 , 2 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 42 , 43 , 35 , 43 , 44 , 45 , 2 , 5 , 46 , 1 , 2 , 35 , 1 , 2 , 5 , 35 , 4 , 3 , 1 , 2 , 35 ,
      Blood Advances
      The American Society of Hematology

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Key Points

          • Germline RUNX1, GATA2, and DDX41 HHMs are associated with driver somatic variants during leukemogenesis which are unique for each syndrome.

          • Ongoing molecular monitoring of germline carriers without HM is needed to assess the risk profile and clinical actionability of somatic markers.

          Visual Abstract

          Abstract

          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.

          Related collections

          Most cited references58

          • Record: found
          • Abstract: found
          • Article: not found

          The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia.

          The World Health Organization (WHO) classification of tumors of the hematopoietic and lymphoid tissues was last updated in 2008. Since then, there have been numerous advances in the identification of unique biomarkers associated with some myeloid neoplasms and acute leukemias, largely derived from gene expression analysis and next-generation sequencing that can significantly improve the diagnostic criteria as well as the prognostic relevance of entities currently included in the WHO classification and that also suggest new entities that should be added. Therefore, there is a clear need for a revision to the current classification. The revisions to the categories of myeloid neoplasms and acute leukemia will be published in a monograph in 2016 and reflect a consensus of opinion of hematopathologists, hematologists, oncologists, and geneticists. The 2016 edition represents a revision of the prior classification rather than an entirely new classification and attempts to incorporate new clinical, prognostic, morphologic, immunophenotypic, and genetic data that have emerged since the last edition. The major changes in the classification and their rationale are presented here.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found
            Is Open Access

            Comprehensive molecular portraits of human breast tumors

            Summary We analyzed primary breast cancers by genomic DNA copy number arrays, DNA methylation, exome sequencing, mRNA arrays, microRNA sequencing and reverse phase protein arrays. Our ability to integrate information across platforms provided key insights into previously-defined gene expression subtypes and demonstrated the existence of four main breast cancer classes when combining data from five platforms, each of which shows significant molecular heterogeneity. Somatic mutations in only three genes (TP53, PIK3CA and GATA3) occurred at > 10% incidence across all breast cancers; however, there were numerous subtype-associated and novel gene mutations including the enrichment of specific mutations in GATA3, PIK3CA and MAP3K1 with the Luminal A subtype. We identified two novel protein expression-defined subgroups, possibly contributed by stromal/microenvironmental elements, and integrated analyses identified specific signaling pathways dominant in each molecular subtype including a HER2/p-HER2/HER1/p-HER1 signature within the HER2-Enriched expression subtype. Comparison of Basal-like breast tumors with high-grade Serous Ovarian tumors showed many molecular commonalities, suggesting a related etiology and similar therapeutic opportunities. The biologic finding of the four main breast cancer subtypes caused by different subsets of genetic and epigenetic abnormalities raises the hypothesis that much of the clinically observable plasticity and heterogeneity occurs within, and not across, these major biologic subtypes of breast cancer.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Age-related clonal hematopoiesis associated with adverse outcomes.

              The incidence of hematologic cancers increases with age. These cancers are associated with recurrent somatic mutations in specific genes. We hypothesized that such mutations would be detectable in the blood of some persons who are not known to have hematologic disorders. We analyzed whole-exome sequencing data from DNA in the peripheral-blood cells of 17,182 persons who were unselected for hematologic phenotypes. We looked for somatic mutations by identifying previously characterized single-nucleotide variants and small insertions or deletions in 160 genes that are recurrently mutated in hematologic cancers. The presence of mutations was analyzed for an association with hematologic phenotypes, survival, and cardiovascular events. Detectable somatic mutations were rare in persons younger than 40 years of age but rose appreciably in frequency with age. Among persons 70 to 79 years of age, 80 to 89 years of age, and 90 to 108 years of age, these clonal mutations were observed in 9.5% (219 of 2300 persons), 11.7% (37 of 317), and 18.4% (19 of 103), respectively. The majority of the variants occurred in three genes: DNMT3A, TET2, and ASXL1. The presence of a somatic mutation was associated with an increase in the risk of hematologic cancer (hazard ratio, 11.1; 95% confidence interval [CI], 3.9 to 32.6), an increase in all-cause mortality (hazard ratio, 1.4; 95% CI, 1.1 to 1.8), and increases in the risks of incident coronary heart disease (hazard ratio, 2.0; 95% CI, 1.2 to 3.4) and ischemic stroke (hazard ratio, 2.6; 95% CI, 1.4 to 4.8). Age-related clonal hematopoiesis is a common condition that is associated with increases in the risk of hematologic cancer and in all-cause mortality, with the latter possibly due to an increased risk of cardiovascular disease. (Funded by the National Institutes of Health and others.).
                Bookmark

                Author and article information

                Contributors
                Journal
                Blood Adv
                Blood Adv
                Blood Advances
                The American Society of Hematology
                2473-9529
                2473-9537
                07 July 2023
                24 October 2023
                07 July 2023
                : 7
                : 20
                : 6092-6107
                Affiliations
                [1 ]Department of Genetics and Molecular Pathology, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, Australia
                [2 ]UniSA Clinical and Health Sciences, University of South Australia, Adelaide, Australia
                [3 ]Departments 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
                [4 ]Division of Intramural Research, Oncogenesis and Development Section, Translational and Functional Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD
                [5 ]ACRF Genomics Facility, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, SA, Australia
                [6 ]HCEMM-SE Molecular Oncohematology Research Group, 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
                [7 ]Division of Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
                [8 ]Department of Molecular Medicine, University of Pavia, Pavia, Italy
                [9 ]Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
                [10 ]Alberta Children’s Hospital, Calgary, Alberta, Canada
                [11 ]Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
                [12 ]Laboratory of Hematology, Biology and Pathology Center, Centre Hospitalier Regional Universitaire de Lille, Lille, France
                [13 ]Jean-Pierre Aubert Research Center, INSERM, Universitaire de Lille, Lille, France
                [14 ]Assistance Publique-Hôpitaux de Paris, Armand Trousseau Children's Hospital, Paris, France
                [15 ]Department of Translational Medical Oncology, National Center for Tumor Diseases and German Cancer Research Center (DKFZ), Heidelberg, Germany
                [16 ]German Cancer Consortium (DKTK), Heidelberg, Germany
                [17 ]Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
                [18 ]St Jude Children's Research Hospital, Memphis, TN
                [19 ]Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany
                [20 ]Department of Hematology & Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
                [21 ]Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore
                [22 ]Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
                [23 ]Imago Biosciences, Inc, San Francisco, CA
                [24 ]Division of Hematology and Hematological Malignancies, Foothills Medical Centre, Calgary, AB, Canada
                [25 ]Institut Gustave Roussy, Université Paris Sud, Equipe Labellisée par la Ligue Nationale Contre le Cancer, Villejuif, France
                [26 ]Department of Human Genetics, Hannover Medical School, Hannover, Germany
                [27 ]Division of Pediatric Hematology and Oncology, Riley Children’s Hospital, Indiana University School of Medicine, Indianapolis, IN
                [28 ]Department of Haematology, Addenbrooke’s Hospital, Cambridge, United Kingdom
                [29 ]Service 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
                [30 ]Genetics Laboratory, Hospital Israelita Albert Einstein, Sao Paulo, Brazil
                [31 ]National Cancer Institute, National Institutes of Health, Rockville, MD
                [32 ]NIH Intramural Sequencing Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD
                [33 ]National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
                [34 ]Adult Genetics Unit, Royal Adelaide Hospital, Adelaide, SA, Australia
                [35 ]Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia
                [36 ]Department of Haematology, Peter McCallum Cancer Centre, Royal Melbourne Hospital, Walter and Eliza Hall Institute of Medical Research, The University of Melbourne, Melbourne, VIC, Australia
                [37 ]Central Coast Haematology, North Gosford, NSW, Australia
                [38 ]Department of Medicine, The University of Queensland, Brisbane, QLD, Australia
                [39 ]Adelaide Oncology & Haematology, North Adelaide, SA, Australia
                [40 ]Department of Haematology, Fiona Stanley Hospital, Murdoch, WA, Australia
                [41 ]Genetic Health Queensland, Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia
                [42 ]Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
                [43 ]Department of Haematology, SA Pathology, Adelaide, SA, Australia
                [44 ]Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
                [45 ]Department of Paediatrics and Department of Molecular Biology, The University of Melbourne, Melbourne, VIC, Australia
                [46 ]School of Biological Sciences, The University of Adelaide, Adelaide, SA, Australia
                Author notes
                []Correspondence: Anna L. Brown, Department of Genetics and Molecular Pathology, SA Pathology, Frome Rd, Adelaide, SA 5000, Australia; anna.brown@ 123456sa.gov.au
                Article
                S2473-9529(23)00377-4
                10.1182/bloodadvances.2023010045
                10582382
                37406166
                6bf0064c-abab-4eb2-a255-7146b82e3dfe
                Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 23 February 2023
                : 19 June 2023
                Categories
                Myeloid Neoplasia

                Comments

                Comment on this article