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      Leukemia-Associated Somatic Mutations Drive Distinct Patterns of Age-Related Clonal Hemopoiesis

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          Summary

          Clonal hemopoiesis driven by leukemia-associated gene mutations can occur without evidence of a blood disorder. To investigate this phenomenon, we interrogated 15 mutation hot spots in blood DNA from 4,219 individuals using ultra-deep sequencing. Using only the hot spots studied, we identified clonal hemopoiesis in 0.8% of individuals under 60, rising to 19.5% of those ≥90 years, thus predicting that clonal hemopoiesis is much more prevalent than previously realized. DNMT3A-R882 mutations were most common and, although their prevalence increased with age, were found in individuals as young as 25 years. By contrast, mutations affecting spliceosome genes SF3B1 and SRSF2, closely associated with the myelodysplastic syndromes, were identified only in those aged >70 years, with several individuals harboring more than one such mutation. This indicates that spliceosome gene mutations drive clonal expansion under selection pressures particular to the aging hemopoietic system and explains the high incidence of clonal disorders associated with these mutations in advanced old age.

          Graphical Abstract

          Highlights

          • Clonal hemopoiesis is an almost inevitable consequence of aging in humans

          • Spliceosome gene mutations drove clonal hemopoiesis only in persons aged ≥70 years

          • NPM1 mutations behave as gatekeepers for leukemogenesis

          Abstract

          McKerrell et al. employ ultra-deep sequencing to show that age-related clonal hemopoiesis is much more common than previously realized. They find that clonal hemopoiesis, driven by mutations in spliceosome genes SF3B1 and SRSF2, was noted exclusively in individuals aged 70 years or older and that NPM1 mutations are not seen in association with this phenomenon, endorsing their close association with leukemogenesis.

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          Most cited references18

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          The clonal evolution of tumor cell populations.

          P C Nowell (1976)
          It is proposed that most neoplasms arise from a single cell of origin, and tumor progression results from acquired genetic variability within the original clone allowing sequential selection of more aggressive sublines. Tumor cell populations are apparently more genetically unstable than normal cells, perhaps from activation of specific gene loci in the neoplasm, continued presence of carcinogen, or even nutritional deficiencies within the tumor. The acquired genetic insta0ility and associated selection process, most readily recognized cytogenetically, results in advanced human malignancies being highly individual karyotypically and biologically. Hence, each patient's cancer may require individual specific therapy, and even this may be thwarted by emergence of a genetically variant subline resistant to the treatment. More research should be directed toward understanding and controlling the evolutionary process in tumors before it reaches the late stage usually seen in clinical cancer.
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            Stems cells and the pathways to aging and cancer.

            The aging of tissue-specific stem cell and progenitor cell compartments is believed to be central to the decline of tissue and organ integrity and function in the elderly. Here, we examine evidence linking stem cell dysfunction to the pathophysiological conditions accompanying aging, focusing on the mechanisms underlying stem cell decline and their contribution to disease pathogenesis.
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              Detectable clonal mosaicism from birth to old age and its relationship to cancer

              Clonal mosaicism for large chromosomal anomalies (duplications, deletions and uniparental disomy) was detected using SNP microarray data from over 50,000 subjects recruited for genome-wide association studies. This detection method requires a relatively high frequency of cells (>5–10%) with the same abnormal karyotype (presumably of clonal origin) in the presence of normal cells. The frequency of detectable clonal mosaicism in peripheral blood is low (<0.5%) from birth until 50 years of age, after which it rises rapidly to 2–3% in the elderly. Many of the mosaic anomalies are characteristic of those found in hematological cancers and identify common deleted regions that pinpoint the locations of genes previously associated with hematological cancers. Although only 3% of subjects with detectable clonal mosaicism had any record of hematological cancer prior to DNA sampling, those without a prior diagnosis have an estimated 10-fold higher risk of a subsequent hematological cancer (95% confidence interval = 6–18).
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                Author and article information

                Contributors
                Journal
                Cell Rep
                Cell Rep
                Cell Reports
                Cell Press
                2211-1247
                26 February 2015
                03 March 2015
                26 February 2015
                : 10
                : 8
                : 1239-1245
                Affiliations
                [1 ]Haematological Cancer Genetics, Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK
                [2 ]Sequencing Research Group, Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK
                [3 ]Instituto de Biomedicina y Biotecnología de Cantabria (CSIC-UC-Sodercan), Departamento de Biología Molecular, Universidad de Cantabria, 39011 Santander, Spain
                [4 ]Department of Haematology, Cambridge Biomedical Campus, University of Cambridge, Cambridge CB2 0XY, UK
                [5 ]NHS Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK
                [6 ]Institute for Social and Economic Research, University of Essex, Colchester CO4 3SQ, UK
                [7 ]Department of Haematology, Cambridge University Hospitals NHS Trust, Cambridge CB2 0QQ, UK
                [8 ]Cambridge Blood and Stem Cell Biobank, Department of Haematology, University of Cambridge, Cambridge CB2 0XY, UK
                [9 ]Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, 81675 München, Germany
                [10 ]German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
                [11 ]Department of Medicine for the Elderly, Cambridge University Hospitals NHS Trust, Cambridge CB2 0QQ, UK
                [12 ]Human Genetics, Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK
                Author notes
                []Corresponding author gsv20@ 123456sanger.ac.uk
                [13]

                Co-first author

                Article
                S2211-1247(15)00113-8
                10.1016/j.celrep.2015.02.005
                4542313
                25732814
                38044fbb-f096-485b-96ec-7a1f43ed2651
                © 2015 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/).

                History
                : 14 December 2014
                : 19 January 2015
                : 29 January 2015
                Categories
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                Cell biology
                Cell biology

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