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Cell Rep. 2015 Mar 3;10(8):1239-45. doi: 10.1016/j.celrep.2015.02.005. Epub 2015 Feb 26.

Leukemia-associated somatic mutations drive distinct patterns of age-related clonal hemopoiesis.

Author information

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; NHS Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.
5
Department of Haematology, Cambridge University Hospitals NHS Trust, Cambridge CB2 0QQ, UK.
6
Department of Haematology, Cambridge Biomedical Campus, University of Cambridge, Cambridge CB2 0XY, UK; Cambridge Blood and Stem Cell Biobank, Department of Haematology, University of Cambridge, Cambridge CB2 0XY, UK.
7
Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, 81675 München, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
8
Department of Medicine for the Elderly, Cambridge University Hospitals NHS Trust, Cambridge CB2 0QQ, UK.
9
Human Genetics, Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.
10
Department of Haematology, Cambridge Biomedical Campus, University of Cambridge, Cambridge CB2 0XY, UK; NHS Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK; Human Genetics, Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.
11
Haematological Cancer Genetics, Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK; Department of Haematology, Cambridge Biomedical Campus, University of Cambridge, Cambridge CB2 0XY, UK; Department of Haematology, Cambridge University Hospitals NHS Trust, Cambridge CB2 0QQ, UK. Electronic address: gsv20@sanger.ac.uk.

Abstract

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.

PMID:
25732814
PMCID:
PMC4542313
DOI:
10.1016/j.celrep.2015.02.005
[Indexed for MEDLINE]
Free PMC Article

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