Leukemia-associated somatic mutations drive distinct patterns of age-related clonal hemopoiesis.
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.
Haematological Cancer Genetics, Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.
Thomas
T
McKerrell
Sequencing Research Group, Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.
Naomi
N
Park
Instituto de Biomedicina y Biotecnología de Cantabria (CSIC-UC-Sodercan), Departamento de Biología Molecular, Universidad de Cantabria, 39011 Santander, Spain.
Thaidy
T
Moreno
Haematological Cancer Genetics, Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.
Carolyn S
CS
Grove
Haematological Cancer Genetics, Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.
Hannes
H
Ponstingl
Department of Haematology, Cambridge Biomedical Campus, University of Cambridge, Cambridge CB2 0XY, UK; NHS Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.
Jonathan
J
Stephens
Department of Haematology, Cambridge University Hospitals NHS Trust, Cambridge CB2 0QQ, UK.
Charles
C
Crawley
Department of Haematology, Cambridge University Hospitals NHS Trust, Cambridge CB2 0QQ, UK.
Jenny
J
Craig
Department of Haematology, Cambridge University Hospitals NHS Trust, Cambridge CB2 0QQ, UK.
Mike A
MA
Scott
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.
Clare
C
Hodkinson
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.
Joanna
J
Baxter
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.
Roland
R
Rad
Department of Medicine for the Elderly, Cambridge University Hospitals NHS Trust, Cambridge CB2 0QQ, UK.
Duncan R
DR
Forsyth
Sequencing Research Group, Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.
Michael A
MA
Quail
Human Genetics, Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.
Eleftheria
E
Zeggini
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.
Willem
W
Ouwehand
Instituto de Biomedicina y Biotecnología de Cantabria (CSIC-UC-Sodercan), Departamento de Biología Molecular, Universidad de Cantabria, 39011 Santander, Spain.
Ignacio
I
Varela
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.
George S
GS
Vassiliou
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging; D019295:Computational Biology; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D000090205:DNA Methyltransferase 3A; D006410:Hematopoiesis / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007938:Leukemia / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000235:genetics; D012261:Ribonucleoproteins / Q000235:genetics; D017422:Sequence Analysis, DNA; D000068103:Serine-Arginine Splicing Factors; D055815:Young Adult
C000717967:DNMT3A protein, human; D009687:Nuclear Proteins; D010750:Phosphoproteins; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear; D012261:Ribonucleoproteins; C112491:SF3B1 protein, human; C073288:SRSF2 protein, human; D000068103:Serine-Arginine Splicing Factors; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A