title: Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults.
abstract: Clonal haematopoiesis is thought to be a rare condition that increases in frequency with age and predisposes individuals to haematological malignancy. Recent studies, utilizing next-generation sequencing (NGS), observed haematopoietic clones in 10% of 70-year olds and rarely in younger individuals. However, these studies could only detect common haematopoietic clones->0.02 variant allele fraction (VAF)-due to the error rate of NGS. To identify and characterize clonal mutations below this threshold, here we develop methods for targeted error-corrected sequencing, which enable the accurate detection of clonal mutations as rare as 0.0003 VAF. We apply these methods to study serially banked peripheral blood samples from healthy 50-60-year-old participants in the Nurses' Health Study. We observe clonal haematopoiesis, frequently harbouring mutations in DNMT3A and TET2, in 95% of individuals studied. These clonal mutations are often stable longitudinally and present in multiple haematopoietic compartments, suggesting a long-lived haematopoietic stem and progenitor cell of origin.
authors.affiliation: Department of Pediatrics, Division of Hematology and Oncology, Washington University School of Medicine, Saint Louis, Missouri 63108, USA.|Center for Genome Sciences and Systems Biology, Washington University School of Medicine, Saint Louis, Missouri 63108, USA.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Young
authors.affiliation: Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, Saint Louis, Missouri 63108, USA.
authors.forename: Grant A
authors.initials: GA
authors.lastname: Challen
authors.affiliation: Department of Medicine, Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Brenda M
authors.initials: BM
authors.lastname: Birmann
authors.affiliation: Department of Pediatrics, Division of Hematology and Oncology, Washington University School of Medicine, Saint Louis, Missouri 63108, USA.|Center for Genome Sciences and Systems Biology, Washington University School of Medicine, Saint Louis, Missouri 63108, USA.
authors.forename: Todd E
authors.identifier: 0000-0002-3245-7561
authors.initials: TE
authors.lastname: Druley
mesh_terms: D000208:Acute Disease; D000368:Aged; D002999:Clone Cells / Q000378:metabolism; D015331:Cohort Studies; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D000090205:DNA Methyltransferase 3A; D004268:DNA-Binding Proteins / Q000235:genetics; D049308:Dioxygenases; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation; D006410:Hematopoiesis / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C000717967:DNMT3A protein, human; D011518:Proto-Oncogene Proteins; D049308:Dioxygenases; C541081:TET2 protein, human; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A