title: Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence.
abstract: BACKGROUND
  Cancers arise from multiple acquired mutations, which presumably occur over many years. Early stages in cancer development might be present years before cancers become clinically apparent.
  
  
  METHODS
  We analyzed data from whole-exome sequencing of DNA in peripheral-blood cells from 12,380 persons, unselected for cancer or hematologic phenotypes. We identified somatic mutations on the basis of unusual allelic fractions. We used data from Swedish national patient registers to follow health outcomes for 2 to 7 years after DNA sampling.
  
  
  RESULTS
  Clonal hematopoiesis with somatic mutations was observed in 10% of persons older than 65 years of age but in only 1% of those younger than 50 years of age. Detectable clonal expansions most frequently involved somatic mutations in three genes (DNMT3A, ASXL1, and TET2) that have previously been implicated in hematologic cancers. Clonal hematopoiesis was a strong risk factor for subsequent hematologic cancer (hazard ratio, 12.9; 95% confidence interval, 5.8 to 28.7). Approximately 42% of hematologic cancers in this cohort arose in persons who had clonality at the time of DNA sampling, more than 6 months before a first diagnosis of cancer. Analysis of bone marrow-biopsy specimens obtained from two patients at the time of diagnosis of acute myeloid leukemia revealed that their cancers arose from the earlier clones.
  
  
  CONCLUSIONS
  Clonal hematopoiesis with somatic mutations is readily detected by means of DNA sequencing, is increasingly common as people age, and is associated with increased risks of hematologic cancer and death. A subset of the genes that are mutated in patients with myeloid cancers is frequently mutated in apparently healthy persons; these mutations may represent characteristic early events in the development of hematologic cancers. (Funded by the National Human Genome Research Institute and others.).
authors.affiliation: The authors' affiliations are listed in the Appendix.
authors.forename: Giulio
authors.initials: G
authors.lastname: Genovese
authors.forename: Anna K
authors.initials: AK
authors.lastname: Kähler
authors.forename: Robert E
authors.initials: RE
authors.lastname: Handsaker
authors.forename: Johan
authors.initials: J
authors.lastname: Lindberg
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Rose
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Bakhoum
authors.forename: Kimberly
authors.initials: K
authors.lastname: Chambert
authors.forename: Eran
authors.initials: E
authors.lastname: Mick
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Neale
authors.forename: Menachem
authors.initials: M
authors.lastname: Fromer
authors.forename: Shaun M
authors.initials: SM
authors.lastname: Purcell
authors.forename: Oscar
authors.initials: O
authors.lastname: Svantesson
authors.forename: Mikael
authors.initials: M
authors.lastname: Landén
authors.forename: Martin
authors.initials: M
authors.lastname: Höglund
authors.forename: Sören
authors.initials: S
authors.lastname: Lehmann
authors.forename: Stacey B
authors.initials: SB
authors.lastname: Gabriel
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Moran
authors.forename: Eric S
authors.initials: ES
authors.lastname: Lander
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Sullivan
authors.forename: Pamela
authors.initials: P
authors.lastname: Sklar
authors.forename: Henrik
authors.initials: H
authors.lastname: Grönberg
authors.forename: Christina M
authors.initials: CM
authors.lastname: Hultman
authors.forename: Steven A
authors.initials: SA
authors.lastname: McCarroll
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D001769:Blood; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002999:Clone Cells; D004252:DNA Mutational Analysis; D059472:Exome; D019337:Hematologic Neoplasms / Q000235:genetics* / Q000503:physiopathology; D006410:Hematopoiesis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D012307:Risk Factors; D055815:Young Adult