title: Age-related mutations associated with clonal hematopoietic expansion and malignancies.
abstract: Several genetic alterations characteristic of leukemia and lymphoma have been detected in the blood of individuals without apparent hematological malignancies. The Cancer Genome Atlas (TCGA) provides a unique resource for comprehensive discovery of mutations and genes in blood that may contribute to the clonal expansion of hematopoietic stem/progenitor cells. Here, we analyzed blood-derived sequence data from 2,728 individuals from TCGA and discovered 77 blood-specific mutations in cancer-associated genes, the majority being associated with advanced age. Remarkably, 83% of these mutations were from 19 leukemia and/or lymphoma-associated genes, and nine were recurrently mutated (DNMT3A, TET2, JAK2, ASXL1, TP53, GNAS, PPM1D, BCORL1 and SF3B1). We identified 14 additional mutations in a very small fraction of blood cells, possibly representing the earliest stages of clonal expansion in hematopoietic stem cells. Comparison of these findings to mutations in hematological malignancies identified several recurrently mutated genes that may be disease initiators. Our analyses show that the blood cells of more than 2% of individuals (5-6% of people older than 70 years) contain mutations that may represent premalignant events that cause clonal hematopoietic expansion.
authors.affiliation: 1] The Genome Institute, Washington University in St. Louis, St. Louis, Missouri, USA. [2] Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA.
authors.forename: Mingchao
authors.initials: M
authors.lastname: Xie
authors.affiliation: The Genome Institute, Washington University in St. Louis, St. Louis, Missouri, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Lu
authors.affiliation: 1] The Genome Institute, Washington University in St. Louis, St. Louis, Missouri, USA. [2] Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA.
authors.forename: Jiayin
authors.initials: J
authors.lastname: Wang
authors.affiliation: The Genome Institute, Washington University in St. Louis, St. Louis, Missouri, USA.
authors.forename: Michael D
authors.identifier: 0000000227038784
authors.initials: MD
authors.lastname: McLellan
authors.affiliation: Brown School Master of Public Health Program, Washington University in St. Louis, St. Louis, Missouri, USA.
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Johnson
authors.affiliation: 1] The Genome Institute, Washington University in St. Louis, St. Louis, Missouri, USA. [2] Department of Genetics, Washington University in St. Louis, St. Louis, Missouri, USA. [3] Department of Mathematics, Washington University in St. Louis, St. Louis, Missouri, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Wendl
authors.affiliation: The Genome Institute, Washington University in St. Louis, St. Louis, Missouri, USA.
authors.forename: Joshua F
authors.initials: JF
authors.lastname: McMichael
authors.affiliation: The Genome Institute, Washington University in St. Louis, St. Louis, Missouri, USA.
authors.forename: Heather K
authors.initials: HK
authors.lastname: Schmidt
authors.affiliation: 1] The Genome Institute, Washington University in St. Louis, St. Louis, Missouri, USA. [2] Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA.
authors.forename: Venkata
authors.initials: V
authors.lastname: Yellapantula
authors.affiliation: The Genome Institute, Washington University in St. Louis, St. Louis, Missouri, USA.
authors.forename: Christopher A
authors.identifier: 0000000342666700
authors.initials: CA
authors.lastname: Miller
authors.affiliation: 1] The Genome Institute, Washington University in St. Louis, St. Louis, Missouri, USA. [2] Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA.
authors.forename: Bradley A
authors.identifier: 0000000222767013
authors.initials: BA
authors.lastname: Ozenberger
authors.affiliation: 1] Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA. [2] Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Welch
authors.affiliation: 1] Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA. [2] Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri, USA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Link
authors.affiliation: 1] Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA. [2] Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Walter
authors.affiliation: 1] The Genome Institute, Washington University in St. Louis, St. Louis, Missouri, USA. [2] Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA. [3] Department of Genetics, Washington University in St. Louis, St. Louis, Missouri, USA. [4] Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri, USA.
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Mardis
authors.affiliation: 1] Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA. [2] Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: Dipersio
authors.affiliation: 1] Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA. [2] Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Chen
authors.affiliation: 1] The Genome Institute, Washington University in St. Louis, St. Louis, Missouri, USA. [2] Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA. [3] Department of Genetics, Washington University in St. Louis, St. Louis, Missouri, USA. [4] Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri, USA.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Wilson
authors.affiliation: 1] The Genome Institute, Washington University in St. Louis, St. Louis, Missouri, USA. [2] Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA. [3] Department of Genetics, Washington University in St. Louis, St. Louis, Missouri, USA. [4] Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Ley
authors.affiliation: 1] The Genome Institute, Washington University in St. Louis, St. Louis, Missouri, USA. [2] Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA. [3] Department of Genetics, Washington University in St. Louis, St. Louis, Missouri, USA. [4] Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Ding
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics*; D002648:Child; D005260:Female; D006410:Hematopoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics*; D055815:Young Adult