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Age-Related Clonal Hematopoiesis Associated with Adverse Outcomes.

In English

Författare

  • Siddhartha Jaiswal
  • Pierre Fontanillas
  • Jason Flannick
  • Alisa Manning
  • Peter V Grauman
  • Brenton G Mar
  • R Coleman Lindsley
  • Craig H Mermel
  • Noel Burtt
  • Alejandro Chavez
  • John M Higgins
  • Vladislav Moltchanov
  • Frank C Kuo
  • Michael J Kluk
  • Brian Henderson
  • Leena Kinnunen
  • Heikki A Koistinen
  • Claes Ladenvall
  • Gad Getz
  • Adolfo Correa
  • Benjamin F Banahan
  • Stacey Gabriel
  • Sekar Kathiresan
  • Heather M Stringham
  • Mark I McCarthy
  • Michael Boehnke
  • Jaakko Tuomilehto
  • Christopher Haiman
  • Leif Groop
  • Gil Atzmon
  • James G Wilson
  • Donna Neuberg
  • David Altshuler
  • Benjamin L Ebert
Visa allt

Summary, in English

Background The incidence of hematologic cancers increases with age. These cancers are associated with recurrent somatic mutations in specific genes. We hypothesized that such mutations would be detectable in the blood of some persons who are not known to have hematologic disorders. Methods We analyzed whole-exome sequencing data from DNA in the peripheral-blood cells of 17,182 persons who were unselected for hematologic phenotypes. We looked for somatic mutations by identifying previously characterized single-nucleotide variants and small insertions or deletions in 160 genes that are recurrently mutated in hematologic cancers. The presence of mutations was analyzed for an association with hematologic phenotypes, survival, and cardiovascular events. Results Detectable somatic mutations were rare in persons younger than 40 years of age but rose appreciably in frequency with age. Among persons 70 to 79 years of age, 80 to 89 years of age, and 90 to 108 years of age, these clonal mutations were observed in 9.5% (219 of 2300 persons), 11.7% (37 of 317), and 18.4% (19 of 103), respectively. The majority of the variants occurred in three genes: DNMT3A, TET2, and ASXL1. The presence of a somatic mutation was associated with an increase in the risk of hematologic cancer (hazard ratio, 11.1; 95% confidence interval [CI], 3.9 to 32.6), an increase in all-cause mortality (hazard ratio, 1.4; 95% CI, 1.1 to 1.8), and increases in the risks of incident coronary heart disease (hazard ratio, 2.0; 95% CI, 1.2 to 3.4) and ischemic stroke (hazard ratio, 2.6; 95% CI, 1.4 to 4.8). Conclusions Age-related clonal hematopoiesis is a common condition that is associated with increases in the risk of hematologic cancer and in all-cause mortality, with the latter possibly due to an increased risk of cardiovascular disease. (Funded by the National Institutes of Health and others.).

Publiceringsår

2014

Språk

Engelska

Sidor

2488-2498

Publikation/Tidskrift/Serie

New England Journal of Medicine

Volym

371

Issue

26

Dokumenttyp

Artikel i tidskrift

Förlag

Massachusetts Medical Society

Ämne

  • Endocrinology and Diabetes

Status

Published

Forskningsgrupp

  • Genomics, Diabetes and Endocrinology

ISBN/ISSN/Övrigt

  • ISSN: 0028-4793