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Age-Related Clonal Hematopoiesis Associated with Adverse Outcomes

Age-Related Clonal Hematopoiesis Associated with Adverse Outcomes BackgroundThe 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.MethodsWe 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.ResultsDetectable 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).ConclusionsAge-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.) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The New England Journal of Medicine The New England Journal of Medicine

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  • M. Walter, L. Ding, D. Shen, J. Shao, Marcus Grillot, M. McLellan, R. Fulton, Heather Schmidt, Joelle Kalicki-Veizer, M. O'Laughlin, C. Kandoth, J. Baty, P. Westervelt, J. Dipersio, E. Mardis, R. Wilson, T. Ley, T. Graubert (2011)

    Recurrent DNMT3A Mutations in Patients with Myelodysplastic Syndromes

    Leukemia, 25

  • G. Lenz, R. Davis, V. Ngo, L. Lam, T. George, George Wright, S. Dave, Hong Zhao, Weihong Xu, A. Rosenwald, G. Ott, G. Ott, H. Müller-hermelink, R. Gascoyne, J. Connors, L. Rimsza, E. Campo, E. Jaffe, J. Delabie, E. Smeland, R. Fisher, W. Chan, L. Staudt (2008)

    Oncogenic CARD11 Mutations in Human Diffuse Large B Cell Lymphoma

    Science, 319

Publisher
The New England Journal of Medicine
Copyright
Copyright © 2014 Massachusetts Medical Society. All rights reserved.
ISSN
0028-4793
eISSN
1533-4406
DOI
10.1056/NEJMoa1408617
pmid
25426837
Publisher site
See Article on Publisher Site

Abstract

BackgroundThe 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.MethodsWe 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.ResultsDetectable 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).ConclusionsAge-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.)

Journal

The New England Journal of MedicineThe New England Journal of Medicine

Published: Dec 25, 2014

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