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Age-Related Clonal Hematopoiesis Associated with Adverse Outcomes.

Jaiswal, Siddhartha; Fontanillas, Pierre; Flannick, Jason; Manning, Alisa; Grauman, Peter V; Mar, Brenton G; Lindsley, R Coleman; Mermel, Craig H; Burtt, Noel and Chavez, Alejandro, et al. (2014) In New England Journal of Medicine 371(26). p.2488-2498
Abstract
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... (More)
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.). (Less)
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New England Journal of Medicine
volume
371
issue
26
pages
2488 - 2498
publisher
Massachusetts Medical Society
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  • pmid:25426837
  • wos:000346920300008
  • scopus:84920053873
ISSN
0028-4793
DOI
10.1056/NEJMoa1408617
language
English
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yes
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f5a824e3-b02f-435f-9668-5d0ace66414a (old id 4815904)
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http://www.ncbi.nlm.nih.gov/pubmed/25426837?dopt=Abstract
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2014-12-06 19:01:10
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@article{f5a824e3-b02f-435f-9668-5d0ace66414a,
  abstract     = {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.).},
  author       = {Jaiswal, Siddhartha and Fontanillas, Pierre and Flannick, Jason and Manning, Alisa and Grauman, Peter V and Mar, Brenton G and Lindsley, R Coleman and Mermel, Craig H and Burtt, Noel and Chavez, Alejandro and Higgins, John M and Moltchanov, Vladislav and Kuo, Frank C and Kluk, Michael J and Henderson, Brian and Kinnunen, Leena and Koistinen, Heikki A and Ladenvall, Claes and Getz, Gad and Correa, Adolfo and Banahan, Benjamin F and Gabriel, Stacey and Kathiresan, Sekar and Stringham, Heather M and McCarthy, Mark I and Boehnke, Michael and Tuomilehto, Jaakko and Haiman, Christopher and Groop, Leif and Atzmon, Gil and Wilson, James G and Neuberg, Donna and Altshuler, David and Ebert, Benjamin L},
  issn         = {0028-4793},
  language     = {eng},
  number       = {26},
  pages        = {2488--2498},
  publisher    = {Massachusetts Medical Society},
  series       = {New England Journal of Medicine},
  title        = {Age-Related Clonal Hematopoiesis Associated with Adverse Outcomes.},
  url          = {http://dx.doi.org/10.1056/NEJMoa1408617},
  volume       = {371},
  year         = {2014},
}