Age-related clonal hematopoiesis associated with adverse outcomes.

N Engl J Med
Authors
Keywords
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.).

Year of Publication
2014
Journal
N Engl J Med
Volume
371
Issue
26
Pages
2488-98
Date Published
2014 Dec 25
ISSN
1533-4406
URL
DOI
10.1056/NEJMoa1408617
PubMed ID
25426837
PubMed Central ID
PMC4306669
Links
Grant list
U01 DK085501 / DK / NIDDK NIH HHS / United States
R01 AG042188 / AG / NIA NIH HHS / United States
T32 HL066987 / HL / NHLBI NIH HHS / United States
090532 / Wellcome Trust / United Kingdom
U54 HG003067 / HG / NHGRI NIH HHS / United States
HHSN268201300049C / PHS HHS / United States
U01 DK085524 / DK / NIDDK NIH HHS / United States
U01 DK085545 / DK / NIDDK NIH HHS / United States
HHSN268201300048C / PHS HHS / United States
P01 AG021654 / AG / NIA NIH HHS / United States
R01 HL082945 / HL / NHLBI NIH HHS / United States
P01AG021654 / AG / NIA NIH HHS / United States
HHSN268201300047C / PHS HHS / United States
HHSN268201300048C / HL / NHLBI NIH HHS / United States
P01 CA066996 / CA / NCI NIH HHS / United States
T32 CA009172 / CA / NCI NIH HHS / United States
P30AG038072 / AG / NIA NIH HHS / United States
HHSN268201300049C / HL / NHLBI NIH HHS / United States
085475 / Wellcome Trust / United Kingdom
T32 CA009216 / CA / NCI NIH HHS / United States
HHSN268201300050C / PHS HHS / United States
RC2 DK088389 / DK / NIDDK NIH HHS / United States
G0900747 91070 / Medical Research Council / United Kingdom
DP2 DK098087 / DK / NIDDK NIH HHS / United States
HHSN268201300047C / HL / NHLBI NIH HHS / United States
U01 DK085526 / DK / NIDDK NIH HHS / United States
HHSN268201300050C / HL / NHLBI NIH HHS / United States
090367 / Wellcome Trust / United Kingdom
U01 DK085584 / DK / NIDDK NIH HHS / United States
DK088389 / DK / NIDDK NIH HHS / United States
HSN268201300046C / PHS HHS / United States
P30 AG038072 / AG / NIA NIH HHS / United States
1R01AG042188 / AG / NIA NIH HHS / United States
5T32HL066987 / HL / NHLBI NIH HHS / United States
P30 DK020572 / DK / NIDDK NIH HHS / United States
083948 / Wellcome Trust / United Kingdom
098381 / Wellcome Trust / United Kingdom
R01HL082945 / HL / NHLBI NIH HHS / United States
G0601261 / Medical Research Council / United Kingdom