PMID- 25426837
OWN - NLM
STAT- MEDLINE
DCOM- 20150109
LR  - 20240214
IS  - 1533-4406 (Electronic)
IS  - 0028-4793 (Print)
IS  - 0028-4793 (Linking)
VI  - 371
IP  - 26
DP  - 2014 Dec 25
TI  - Age-related clonal hematopoiesis associated with adverse outcomes.
PG  - 2488-98
LID - 10.1056/NEJMoa1408617 [doi]
AB  - 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.).
FAU - Jaiswal, Siddhartha
AU  - Jaiswal S
AD  - The authors' affiliations are listed in the Appendix.
FAU - Fontanillas, Pierre
AU  - Fontanillas P
FAU - Flannick, Jason
AU  - Flannick J
FAU - Manning, Alisa
AU  - Manning A
FAU - Grauman, Peter V
AU  - Grauman PV
FAU - Mar, Brenton G
AU  - Mar BG
FAU - Lindsley, R Coleman
AU  - Lindsley RC
FAU - Mermel, Craig H
AU  - Mermel CH
FAU - Burtt, Noel
AU  - Burtt N
FAU - Chavez, Alejandro
AU  - Chavez A
FAU - Higgins, John M
AU  - Higgins JM
FAU - Moltchanov, Vladislav
AU  - Moltchanov V
FAU - Kuo, Frank C
AU  - Kuo FC
FAU - Kluk, Michael J
AU  - Kluk MJ
FAU - Henderson, Brian
AU  - Henderson B
FAU - Kinnunen, Leena
AU  - Kinnunen L
FAU - Koistinen, Heikki A
AU  - Koistinen HA
FAU - Ladenvall, Claes
AU  - Ladenvall C
FAU - Getz, Gad
AU  - Getz G
FAU - Correa, Adolfo
AU  - Correa A
FAU - Banahan, Benjamin F
AU  - Banahan BF
FAU - Gabriel, Stacey
AU  - Gabriel S
FAU - Kathiresan, Sekar
AU  - Kathiresan S
FAU - Stringham, Heather M
AU  - Stringham HM
FAU - McCarthy, Mark I
AU  - McCarthy MI
FAU - Boehnke, Michael
AU  - Boehnke M
FAU - Tuomilehto, Jaakko
AU  - Tuomilehto J
FAU - Haiman, Christopher
AU  - Haiman C
FAU - Groop, Leif
AU  - Groop L
FAU - Atzmon, Gil
AU  - Atzmon G
FAU - Wilson, James G
AU  - Wilson JG
FAU - Neuberg, Donna
AU  - Neuberg D
FAU - Altshuler, David
AU  - Altshuler D
FAU - Ebert, Benjamin L
AU  - Ebert BL
LA  - eng
GR  - P01 AG021654/AG/NIA NIH HHS/United States
GR  - HHSN268201300048C/HL/NHLBI NIH HHS/United States
GR  - 085475/WT_/Wellcome Trust/United Kingdom
GR  - T32 CA009216/CA/NCI NIH HHS/United States
GR  - DK088389/DK/NIDDK NIH HHS/United States
GR  - 5T32HL066987/HL/NHLBI NIH HHS/United States
GR  - 098381/WT_/Wellcome Trust/United Kingdom
GR  - R01HL082945/HL/NHLBI NIH HHS/United States
GR  - G0601261/MRC_/Medical Research Council/United Kingdom
GR  - U01 DK085501/DK/NIDDK NIH HHS/United States
GR  - R01 AG042188/AG/NIA NIH HHS/United States
GR  - T32 HL066987/HL/NHLBI NIH HHS/United States
GR  - 090532/WT_/Wellcome Trust/United Kingdom
GR  - U54 HG003067/HG/NHGRI NIH HHS/United States
GR  - HHSN268201300049C/HL/NHLBI NIH HHS/United States
GR  - U01 DK085524/DK/NIDDK NIH HHS/United States
GR  - U01 DK085545/DK/NIDDK NIH HHS/United States
GR  - HHSN268201300048C/HL/NHLBI NIH HHS/United States
GR  - HHSN268201300047C/HL/NHLBI NIH HHS/United States
GR  - R01 HL082945/HL/NHLBI NIH HHS/United States
GR  - P01AG021654/AG/NIA NIH HHS/United States
GR  - P01 CA066996/CA/NCI NIH HHS/United States
GR  - T32 CA009172/CA/NCI NIH HHS/United States
GR  - G0900747/MRC_/Medical Research Council/United Kingdom
GR  - P30AG038072/AG/NIA NIH HHS/United States
GR  - HHSN268201300049C/HL/NHLBI NIH HHS/United States
GR  - G0900747 91070/MRC_/Medical Research Council/United Kingdom
GR  - DP2 DK098087/DK/NIDDK NIH HHS/United States
GR  - HHSN268201300050C/HL/NHLBI NIH HHS/United States
GR  - RC2 DK088389/DK/NIDDK NIH HHS/United States
GR  - HHSN268201300047C/HL/NHLBI NIH HHS/United States
GR  - U01 DK085526/DK/NIDDK NIH HHS/United States
GR  - HHSN268201300050C/HL/NHLBI NIH HHS/United States
GR  - 090367/WT_/Wellcome Trust/United Kingdom
GR  - U01 DK085584/DK/NIDDK NIH HHS/United States
GR  - P30 AG038072/AG/NIA NIH HHS/United States
GR  - 1R01AG042188/AG/NIA NIH HHS/United States
GR  - P30 DK020572/DK/NIDDK NIH HHS/United States
GR  - 083948/WT_/Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20141126
PL  - United States
TA  - N Engl J Med
JT  - The New England journal of medicine
JID - 0255562
SB  - IM
CIN - N Engl J Med. 2014 Dec 25;371(26):2523-5. PMID: 25426835
CIN - Nat Rev Genet. 2015 Feb;16(2):69. PMID: 25534323
MH  - Adult
MH  - Age Factors
MH  - Aged
MH  - Aged, 80 and over
MH  - *Blood
MH  - Cell Transformation, Neoplastic/*genetics
MH  - Clone Cells
MH  - DNA Mutational Analysis
MH  - Exome
MH  - Hematologic Neoplasms/*genetics
MH  - *Hematopoiesis
MH  - Hematopoietic Stem Cells/*physiology
MH  - Humans
MH  - Middle Aged
MH  - *Mutation
MH  - Risk Factors
MH  - Young Adult
PMC - PMC4306669
MID - NIHMS653107
EDAT- 2014/11/27 06:00
MHDA- 2015/01/13 06:00
PMCR- 2015/06/25
CRDT- 2014/11/27 06:00
PHST- 2014/11/27 06:00 [entrez]
PHST- 2014/11/27 06:00 [pubmed]
PHST- 2015/01/13 06:00 [medline]
PHST- 2015/06/25 00:00 [pmc-release]
AID - 10.1056/NEJMoa1408617 [doi]
PST - ppublish
SO  - N Engl J Med. 2014 Dec 25;371(26):2488-98. doi: 10.1056/NEJMoa1408617. Epub 2014 
      Nov 26.