4.8 Article

High burden of clonal hematopoiesis in first responders exposed to the World Trade Center disaster

Journal

NATURE MEDICINE
Volume 28, Issue 3, Pages 468-+

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s41591-022-01708-3

Keywords

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Funding

  1. National Institutes of Health [U01OH011933, U01OH012271, U01OH11300, F30DK127699, R01HL119326, R00HL136870, T32GM007347]
  2. NIOSH [200-2011-39383, 200-2011-39378, 200-2017-93326]
  3. Jane and Myles Dempsey Fund
  4. Leukemia Lymphoma Society
  5. Evans MDS Foundation
  6. Valvano Foundation
  7. Adventure Alle Fund
  8. Biff Ruttenberg Foundation
  9. Ann Melly Scholarship
  10. NIH [S10RR025141, S10OD025092, S10OD017985]
  11. CTSA [UL1TR002243, UL1TR000445, UL1RR024975]
  12. Beverly and George Rawlings Directorship
  13. [U01HG004798]
  14. [R01NS032830]
  15. [RC2GM092618]
  16. [P50GM115305]
  17. [U01HG006378]
  18. [U19HL065962]
  19. [R01HD074711]

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The terrorist attacks on the World Trade Center led to a high burden of somatic mutations in blood cells among first responders, raising their risk for cancer. Exposure to WTC particulate matter caused dysregulation of DNA replication and increased mutation burden in mice. Enhanced screening and preventative efforts are needed for first responders to the WTC disaster.
The terrorist attacks on the World Trade Center (WTC) created an unprecedented environmental exposure to aerosolized dust, gases and potential carcinogens. Clonal hematopoiesis (CH) is defined as the acquisition of somatic mutations in blood cells and is associated with smoking and exposure to genotoxic stimuli. Here we show that deep targeted sequencing of blood samples identified a significantly higher proportion of WTC-exposed first responders with CH (10%; 48 out of 481) when compared with non-WTC-exposed firefighters (6.7%; 17 out of 255; odds ratio, 3.14; 95% confidence interval, 1.64-6.03; P = 0.0006) after controlling for age, sex and race/ethnicity. The frequency of somatic mutations in WTC-exposed first responders showed an age-related increase and predominantly affected DNMT3A, TET2 and other CH-associated genes. Exposure of lymphoblastoid cells to WTC particulate matter led to dysregulation of DNA replication at common fragile sites in vitro. Moreover, mice treated with WTC particulate matter developed an increased burden of mutations in hematopoietic stem and progenitor cell compartments. In summary, the high burden of CH in WTC-exposed first responders provides a rationale for enhanced screening and preventative efforts in this population. First responders to the World Trade Center disaster, who were exposed to particulate matter containing potential carcinogens, have a high burden of somatic mutations in blood cells, raising their risk for cancer and other diseases and highlighting the need for enhanced health screening of these individuals.

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