World Trade Center responders have higher burden of mutations linked to blood cancers
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First responders to the World Trade Center had higher rates of clonal hematopoiesis-associated mutations than firefighters not exposed to the dust, gases and potential carcinogens at the site, according to a study in Nature Medicine.
“There are exposures that increase risk of [clonal hematopoiesis], and the World Trade Center particulate matter, specifically, provided significant increased risk over normal exposures seen in line of duty for a firefighter,” Michael R. Savona, MD, director of hematologic malignancies research and the early therapy program and professor of internal medicine and cancer biology at Vanderbilt University, told Healio. “The toxicity of the World Trade Center dust was profound, but also, broken into parts, revealed potential testable substances and links to clonal hematopoiesis.”
Background and methodology
Savona and colleagues had previously investigated causes of clonal hematopoiesis, an age-associated phenomenon characterized by mutations in commonly mutated genes within blood cells that is associated with increased risk for blood cancer and cardiovascular disease. They knew the germline risks of clonal hematopoiesis, but they did not know if potentially toxic exposures could change the way blood cells grow, Savona said.
“The World Trade Center catastrophe was an opportunity to determine whether World Trade Center dust exposure accelerated clonal hematopoiesis as it did some cancers, and if this additive was normal in exposures to fires,” Savona said.
The analysis included 736 individuals, including 429 firefighters and 52 emergency medical services workers from Fire Department of the City of New York who had been exposed to the World Trade Center site and a control group of 203 Nashville firefighters and 52 members of the International Association of Firefighters who had not exposed to the site and had comparable baseline demographics.
Researchers collected blood samples from all individuals between December 2013 to October 2015 and used deep targeted sequencing to analyze 237 genes frequently mutated in hematologic malignancies.
Key findings
Results showed a significantly higher percentage of World Trade Center first responders had an increased mutational burden (10% had evidence of clonal hematopoiesis) when compared with non-World Trade Center first responders (6.7%), for an OR of 3.14 (95% CI, 1.64-6.03) after controlling for age, sex and race/ethnicity.
Additionally, in the World Trade Center responders’ cohort, six of 48 individuals (12.5%) carried more than one somatic mutation.
“Firefighters who never traveled to the World Trade Center rescue mission had statistically significant less clonal hematopoiesis than those who were exposed to the particulate matter in the air for weeks after the World Trade Center explosions,” Savona said.
Implications
During the study, researchers also used wild-type mice to determine the effects of World Trade Center exposure on hematopoietic stem cells in vivo. They exposed mice to World Trade Center particulate matter thought to be equivalent to what first responders absorbed to mimic the respiratory and gastrointestinal exposure., Researchers reported a significant expansion of hematopoietic stem cells within 30 days after exposure.
Additional research on the particulate matter and the mechanism of blood cancer development are ongoing, Savona said.
“We remain very interested in the mechanisms of clonal hematopoiesis, the kinetics of disease progression and, ultimately, therapeutics to use in secondary prevention for higher risk clonal hematopoiesis,” he told Healio.
References:
Jasra S, et al. Nat Med. 2022;doi:10.1038/s41591-022-01708-3.
Study finds World Trade Center responders at higher risk for blood cancer-associated mutations (press release). https://news.vumc.org/2022/03/07/study-finds-world-trade-center-responders-at-higher-risk-for-blood-cancer-associated-mutations/. Published March 7, 2022. Accessed March 23, 2022.
For more information:
Michael R. Savona, MD, can be reached at Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, 2200 Pierce Ave., Preston Research Building 777, Nashville, TN 37232; email: michael.savona@vanderbilt.edu.
Perspective
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Abhay Singh, MD, MPH
More than 50,000 people worked on the rescue and recovery efforts following the 9/11 attacks. Extensive comorbidities and numerous stressors — physical and mental — have since been reported.
Expanding population of hematopoietic stem/progenitor cell (stem cell) clones carrying mutational defects characterizes clonal hematopoiesis. The mutant stem cell clones often remain stable over one’s lifetime, unless certain external environmental stressors result in selective expansion of these mutant clones.
This extraordinary work from Jasra and colleagues has brought to light such selective expansion of mutant clones in response to external stressor (ie, World Trade Center particulate matter), providing rationale for clonal hematopoiesis screening and longitudinal monitoring as a risk-mitigation strategy.
Interestingly, however, there was no clonal expansion in mutant clones of PPM1D or TP53 — mutations often associated with DNA damage — that one would have expected given exposure to particulate matter and dense black smoke that contained benzene, volatile organics and polycyclic aromatic hydrocarbons, all arguably DNA-damaging compounds.
Instead, researchers noted expansion in aging- and inflammation-associated mutant clones of DNMT3A and TET2, speaking to the possibility of accelerating aging and possibly inflammation — or “inflammaging” — in this cohort.
The high cumulative incidence of conditions such as depression, PTSD and panic disorder have been highlighted in prior studies. World Trade Center rescue and recovery workers suffer from PTSD at rates as much as four times greater than the general population, and studies have described lingering mental health problems among these workers. These mental stressors — often under-addressed and sometimes overlooked — contribute greatly to cumulative stress and promote accelerated aging.
In addition to longitudinal clonal hematopoiesis monitoring — undoubtedly an issue of great importance — one can never emphasize enough the need for continued monitoring for these mental health stressors and optimal treatment of World Trade Center rescue and recovery personnel.
The findings by Jasra and colleagues add greatly to the growing clonal hematopoiesis literature and our understanding of hematopoietic clones. Future efforts should consider studying clonal hematopoiesis associations with mental health screens (eg, patient health questionnaires for depression/panic disorders, PTSD symptom checklist, etc.) that might have been obtained previously for World Trade Center first responders. This may go some way to fill the gap in understanding why aging-associated DNMT3A and TET2 clones preferentially expanded in the current study, and not the mutant clones that arise as a result of genotoxic insult (World Trade Center particulate matter).
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