Blood mutations and cancer associations among WTC-exposed Firefighters

Albert Einstein College Of Medicine, Bronx NY

Investigators

Abstract

ABSTRACT Clonal hematopoiesis (CH) is the acquisition of somatic mutations in the blood that carry increased risk of blood cancers, and inflammatory conditions, as well as mortality.1, 2 Environmental exposures and the subsequent inflammation play a major role in causing and supporting the growth of mutations in blood cells. The World Trade Center (WTC) disaster led to an unprecedented environmental exposure to aerosolized genotoxic dust and gases. Studies from our group in the WTC exposed Fire Department of the City of New York (FDNY) cohort, have reported an excess of cancer cases compared to the general population.3 We have built a biorepository of samples consisting of fractionated blood components and serum from over 2,000 WTC-exposed firefighters and non-WTC-exposed firefighter controls and propose to determine the prevalence of blood mutations and thus enable early detection of blood cancers and other diseases. Using this cohort, we published a pilot study documenting results of our deep targeted genome sequencing of WTC-exposed firefighters and non-WTC- exposed age matched firefighter controls. We observed a significantly higher prevalence of CH mutations (10%) in WTC-exposed firefighters when compared with controls (7%).4 Since this pilot study, we have conducted additional CH sequencing for a total of nearly 1,000 WTC-exposed individuals. We now propose, in Aim 1, to determine the association of CH with the development of cancers in a cohort of 988 FDNY WTC-exposed responders. Aim 2 will determine the functional effects of WTC particulate matter on development of clonal hematopoiesis in vivo by using mouse models. Comprehensive assessments will be conducted of WTC dust exposure in our CH models to determine the combined role of blood mutations and WTC-exposure on inflammation and precancerous changes. Lastly, Aim 3 will determine the efficacy of inhibiting the IL-1/IL- 1RAP/IRAK4 pathways in CH models with clinically relevant inhibitors. These results will further our understanding of the mechanisms through which the WTC disaster exposures lead to cancer and chronic inflammation. Importantly, detection of CH mutations, disease associations and potential therapeutics will enable clinical evaluations of the WTC-exposed FDNY cohort, enabling early diagnosis and future disease altering interventions.