Clonal hematopoiesis of indeterminate potential-associated non-small cell lung cancer risk is potentiated by small particulate matter air pollution among non-smokers: a novel somatic variant–environment interaction

Abstract

AbstractSmall particulate matter air pollution (PM2.5) is a recognized driver of non-small cell lung cancer (NSCLC) among non-smoking individuals. Inhaled PM2.5recruits pro-inflammatory macrophages to the air-lung interface, which promotes malignant lung epithelial cell growth and progression to overt cancer. We sought to determine whether clonal hematopoiesis of indeterminate potential (CHIP), a common age-related condition characterized by hyperinflammatory macrophages, exacerbates PM2.5-associated NSCLC in non-smokers using genetic, environmental, and phenotypic data from 413,901 individuals in the UK Biobank. Among non-smokers, PM2.5is not associated with NSCLC and not associated with prevalence of CHIP, but CHIP is associated with a doubling of NSCLC risk (hazard ratio (HR) 2.01, 95% confidence interval (CI): 1.34-3.00). Moreover, CHIP-associated NSCLC risk is exacerbated in the setting of above-median PM2.5levels (HR 2.70, 95% CI: 1.60–4.55). PM2.5× CHIP is also associated with significantly greater markers of systemic inflammation (CRP, IL-6, and IL-1β) than expected. Altogether, these results suggest CHIP and PM2.5form a novel gene × environment interaction promoting NSCLC tumorigenesis in non-smokers.