Gene-environment interactions between clonal hematopoiesis of indeterminate potential and air pollution in non-small cell lung cancer among non-smokers.
Authors: Marco M Buttigieg, Caitlyn Vlasschaert, Yash Pershad, Matthew Lanktree, Melinda C Aldrich, Michael J Rauh, Alexander G Bick
Journal: Journal of Clinical Oncology (2024)

10514 Background: Small particulate matter air pollution (≤ 2.5µm diameter; PM 2.5 ) is a recognized driver of non-small cell lung cancer (NSCLC) among non-smokers. PM 2.5 recruits pro-inflammatory macrophages to the lungs, which facilitate the clonal expansion of mutated epithelial cells and eventual transformation to NSCLC. Clonal hematopoiesis of indeterminate potential (CHIP) is a common age-related condition caused by the acquisition of somatic mutations in hematopoietic stem cells. CHIP and its accompanying pro-inflammatory phenotype have been linked with various age-related diseases, including incident NSCLC; however, the mechanisms underlying this relationship are unknown. In this study, we aimed to explore the interaction between CHIP and exposure to PM 2.5 in the development of incident NSCLC. Methods: This study was conducted using data from participants in the UK Biobank (n = 451,095). CHIP status was determined from peripheral blood whole exome sequencing data, and defined as the presence of a somatic driver mutation in the blood at variant allele frequency (VAF) ≥2% (PMID: 36652671). Incident NSCLC was determined from UK cancer registry data, and PM 2.5 exposure was determined based on ambient regional measures from 2010. Cox proportional hazard models were used to evaluate associations between CHIP, PM 2.5 , and NSCLC. Proteomics data was measured using OLINK proteomics in a subset of UK Biobank participants (n = 44,625). Results: CHIP was prevalent in 3.4% of UK Biobank participants (n = 15,633; never smokers: 3.0%, n = 6,916/227,133). There were 1983 incident cases of NSCLC (never smokers: n = 307). CHIP status was associated with incident NSCLC when adjusting for smoking status (HR = 1.73, 95% CI: 1.48–2.02) and analyzing exclusively non-smokers (HR = 2.01, 95% CI: 1.34-3.00). PM 2.5 levels were not associated with NSCLC in non-smokers (HR = 1.00, 95% CI: 0.89–1.12 per µg/m 3 increase in PM 2.5 ); however, there was a significant interaction between PM 2.5 and CHIP (HR = 1.46, 95% CI: 1.02–2.11, p int = 0.04), suggesting that it is the interplay between the two that drives incident NSCLC risk. We found no association between PM 2.5 levels and increased CHIP prevalence or CHIP VAF. PM 2.5 and CHIP were also found to interact to increase systemic inflammatory markers C-reactive peptide (p int = 0.01) and IL-6 (p int = 0.002). Conclusions: PM 2.5 and CHIP act as a novel gene x environment interaction pair that play a key role in NSCLC etiology among non-smokers. Rather than acting in isolation to increase risk of NSCLC, PM 2.5 intensifies the relationship between CHIP and NSCLC, presumably by exacerbating systemic inflammation and the hyper-inflammatory lung microenvironment. With PM 2.5 levels in the UK among the lowest in the world, we posit that the CHIP x PM 2.5 interaction contributes substantially to the global burden of NSCLC in non-smokers.