Clonal hematopoiesis associated non-small cell lung cancer risk is potentiated by small particulate matter air pollution

Small particulate matter air pollution (PM2.5) is a recognized driver of non-small cell lung cancer (NSCLC) among non-smoking individuals. Inhaled PM2.5 recruits 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, PM2.5 is 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 PM2.5 levels (HR 2.70, 95% CI: 1.60-4.55). PM2.5 x CHIP is also associated with significantly greater markers of systemic inflammation (CRP, IL-6, and IL-1B) than expected. Altogether, these results suggest CHIP and PM2.5 form a novel gene x environment interaction promoting NSCLC tumorigenesis in non-smokers. ### Competing Interest Statement A.G.B. is a co-founder, equity holders, and on the scientific advisory board of TenSixteen Bio. M.B.L. has received speaking and advisory board fees from Bayer, Otsuka, Reata and Sanofi. All other authors declare no conflicts of interest. M.C.A. has received advisory board fees from Guardant Health. ### Funding Statement This work was supported by NIH grants DP5 OD029586, R01 AG083736, a Burroughs Wellcome Fund Career Award for Medical Scientists, the E.P. Evans Foundation, RUNX1 Research Program, a Pew-Stewart Scholar for Cancer Research award, supported by the Pew Charitable Trusts and the Alexander and Margaret Stewart Trust to A.G.B., a National Institutes of Health/National Cancer Institute (NIH/NCI) grant #U01CA253560 awarded to M.C.A., a Canadian Institute of Health Research (CIHR) Project Grant (#202010PJT-451137) awarded to M.J.R, a PSI Foundation grant #2020-1910 awarded to C.V. and M.J.R, and a CIHR Canadian Graduate Scholarship (CGS) - Doctoral awarded to C.V. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Access to the UK Biobank dataset was provided under applications 43397 and 101583 and local approval for secondary analyses of the data was obtained from the Vanderbilt University Medical Center and Queens University institutional review boards. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes CHIP calls for UKB participants have been returned to the UKB Access Management System (AMS) and will be available to all registered researchers once processed by the UKB AMS team. All other data is available to registered UKB researchers.