The individual and joint effects of air pollution exposure on plasma proteome among vulnerable elderly: Implications for lung cancer risk in the Cancer Prevention Study-II Nutrition Cohort.

e22576 Background: The biological mechanisms underlying air pollution-induced lung carcinogenesis remained underexplored. We assessed individual and joint effects of six air pollutants on human proteome and their associations with lung cancer risk, aiming to identify key proteins and pathways involved in mediating this process. Methods: We included 95 matched case-control pairs of elderly with pre-diagnosis blood samples from the Cancer Prevention Study-II Nutrition Cohort (1998-2001). Plasma levels of 484 proteins were measured. Annual individual exposures to fine and coarse particulate matter (PM 10 ), nitrogen dioxide, ozone, sulfur dioxide, and carbon monoxide in the year of blood draw were retrieved. We used linear regression for individual pollutant effects and quantile g-computation for joint effects on proteins, and conditional logistic regression for proteins and lung cancer risk, adjusting for confounders and multiple testing. We then conducted pathway analysis to identify overlapping proteins and pathways associated with both exposures and lung cancer risk, followed by an exploratory high-dimensional mediation analysis to investigate the potential mediation roles of proteins. Results: Fifteen proteins were associated with air pollution and six with lung cancer risk (FDR < 0.2). Pathway analysis revealed five pathways related to air pollution and two to lung cancer risk, closely linked to immunity and signaling. Seventeen proteins were associated with both exposures and lung cancer risk ( P < 0.05 or FDR < 0.2), including ADAM15, ATRN, and CX3CL1. The PI3K-Akt signaling pathway was associated with both PM 10 and lung cancer risk. Twenty-two proteins were identified as significant mediators of the association between air pollution and lung cancer risk, including several ILs, CCL20, and IFN-gamma. Conclusions: Various immunity and signaling related proteins and pathways may play significant roles in the association between air pollution exposures and lung cancer. The findings provide novel insights into understanding the underlying etiology and contribute to future biomarker development for preventive and therapeutic strategies.