HSA Adductomics in the Shanghai Women’s Health Study Links Lung Cancer in Never-Smokers with Air Pollution, Redox Biology, and One-Carbon Metabolism

Nearly one fourth of lung cancers occur among never-smokers and are predominately lung adenocarcinomas (LUADs) that are distinct from smoking-related cancers. Causal links between LUADs in never-smokers have been attributed to reactive oxygen species (ROS) arising from airborne fine particulate matter (PM_2.5) and polycyclic aromatic hydrocarbons (PAHs). These effects are pronounced among East Asian women who experience massive exposures to PM_2.5 and PAHs and have the highest incidence of LUADs in the world. We employed untargeted adductomics to establish ROS adduct signatures in human serum albumin (HSA) from lung cancer cases and controls from never-smokers in the Shanghai Women's Health Study. Forty-seven HSA adducts were quantified by mass spectrometry, nine of which were selected for association with lung cancer, including Cys34 sulfoxidation products and disulfides of cysteine and homocysteine and two modifications to Lys525. Associated adducts include constituents of redox biology and one-carbon metabolism (OCM), which are pathways associated with lung cancer. Differences in adduct abundance between cases and controls and correlations of adducts with urinary PAHs and dietary factors provide additional evidence linking air pollutants, OCM, and redox biology with lung cancer in never-smokers.