Genomic Characterization Revealed PM2.5-Associated Mutational Signatures in Lung Cancer Including Activation of APOBEC3B

Fine particulate matter (PM_2.5) exposure causes DNA mutations and abnormal gene expression leading to lung cancer, but the detailed mechanisms remain unknown. Here, analysis of genomic and transcriptomic changes upon a PM_2.5 exposure-induced human bronchial epithelial cell-based malignant transformed cell model in vitro showed that PM_2.5 exposure led to APOBEC mutational signatures and transcriptional activation of APOBEC3B along with other potential oncogenes. Moreover, by analyzing mutational profiles of 1117 non-small cell lung cancers (NSCLCs) from patients across four different geographic regions, we observed a significantly higher prevalence of APOBEC mutational signatures in non-smoking NSCLCs than smoking in the Chinese cohorts, but this difference was not observed in TCGA or Singapore cohorts. We further validated this association by showing that the PM_2.5 exposure-induced transcriptional pattern was significantly enriched in Chinese NSCLC patients compared with other geographic regions. Finally, our results showed that PM_2.5 exposure activated the DNA damage repair pathway. Overall, here we report a previously uncharacterized association between PM_2.5 and APOBEC activation, revealing a potential molecular mechanism of PM_2.5 exposure and lung cancer.