Genomic Characterization Revealed PM_2.5-Associated Mutational Signatures in Lung Cancer Including Activation of APOBEC3B

Abstract

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.