Proteogenomic analysis of air-pollution-associated lung cancer reveals prevention and therapeutic opportunities.

Abstract

Air pollution significantly impacts lung cancer progression, but there is a lack of a comprehensive molecular characterization of clinical samples associated with air pollution. Here, we performed a proteogenomic analysis of lung adenocarcinoma (LUAD) in 169 female never-smokers from the Xuanwei area (XWLC cohort), where coal smoke is the primary contributor to the high lung cancer incidence. Genomic mutation analysis revealed XWLC as a distinct subtype of LUAD separate from cases associated with smoking or endogenous factors. Mutational signature analysis suggested that Benzo[a]pyrene (BaP) is the major risk factor in XWLC. The BaP-induced mutation hotspot, EGFR-G719X, was present in 20% of XWLC which endowed XWLC with elevated MAPK pathway activations and worse outcomes compared to common <i>EGFR</i> mutations. Multi-omics clustering of XWLC identified four clinically relevant subtypes. These subgroups exhibited distinct features in biological processes, genetic alterations, metabolism demands, immune landscape, and radiomic features. Finally, <i>MAD1 and TPRN</i> were identified as novel potential therapeutic targets in XWLC. Our study provides a valuable resource for researchers and clinicians to explore prevention and treatment strategies for air-pollution-associated lung cancers.