空气污染显着影响肺癌的进展，但缺乏与空气污染相关的临床样本的全面分子特征。在这里，我们对宣威地区 169 名从不吸烟的女性（XWLC 队列）进行了肺腺癌 (LUAD) 的蛋白质组学分析，煤烟是宣威地区肺癌高发病率的主要原因。基因组突变分析显示，XWLC 是 LUAD 的一种独特亚型，与吸烟或内源性因素相关的病例不同。突变特征分析表明苯并[a]芘 (BaP) 是 XWLC 的主要危险因素。 BaP 诱导的突变热点 EGFR-G719X 存在于 20% 的 XWLC 中，这使得 XWLC 的 MAPK 通路激活升高，并且与常见 EGFR 突变相比，结果更差。 XWLC 的多组学聚类确定了四种临床相关亚型。这些亚组在生物过程、遗传改变、代谢需求、免疫景观和放射组学特征方面表现出独特的特征。最后，MAD1 和 TPRN 被确定为 XWLC 中新的潜在治疗靶点。我们的研究为研究人员和临床医生探索空气污染相关肺癌的预防和治疗策略提供了宝贵的资源。© 2024，Zhang、Liu、Wang 等人。

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 EGFR 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, MAD1 and TPRN 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.© 2024, Zhang, Liu, Wang et al.