肺癌是全球癌症死亡的首要原因。尽管非吸烟者仅占所有病例的10%至25%，但从病因学和生物学角度来看，非吸烟者肺癌（LCNS）相对缺乏详细描述。在大规模患者队列上应用多组学技术显著推进了对LCNS肿瘤生物学的当前理解。通过从临床角度综合多组学研究在LCNS上的发现，我们可以直接将有关肿瘤生物学的知识转化为对患者护理的影响。本综述主要关注肺腺癌的非吸烟者，并详细说明驱动基因突变的优势，特别是在东亚患者中的优势，以及LCNS中常见和重要的种系变异的频率。全面探讨了LCNS肿瘤中出现的突变模式，突出了APOBEC签名的高丰度。此外，本综述认识到LCNS肿瘤中存在的免疫谱，并提出如何将其转化为治疗选择。多组学研究在LCNS肿瘤生物学方面的反复和新颖见解具有广泛的临床意义。如户外空气污染、二手烟和潜在饮食等风险因素在不同程度上在LCNS中留下了基因组印记，虽然这些风险因素并没有涵盖所有LCNS病例，但可以用来对风险进行分层。种系变异同样对LCNS的相当比例有贡献，这要求详细记录非吸烟者肺癌的家族史，并且在未来的早期检测中开展有关致病变异的测试具有价值。分子驱动亚型和特定的共突变和突变特征在LCNS中具有预后价值，并可以指导治疗选择。无已知驱动基因突变的LCNS肿瘤倾向于具有干细胞样状态，贡献于此状态的基因可能成为潜在的治疗靶点。总的来说，多组学研究的综合发现对LCNS领域的临床管理和未来的研究方向具有广泛的影响。© 2023. BioMed Central Ltd., part of Springer Nature.

Lung cancer is the leading cause of cancer deaths worldwide. Despite never smokers comprising between 10 and 25% of all cases, lung cancer in never smokers (LCNS) is relatively under characterized from an etiological and biological perspective. The application of multi-omics techniques on large patient cohorts has significantly advanced the current understanding of LCNS tumor biology. By synthesizing the findings of multi-omics studies on LCNS from a clinical perspective, we can directly translate knowledge regarding tumor biology into implications for patient care. Primarily focused on never smokers with lung adenocarcinoma, this review details the predominance of driver mutations, particularly in East Asian patients, as well as the frequency and importance of germline variants in LCNS. The mutational patterns present in LCNS tumors are thoroughly explored, highlighting the high abundance of the APOBEC signature. Moreover, this review recognizes the spectrum of immune profiles present in LCNS tumors and posits how it can be translated to treatment selection. The recurring and novel insights from multi-omics studies on LCNS tumor biology have a wide range of clinical implications. Risk factors such as exposure to outdoor air pollution, second hand smoke, and potentially diet have a genomic imprint in LCNS at varying degrees, and although they do not encompass all LCNS cases, they can be leveraged to stratify risk. Germline variants similarly contribute to a notable proportion of LCNS, which warrants detailed documentation of family history of lung cancer among never smokers and demonstrates value in developing testing for pathogenic variants in never smokers for early detection in the future. Molecular driver subtypes and specific co-mutations and mutational signatures have prognostic value in LCNS and can guide treatment selection. LCNS tumors with no known driver alterations tend to be stem-like and genes contributing to this state may serve as potential therapeutic targets. Overall, the comprehensive findings of multi-omics studies exert a wide influence on clinical management and future research directions in the realm of LCNS.© 2023. BioMed Central Ltd., part of Springer Nature.