国家癌症研究所Soo-Ryum Yang研究小组报道了塑造从不吸烟者肺癌基因组的诱变力量。该项研究成果发表在2025年7月2日出版的《自然》上。

在这里，研究小组利用Sherlock-Lung研究的数据，通过检查来自28个地理位置的871名从未吸烟的肺癌患者的癌症基因组，来评估LCINS中的诱变暴露。KRAS突变在北美和欧洲从不吸烟者腺癌中的发生率是东亚从不吸烟者腺癌的3.8倍，而EGFR和TP53突变在东亚从不吸烟者腺癌中的发生率更高。具有未知catheme的签名SBS40a在腺癌中贡献了最大比例的单碱基替换，并且在EGFR突变的病例中富集。SBS22a与马兜铃酸暴露有关，几乎只在中国台湾患者中观察到。暴露于二手烟与个体驱动突变或突变特征无关。相比之下，来自空气污染严重地区的患者更有可能发生TP53突变，端粒更短。他们还表现出大多数类型的突变增加，包括签名SBS4增加了3.9倍，之前被认为与吸烟有关，签名SBS5增加了76%。空气污染水平观察到正剂量反应效应，与端粒长度减少和体细胞突变增加相关，主要归因于特征SBS4和SBS5。他们的研究结果阐明了在不吸烟者中形成肺癌基因组景观的突变过程的多样性。

据了解，在观察性研究中，从不吸烟者肺癌（LCINS）约占所有肺癌的25%，并与暴露于二手烟草烟雾和空气污染有关。

附：英文原文

Title: The mutagenic forces shaping the genomes of lung cancer in never smokers

Author: Daz-Gay, Marcos, Zhang, Tongwu, Hoang, Phuc H., Leduc, Charles, Baine, Marina K., Travis, William D., Sholl, Lynette M., Joubert, Philippe, Khandekar, Azhar, Zhao, Wei, Steele, Christopher D., Otlu, Burak, Nandi, Shuvro P., Vangara, Raviteja, Bergstrom, Erik N., Kazachkova, Mariya, Pich, Oriol, Swanton, Charles, Hsiung, Chao Agnes, Chang, I-Shou, Wong, Maria Pik, Leung, Kin Chung, Sang, Jian, McElderry, John P., Hartman, Caleb, Coln-Matos, Frank J., Miraftab, Mona, Saha, Monjoy, Lee, Olivia W., Jones, Kristine M., Gallego-Garca, Pilar, Yang, Yang, Zhong, Xiaoming, Edell, Eric S., Santamara, Jacobo Martnez, Schabath, Matthew B., Yendamuri, Sai S., Manczuk, Marta, Lissowska, Jolanta, witkowska, Beata, Mukeria, Anush, Shangina, Oxana, Zaridze, David, Holcatova, Ivana, Mates, Dana, Milosavljevic, Sasa, Kontic, Millica, Boss, Yohan, Rothberg, Bonnie E. Gould, Christiani, David C., Gaborieau, Valerie, Brennan, Paul, Liu, Geoffrey, Hofman, Paul, Yang, Lixing, Nowak, Martin A., Shi, Jianxin, Rothman, Nathaniel, Wedge, David C., Homer, Robert, Yang, Soo-Ryum

Issue&Volume: 2025-07-02

Abstract: Lung cancer in never smokers (LCINS) accounts for around 25% of all lung cancers1,2 and has been associated with exposure to second-hand tobacco smoke and air pollution in observational studies3,4,5. Here we use data from the Sherlock-Lung study to evaluate mutagenic exposures in LCINS by examining the cancer genomes of 871 treatment-naive individuals with lung cancer who had never smoked, from 28 geographical locations. KRAS mutations were 3.8 times more common in adenocarcinomas of never smokers from North America and Europe than in those from East Asia, whereas a higher prevalence of EGFR and TP53 mutations was observed in adenocarcinomas of never smokers from East Asia. Signature SBS40a, with unknown cause6, contributed the largest proportion of single base substitutions in adenocarcinomas, and was enriched in cases with EGFR mutations. Signature SBS22a, which is associated with exposure to aristolochic acid7,8, was observed almost exclusively in patients from Taiwan. Exposure to secondhand smoke was not associated with individual driver mutations or mutational signatures. By contrast, patients from regions with high levels of air pollution were more likely to have TP53 mutations and shorter telomeres. They also exhibited an increase in most types of mutations, including a 3.9-fold increase in signature SBS4, which has previously been linked with tobacco smoking9, and a 76% increase in the clock-like10 signature SBS5. A positive dose–response effect was observed with air-pollution levels, correlating with both a decrease in telomere length and an increase in somatic mutations, mainly attributed to signatures SBS4 and SBS5. Our results elucidate the diversity of mutational processes shaping the genomic landscape of lung cancer in never smokers.

DOI: 10.1038/s41586-025-09219-0

Source: https://www.nature.com/articles/s41586-025-09219-0