Díaz-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 Burçak, 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, Colón-Matos Frank J, Miraftab Mona, Saha Monjoy, Lee Olivia W, Jones Kristine M, Gallego-García Pilar, Yang Yang, Zhong Xiaoming, Edell Eric S, Santamaría Jacobo Martínez, Schabath Matthew B, Yendamuri Sai S, Manczuk Marta, Lissowska Jolanta, Świątkowska Beata, Mukeria Anush, Shangina Oxana, Zaridze David, Holcatova Ivana, Mates Dana, Milosavljevic Sasa, Kontic Millica, Bossé 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, Pesatori Angela C, Consonni Dario, Lan Qing, Zhu Bin, Chanock Stephen J, Choi Jiyeon, Alexandrov Ludmil B, Landi Maria Teresa
Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
Department of Bioengineering, University of California San Diego, La Jolla, CA, USA.
Nature. 2025 Jul 2. doi: 10.1038/s41586-025-09219-0.
Lung cancer in never smokers (LCINS) accounts for around 25% of all lung cancers and has been associated with exposure to second-hand tobacco smoke and air pollution in observational studies. 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 cause, 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 acid, 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 smoking, and a 76% increase in the clock-like 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.
非吸烟肺癌（LCINS）约占所有肺癌的25%，在观察性研究中，它与接触二手烟和空气污染有关。在这里，我们使用来自Sherlock-Lung研究的数据，通过检查来自28个地理位置的871名未吸烟的初治肺癌患者的癌症基因组，来评估LCINS中的诱变暴露情况。KRAS突变在北美和欧洲非吸烟腺癌患者中出现的频率比东亚患者高3.8倍，而在东亚非吸烟腺癌患者中，EGFR和TP53突变的发生率更高。原因不明的特征性SBS40a在腺癌的单碱基替换中占比最大，且在EGFR突变病例中富集。与接触马兜铃酸有关的特征性SBS22a几乎仅在台湾患者中观察到。接触二手烟与个体驱动基因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突变且端粒较短。他们还表现出大多数类型突变的增加，包括与吸烟有关的特征性SBS4增加了3.9倍，以及类似时钟的特征性SBS5增加了76%。空气污染水平与端粒长度缩短和体细胞突变增加呈正剂量反应效应，主要归因于特征性SBS4和SBS5。我们的研究结果阐明了塑造非吸烟肺癌基因组格局的突变过程的多样性。
