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

• 成果类型: Article
• 署名作者: Diaz-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, Burcak; 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; Colon-Matos, Frank J.; Miraftab, Mona; Saha, Monjoy; Lee, Olivia W.; Jones, Kristine M.; Gallego-Garcia, Pilar; Yang, Yang; Zhong, Xiaoming; Edell, Eric S.; Santamaria, Jacobo Martinez; Schabath, Matthew B.; Yendamuri, Sai S.; Manczuk, Marta; Lissowska, Jolanta; Swiatkowska, Beata; Mukeria, Anush; Shangina, Oxana; Zaridze, David; Holcatova, Ivana; Mates, Dana; Milosavljevic, Sasa; Kontic, Millica; Bosse, 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
• 署名单位: University of California System; University of California San Diego; University of California System; University of California San Diego; University of California System; University of California San Diego; Centro Nacional de Investigaciones Oncologicas (CNIO); National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); NIH National Cancer Institute- Division of Cancer Epidemiology & Genetics; Universite de Montreal; Memorial Sloan Kettering Cancer Center; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Laval University; Laval University Hospital; Middle East Technical University; Francis Crick Institute; University of London; University College London; Cancer Research UK; National Health Research Institutes - Taiwan; National Health Research Institutes - Taiwan; University of Hong Kong; University of Hong Kong; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); Frederick National Laboratory for Cancer Research; University of Chicago; Mayo Clinic; H Lee Moffitt Cancer Center & Research Institute; Roswell Park Comprehensive Cancer Center; Nofer Institute of Occupational Medicine; Motol University Hospital; Charles University Prague; Charles University Prague; Motol University Hospital; Motol University Hospital; Clinical Centre of Serbia; University of Belgrade; University of Miami; Harvard University; Harvard T.H. Chan School of Public Health; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; World Health Organization; International Agency for Research on Cancer (IARC); University of Toronto; University Health Network Toronto; Princess Margaret Cancer Centre; Universite Cote d'Azur; University of Chicago; Robert H. Lurie Comprehensive Cancer Center; University of Chicago; Harvard University; Harvard University; University of Manchester; University of Manchester; Yale University; University of Milan; IRCCS Ca Granda Ospedale Maggiore Policlinico; University of California System; University of California San Diego
• 刊物名称: Nature
• ISSN/ISSBN: 0028-2142
• DOI: 10.1038/s41586-025-09219-0
• 发表日期: 2025-08-07
• 关键词: mutational signatures; somatic mutations; adenocarcinoma; Heterogeneity; landscape; EVOLUTION; selection; variants; germline; HISTORY

摘要

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.