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

Date

2025-01-01

Author

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 Sarıtaş, 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

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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.

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https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=105009633828&origin=inward
https://hdl.handle.net/11511/115373

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Graduate School of Informatics, Article