Revealing the Drivers Underlying Distinct Evolutionary Trajectories in Lung Adenocarcinoma

Elucidating the evolution of cancers allows us to understand their key events, and the order in which they occur. To chart and interpret these evolutionary trajectories, we leverage whole-genome sequencing of lung tumours, including those from the largest cohort to date of lung cancers in subjects who have never smoked. Through ordering frequent genomic alterations, we discover three distinct evolutionary paths taken by lung adenocarcinomas; two dominated by tumours from people who have never smoked (NS-LUAD), and one followed by the vast majority of those who have smoked (S-LUAD). However, one in six NS-LUAD follow the smoking-dominant trajectory. These tumours, surprisingly, have fewer somatic alterations than the other NS-LUAD, and have shorter latency. They are strongly enriched for <i>KRAS</i> mutations. Our results suggest that gaining <i>KRAS</i> mutations allows these tumours to evolve more rapidly, acquiring a set of smoking-associated key alterations, with less need for genomic instability to progress. These tumours are three times more frequent in subjects of European vs. East Asian ancestry. These findings could shape clinical management strategies for lung adenocarcinoma patients, particularly for tumours driven by smoking-like evolutionary trajectories.

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Publication Details

Journal
bioRxiv (Cold Spring Harbor Laboratory)
Published
2025-12-23
DOI
https://doi.org/10.64898/2025.12.19.695410
Primary Topic
Cancer Genomics and Diagnostics
Type
article
Field-Weighted Citation Impact
0.00

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article

Revealing the Drivers Underlying Distinct Evolutionary Trajectories in Lung Adenocarcinoma

D G Zaridze, Beata Świątkowska, Jolanta Lissowska, Angela Cecilia Pesatori et al.
bioRxiv (Cold Spring Harbor Laboratory)
Cancer Genomics and Diagnostics
article

Revealing the Drivers Underlying Distinct Evolutionary Trajectories in Lung Adenocarcinoma

D G Zaridze, Beata Świątkowska, Jolanta Lissowska, Angela Cecilia Pesatori, P. Hofman, David C. Wedge, Chao A.gnes Hsiung, Geoffrey Liu, John McElderry, D. Christiani, Milan Savić, Kin Chung Leung, Olivia W. Lee, C Y Chen, Azhar Khandekar, Robert Homer, Sai Yendamuri, Matthew B. Schabath, Simona Ognjanovic, Yohan Bossé, Phuc H. Hoang, Ludmil B. Alexandrov, Martin A. Nowak, Marta Mańczuk, S Y Yang, W. Travis, Lynette M. Sholl, Philippe Joubert, Dana Mates, Caleb Hartman, Anush Mukeria, Marcos Díaz-Gay, Valerie Gaborieau, Mona Miraftab, Bonnie E. Gould Rothberg, Lixing Yang, Oxana Shangina, Jian Sang, Jacobo Martinez Santamaria, I-Shou Chang, Kristine M. Jones, Christopher D. Steele, Paul Brennan, Bin Zhu, Vladimir Janout, Christopher Wirth, Maria Teresa Landi, Stephen J. Chanock, Tongwu Zhang, Milica Kontic, Dario Consonni, Qing Lan, Wei Zhao, Marina K. Baine, Nathaniel Rothman, Maria Pik Wong, Jianxin Shi, Yang Yang, Thi-Van-Trinh Tran, Ivana Holcatova, Charles Leduc
article en

Abstract

Elucidating the evolution of cancers allows us to understand their key events, and the order in which they occur. To chart and interpret these evolutionary trajectories, we leverage whole-genome sequencing of lung tumours, including those from the largest cohort to date of lung cancers in subjects who have never smoked. Through ordering frequent genomic alterations, we discover three distinct evolutionary paths taken by lung adenocarcinomas; two dominated by tumours from people who have never smoked (NS-LUAD), and one followed by the vast majority of those who have smoked (S-LUAD). However, one in six NS-LUAD follow the smoking-dominant trajectory. These tumours, surprisingly, have fewer somatic alterations than the other NS-LUAD, and have shorter latency. They are strongly enriched for <i>KRAS</i> mutations. Our results suggest that gaining <i>KRAS</i> mutations allows these tumours to evolve more rapidly, acquiring a set of smoking-associated key alterations, with less need for genomic instability to progress. These tumours are three times more frequent in subjects of European vs. East Asian ancestry. These findings could shape clinical management strategies for lung adenocarcinoma patients, particularly for tumours driven by smoking-like evolutionary trajectories.

bioRxiv (Cold Spring Harbor Laboratory)
Brigham and Women's Hospital (US), Roswell Park Comprehensive Cancer Center (US), Memorial Sloan Kettering Cancer Center (US), Harvard University (US), University of Miami (US), National Health Research Institutes (TW), University of Milan (IT), Nofer Institute of Occupational Medicine (PL), Charles University (CZ), Queen Mary Hospital (CN), Princess Margaret Cancer Centre (CA), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT), University of Manchester (GB), Moffitt Cancer Center (US), Yale University (US), University of California San Diego (US), University of Chicago (US), University of Belgrade (RS), Massachusetts General Hospital (US), Spanish National Cancer Research Centre (ES), Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (ES), Chung Shan Medical University Hospital (TW), Centar za Promociju Nauke (RS), National Institute of Public Health (LA), Institute of International Politics and Economics (RS), Cancer Research UK Manchester Institute (GB), La Jolla Bioengineering Institute (US), Institut universitaire de cardiologie et de pneumologie de Québec (CA), National Cancer Institute (US), Centre Hospitalier de l’Université de Montréal (CA), Hôpital Pasteur (FR), The Maria Sklodowska-Curie National Research Institute of Oncology (PL), Sylvester Comprehensive Cancer Center (US), NIHR Manchester Biomedical Research Centre (GB), Centre international de recherche sur le cancer (FR), Division of Cancer Epidemiology and Genetics, Palacký University Olomouc (CZ), University of Hong Kong (HK), Chung Shan Medical University (TW)
U.S. Department of Health and Human Services, Yale University, Harvard University, Ministry of Health and Welfare, Moffitt Cancer Center, National Institute for Health and Care Research, Department of Health and Social Care, Ministry of Science and Technology, Taiwan, Centre Hospitalier Universitaire de Nice, Connaught Fund, INCLIVA Instituto de Investigación Sanitaria, National Institutes of Health, Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, Manchester Biomedical Research Centre, Fonds de Recherche du Québec - Santé, Health and Medical Research Fund, National Cancer Institute
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