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Deciphering lung adenocarcinoma evolution and the role of LINE-1 retrotransposition

Zhang, T.
; 
Zhao, W.
; 
Wirth, C.
; 
Díaz-Gay, M.
; 
Yin, J.
; 
Cecati, M.
; 
Marchegiani, F.
; 
Hoang, P. H.
; 
Leduc, C.
; 
Baine, M. K.
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Abstract
Understanding lung cancer evolution can identify tools for intercepting its growth. In a landscape analysis of 1024 lung adenocarcinomas (LUAD) with deep whole-genome sequencing integrated with multiomic data, we identified 542 LUAD that displayed diverse clonal architecture. In this group, we observed an interplay between mobile elements, endogenous and exogenous mutational processes, distinct driver genes, and epidemiological features. Our results revealed divergent evolutionary trajectories based on tobacco smoking exposure, ancestry, and sex. LUAD from smokers showed an abundance of tobacco-related C:G>A:T driver mutations in KRAS plus short subclonal diversification. LUAD in never smokers showed early occurrence of copy number alterations and EGFR mutations associated with SBS5 and SBS40a mutational signatures. Tumors harboring EGFR mutations exhibited long latency, particularly in females of European-ancestry (EU_N). In EU_N, EGFR mutations preceded the occurrence of other driver genes, including TP53 and RBM10. Tumors from Asian never smokers showed a short clonal evolution and presented with heterogeneous repetitive patterns for the inferred mutational order. Importantly, we found that the mutational signature ID2 is a marker of a previously unrecognized mechanism for LUAD evolution. Tumors with ID2 showed short latency and high L1 retrotransposon activity linked to L1 promoter demethylation. These tumors exhibited an aggressive phenotype, characterized by increased genomic instability, elevated hypoxia scores, low burden of neoantigens, propensity to develop metastasis, and poor overall survival. Reactivated L1 retrotransposition-induced mutagenesis can contribute to the origin of the mutational signature ID2, including through the regulation of the transcriptional factor ZNF695, a member of the KZFP family. The complex nature of LUAD evolution creates both challenges and opportunities for screening and treatment plans.
Authors
Zhang, T.
Zhao, W.
Wirth, C.
Díaz-Gay, M.
Yin, J.
Cecati, M.
Marchegiani, F.
Hoang, P. H.
Leduc, C.
Baine, M. K.
Travis, W. D.
Sholl, L. M.
Joubert, P.
Sang, J.
McElderry, J. P.
Klein, A.
Khandekar, A.
Hartman, C.
Rosenbaum, J.
Colón-Matos, F. J.
Miraftab, M.
Saha, M.
Lee, O. W.
Jones, K. M.
Caporaso, N. E.
Wong, M. P.
Leung, K. C.
Agnes Hsiung, C.
Chen, C. Y.
Edell, E. S.
Martínez Santamaría, J.
Schabath, M. B.
Yendamuri, S. S.
Manczuk, M.
Lissowska, J.
Świątkowska, B.
Mukeria, A.
Shangina, O.
Zaridze, D.
Holcatova, I.
Mates, D.
Milosavljevic, S.
Savic, M.
Bossé, Y.
Gould Rothberg, B. E.
Christiani, D. C.
Gaborieau, V.
Brennan, P.
Liu, G.
Hofman, P.
Homer, R.
Yang, S. R.
Pesatori, A. C.
Consonni, D.
Yang, L.
Zhu, B.
Shi, J.
Brown, K.
Rothman, N.
Chanock, S. J.
Alexandrov, L. B.
Choi, J.
Cardelli, M.
Lan, Q.
Nowak, M. A.
Wedge, D. C.
Landi, M. T.
Affiliation
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA. Manchester Cancer Research Centre, The University of Manchester, Manchester, UK. 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. Moores Cancer Center, University of California San Diego, La Jolla, CA, USA. Digital Genomics Group, Structural Biology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain. Advanced Technology Center for Aging Research, IRCCS INRCA, Ancona, Italy. Clinic of Laboratory and Precision Medicine, IRCCS INRCA, Ancona, Italy. Department of Pathology, Centre Hospitalier de l'Université de Montréal, Montreal, Canada. Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA. Institut universitaire de cardiologie et de pneumologie de Québec, Laval University, Quebec City, Canada. Westat, Rockville, MD, USA. Cancer Genomics Research Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA. Queen Mary Hospital, The University of Hong Kong, Hong Kong, China. Department of Pathology, The University of Hong Kong, Hong Kong, China. Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan. Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan. Department of Surgery, Division of Thoracic Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan. Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA. Biobanco IBSP-CV FISABIO, Valencia, Spain. Red Valenciana de Biobancos FISABIO, Valencia, Spain. Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. Thoracic Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. Department of Cancer Epidemiology and Primary Prevention, Maria Skłodowska-Curie National Research Institute of Oncology, Warshaw, Poland. Department of Environmental Epidemiology, Nofer Institute of Occupational Medicine, Łódź, Poland. Department of Clinical Epidemiology, N.N. Blokhin National Medical Research Centre of Oncology, Moscow, Russia. Institute of Hygiene and Epidemiology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic. Department of Oncology, 2nd Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic. Department of Occupational Health and Toxicology, National Center for Environmental Risk Monitoring, National Institute of Public Health, Bucharest, Romania. International Organisation for Cancer Prevention and Research (IOCPR), Belgrade, Serbia. Department of Thoracic Surgery, Clinical Center of Serbia, Belgrade, Serbia. Sylvester Comprehensive Cancer Center, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA. Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA. Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France. Princess Margaret Cancer Center, University of Toronto, Toronto, Ontario, Canada. IHU RespirERA, Biobank-BB-0033-0025, Côte d'Azur University, Nice, France. Department of Pathology, Yale School of Medicine, New Haven, CT, USA. Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy. Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA. Department of Human Genetics, The University of Chicago, Chicago, IL, USA. The University of Chicago Medicine Comprehensive Cancer Center, The University of Chicago, Chicago, IL, USA. Sanford Stem Cell Institute, University of California San Diego, La Jolla, CA, USA. Department of Mathematics, Harvard University, Cambridge, MA, USA. Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA, USA. Manchester NIHR Biomedical Research Centre, Manchester, UK.
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Date
2025
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All Paterson Institute for Cancer Research
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Preprint
Citation
Zhang T, Zhao W, Wirth C, Díaz-Gay M, Yin J, Cecati M, et al. Deciphering lung adenocarcinoma evolution and the role of LINE-1 retrotransposition. BioRxiv : the preprint server for biology. 2025 Mar 16. PubMed PMID: 40161734. Pubmed Central PMCID: PMC11952568 equity and receives income. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies. LBA is also a compensated member of the scientific advisory board of Inocras. LBA’s spouse is an employee of Biotheranostics. LBA declares U.S. provisional applications filed with UCSD with serial numbers: 63/269,033, 63/366,392; 63/289,601; 63/483,237; 63/412,835; and 63/492,348. LBA is also an inventor of a US Patent 10,776,718 for source identification by non-negative matrix factorization. SRY has received consulting fees from AstraZeneca, Sanofi, Amgen, AbbVie, and Sanofi; received speaking fees from AstraZeneca, Medscape, PRIME Education, and Medical Learning Institute. All other authors declare that they have no competing interests. Epub 2025/03/31 21:16. eng.
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https://christie.openrepository.com/handle/10541/627638
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