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Panorama of chromosomal instability in lung cancer

Yang, Y.
; 
Zhong, X.
; 
Phillips, W.
; 
Zhao, W.
; 
Hoang, P. H.
; 
Wirth, C.
; 
Yang, S. R.
; 
Leduc, C.
; 
Baine, M. K.
; 
Travis, W. D.
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Abstract
Lung cancer is a highly heterogeneous disease primarily driven by tobacco smoking. About 20% of lung cancers occur among patients who have never smoked (LCINS) with differences in patient ancestry, sex, tumor histology, and clinical features. Our understanding of chromosomal instability in lung cancer, especially LCINS, is still limited. Here, we perform a comprehensive study of 182,429 somatic structural variations (SVs) detected in 1,209 whole-genome sequenced lung cancers, of which 864 LCINS. SVs are more abundant in tumors from patients who have smoked (LCSS); however, they are more complex and play more important roles in tumorigenesis in LCINS. EGFR mutations and KRAS mutations profoundly and independently shape the SV landscape. EGFR-mutant tumors have higher SV burden and more cancer-driving SVs. In contrast, KRAS mutations are associated with lower SV burden and less driver SVs. We decompose 16 SV signatures for both complex and simple SVs that likely represent divergent molecular mechanisms. The SV breakpoints have distinct distributions across the genome depending on the signatures due to mutagenic mechanisms and positive selection. Many established cancer-driving genes are recurrently rearranged by multiple SV signatures suggesting functional convergence of these genome instability mechanisms.
Authors
Yang, Y.
Zhong, X.
Phillips, W.
Zhao, W.
Hoang, P. H.
Wirth, C.
Yang, S. R.
Leduc, C.
Baine, M. K.
Travis, W. D.
Sholl, L. M.
Joubert, P.
Homer, R.
Sang, J.
Khandekar, A.
McElderry, J. P.
Tran, T. V.
Hartman, C.
Miraftab, M.
Saha, M.
Lee, O. W.
Sharma, S.
Jones, K. M.
Zhu, B.
Díaz-Gay, M.
Edell, E. S.
Santamaría, J. M.
Schabath, M. B.
Yendamuri, S. S.
Manczuk, M.
Lissowska, J.
Świątkowska, B.
Mukeria, A.
Shangina, O.
Zaridze, D.
Holcatova, I.
Janout, V.
Mates, D.
Ognjanovic, S.
Savic, M.
Kontic, M.
Bossé, Y.
Rothberg, B. E. G.
Christiani, D. C.
Gaborieau, V.
Brennan, P.
Liu, G.
Hofman, P.
Wong, M. P.
Leung, K. C.
Chen, C. Y.
Hsiung, C. A.
Pesatori, A. C.
Consonni, D.
Rothman, N.
Lan, Q.
Nowak, M. A.
Wedge, D. C.
Alexandrov, L. B.
Chanock, S. J.
Shi, J.
Zhang, T.
Yang, L.
Landi, M. T.
Affiliation
Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA. Manchester Cancer Research Centre, Division of Cancer Sciences, University of Manchester, Manchester, UK. Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Department of Pathology, Centre Hospitalier de l'Université de Montréal, Montreal, Canada. Department of Pathology, Brigham and Women's Hospital, Boston, MA. Institut universitaire de cardiologie et de pneumologie de Québec - Université Laval, Quebec City, Canada, Université Laval, Laval, Québec, Canada. Department of Pathology, Yale School of Medicine, New Haven, CT, USA. Digital Genomics Group, Cancer Genomics Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain. Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota, USA. Biobanco IBSP-CV FISABIO Red Valenciana de Biobancos, Cataluña, Valencia. Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. Thoracic Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, New York. Department of Cancer Epidemiology and Primary Prevention, Maria Skłodowska-Curie National Research Institute of Oncology, Warsaw, 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 Public Health & Preventive Medicine, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic. Department of Oncology, 2nd Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic. Faculty of Health Sciences, Palacky University, Olomouc, 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. Clinic of Pulmonology, University Clinical Center of Serbia, Belgrade. School of Medicine, University of Belgrade. Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, USA. Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts. Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France. Division of Medical Oncology, Medicine, Princess Margaret Cancer Centre, Temerty Faculty of Medicine, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada. Nice University Hospital Centre (Nice UHC) - University Côte d'Azur and the Nice Biobank CRB, Nice, France. Queen Mary Hospital, The University of Hong Kong, Hong Kong, China. Department of Pathology, The University of Hong Kong, Hong Kong, China. Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan. Division of Thoracic Surgery, Department of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan. Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan. Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy. Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. Department of Mathematics, Harvard University, Cambridge, Massachusetts, USA. Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, Massachusetts, United States of America. 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. Sanford Stem Cell Institute, University of California San Diego, La Jolla, CA, USA. Department of Human Genetics, University of Chicago, Chicago, IL, USA. The University of Chicago Medicine Comprehensive Cancer Center, University of Chicago, Chicago, IL, USA.
Description
Date
2025
Publisher
Collections
All Paterson Institute for Cancer Research
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Keywords
Type
Preprint
Citation
Yang Y, Zhong X, Phillips W, Zhao W, Hoang PH, Wirth C, et al. Panorama of chromosomal instability in lung cancer. medRxiv : the preprint server for health sciences. 2025 Sep 12. PubMed PMID: 41018008. Pubmed Central PMCID: PMC12466783 application number EP25305077.7.
Journal Title
Journal ISSN
Volume Title
URI
https://christie.openrepository.com/handle/10541/627959
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