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Here, using 501 longitudinally collected primary and metastatic tumour samples from 24 patients with non-small cell lung cancer (NSCLC) enrolled in the TRACERx lung study and PEACE autopsy programme, we infer tumour evolution from diagnosis to death. With DNA-sequencing data encompassing 70% of the\u00a0metastases that were radiologically detected before death and paired multi-region sampled primary tumours, we show that the genomes of metastases diverge markedly from those of their ancestral primary tumour, with additional\u00a0driver alterations and genome doubling\u00a0events occurring after metastatic dissemination. In 62.5% of patients, multiple primary tumour subclones disseminated, each founding a distinct metastasis. These metastases served as sources of onward spread: more than half of the metastases sampled were seeded by other metastases. The duration that metastases existed in situ influenced their likelihood of seeding further metastases. Most metastatic migrations started and ended in the same anatomical cavity. The few subclones that exited the thorax to seed metastases disseminated widely and were enriched for somatic copy-number alterations, suggesting that chromosomal instability may\u00a0facilitate extrathoracic spread. This spatial and temporal evolutionary analysis sheds light on the extent of metastatic diversity and seeding in advanced NSCLC\u2014which tends to be underestimated in single metastasis biopsies\u2014and identifies genomic and clinical mediators of metastatic progression.\n                  <\/jats:p>","DOI":"10.1038\/s41586-026-10428-4","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T15:02:02Z","timestamp":1777474922000},"page":"911-922","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Evolutionary characterization of lung cancer 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P. Roxburgh has received grant support from CRUK, Beatson Cancer Charity, Wellbeing of Women, AstraZeneca, Atrios and Tesaro; consultancy from Roche, Abbvie and MSD; and speaker fees from AstraZeneca, GSK and pharma&. M.D.F. acknowledges grant support from CRUK, AstraZeneca, Boehringer Ingelheim, MSD, Merck and NIHR; holds appointments with DRA and HCA; serves in unpaid leadership roles at the Ruth Strauss Foundation; is an advisory board member for Transgene; and has consulted for Achilles, Amgen, AstraZeneca, Bayer, BeiOne, Boxer, BMS, Celgene, EQRx, Guardant Health, GSK, Immutep, Janssen, Merck, MSD, Oxford VacMedix, Pharmamar, Regeneron, Roche, Societe Generale, Syncorp, Takeda and UltraHuman. S.B. acknowledges educational grant support from Roche. T.A. acknowledges educational grant support from Boehringer Ingelheim, Roche, Takeda and Johnson & Johnson, and has consulted for AstraZeneca, Daichii Sanko, Johnson & Johnson, Merck, Pfizer, Roche and Takeda. M.G.K. has received funding grants from BerGenBio, Novartis and Roche; advisory board or consultancy fees from Astellas, Bayer, Guardant Health, Johnson & Johnson, Roche, Seattle Genetics and Zai Lab; speaker fees from BMS, Johnson & Johnson and Roche; and support for attending meetings and\/or travel from BMS, Eisai, Johnson & Johnson, Roche and Zai Lab. C.\u00a0Richards. Eli Lilly (Advisory Board), Pfizer, AstraZeneca, Servier laboratories and Dako (talks), Ipsen (conference funding). D.A.F. reports grants from Aldeyra, Boehringer Ingelheim, Astex Therapeutics, Bayer, BMS, GSK, RS Oncology, Clovis, Eli Lilly, BMS, MSD and GSK, and personal fees from Atara, BMS, Boehringer Ingelheim, Cambridge Clinical Laboratories, Targovax, Roche and RS Oncology. C.T.H. has received speaker fees from AstraZeneca and Merck and research funding from Roche and AstraZeneca, and has a paid advisory role for Genesiscare UK. A. Hackshaw has received fees for being a member of independent data monitoring committees for Roche-sponsored clinical trials, and academic projects coordinated by Roche. D.A.M. reports speaker fees from AstraZeneca and Takeda; consultancy fees from AstraZeneca, Thermo Fisher Scientific, Takeda, Amgen, Janssen, MIM Software, Bristol Myers Squibb and Eli Lilly; and has received educational support from Takeda and Amgen. N.M. holds patents related to determining HLA LOH (PCT\/GB2018\/052004), determining B cell fraction in mixed samples (PCT\/EP2024\/062999), determining lymphocyte abundance in mixed samples (PCT\/EP2022\/070694), identifying responders to cancer treatment (PCT\/GB2018\/051912), targeting neoantigens (PCT\/EP2016\/059401), identifying patient response to immune checkpoint blockade (PCT\/EP2016\/071471) and predicting survival rates of patients with cancer (PCT\/GB2020\/050221), and has a patent pending in determining HLA disruption (PCT\/EP2023\/059039). C.S. acknowledges grant support from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Pfizer, Invitae (previously ArcherDX; collaboration in minimal residual disease sequencing technologies), Ono Pharmaceutical, Personalis and Roche\u2013Ventana. He is chief investigator for the AstraZeneca MeRmaiD 1 and 2 clinical trials and is the steering committee chair. He is also co-chief investigator of the NHS Galleri trial funded by GRAIL and a paid member of GRAIL\u2019s scientific advisory board. He has received consultancy fees from Achilles, Bicycle Therapeutics (paid board member, and chair of clinical advisory group), Genentech, Medicxi, China Innovation Centre of Roche (CICoR; formerly Roche Innovation Centre \u2013 Shanghai), Metabomed (until July 2022), Relay Therapeutics (scientific advisory board member), Saga Diagnostics (scientific advisory board member) and the Sarah Cannon Research Institute. C.S. has received honoraria from Amgen, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Illumina, MSD, Novartis, Pfizer and Roche\u2013Ventana. C.S. has previously held stock or options in GRAIL, currently has stock or options in Bicycle Therapeutics and Relay Therapeutics and previously held stock and was co-founder of Achilles Therapeutics. C.S. declares patent applications relating to methods for lung cancer detection (PCT\/US2017\/028013 and US20190106751A1); targeting neoantigens (PCT\/EP2016\/059401); identifying patent response to immune checkpoint blockade (PCT\/EP2016\/071471); identifying patients who respond to cancer treatment (PCT\/GB2018\/051912); determining HLA LOH (PCT\/GB2018\/052004); predicting survival rates of patients with cancer (PCT\/GB2020\/050221); methods and systems for tumour monitoring (PCT\/EP2022\/077987); and analysis of HLA allele transcriptional deregulation (PCT\/EP2023\/059039). C.S. is an inventor on a European patent application (PCT\/GB2017\/053289) relating to assay technology to detect tumour recurrence. This patent has been licensed to a commercial entity and under their terms of employment, C.S. is due a revenue share of any revenue generated from such licence(s). M.J.-H. has received funding from CRUK, the National Institutes of Health (NIH) National Cancer Institute, International Association for the Study of Lung Cancer (IASLC) Foundation, Lung Cancer Research Foundation, Rosetrees Trust, UKI NETs and NIHR; has consulted for Astex Pharmaceutical and Achilles Therapeutics; was a member of the Achilles Therapeutics scientific advisory board and steering committee; and has received speaker honoraria from Pfizer, Astex Pharmaceuticals, Oslo Cancer Cluster, Bristol Myers Squibb and Genentech. M.J.-H. is listed as a co-inventor on a European patent application relating to methods to detect lung cancer (PCT\/ US2017\/028013); this patent has been licensed to commercial entities, and, under terms of employment, M.J.-H. is due a share of any revenue generated from such licence(s). M.J.-H. is also listed as a co-inventor on the GB priority patent application (GB2400424.4) titled \u2018Treatment and prevention of lung cancer\u2019.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}