This research was conducted using the UK Biobank Resource under application number 82693. This work was supported by the Mark Foundation ASPIRE I Award (grant 21-029-ASP), the Lung Cancer Research Foundation Grant on Disparities in Lung Cancer, Advanced Grant (PROTEUS, grant agreement no. 835297), CRUK EDD (EDDPMA-Nov21\100034) and a Rosetrees Out-of-round Award (OoR2020\100009). W.H. is funded by an ERC Advanced Grant (PROTEUS, grant agreement no. 835297), CRUK EDD (EDDPMA-Nov21\100034), The Mark Foundation (grant 21-029-ASP) and has been supported by Rosetrees. E.L.L. receives funding from the NovoNordisk Foundation (ID 16584), The Mark Foundation (grant 21-029-ASP) and has been supported by Rosetrees. C.E.W. is supported by a RESPIRE4 fellowship from the European Respiratory Society and Marie-Sklodowska-Curie Actions. C.L. is supported by the Agency for Science, Technology & Research, Singapore and the Cancer Research UK City of London Centre and the City of London Centre Clinical Academic Training Programme. M.A. is supported by the City of London Centre Clinical Academic Training Programme (Year 3, SEBSTF-2021\100007). K.C. is supported by the Research Unit of Intelligence Diagnosis and Treatment in Early Non-small Cell Lung Cancer, the Chinese Academy of Medical Sciences (2021RU002), the National Natural Science Foundation of China (no. 82072566) and Peking University People’s Hospital Research and Development Funds (RS2019-01). T.K. receives grant support from JSPS Overseas Research Fellowships Program (202060447). S.-H.L. is supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (no. 2020R1A2C3006535), the National Cancer Center Grant (NCC1911269-3) and a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number HR20C0025). L.H.S. receives grant support from the Berta Kamprad Foundation, the Swedish Cancer Society and the Swedish Research Council. R.M. and S.L. acknowledge funding from the Terry Fox Research Institute. N.M. is a Sir Henry Dale Fellow, jointly funded by the Wellcome Trust and the Royal Society (grant number 211179/Z/18/Z) and receives funding from Cancer Research UK, the Rosetrees and the NIHR BRC at University College London Hospitals and the CRUK University College London Experimental Cancer Medicine Centre. J. DeGregori, M.G., Y.E.M., D.T.M. and R.L.K. receive funding from the American Association for Cancer Research/Johnson&Johnson (18-90-52-DEGR), and J. DeGregori is supported by the Courtenay C. and Lucy Patten Davis Endowed Chair in Lung Cancer Research and a Merit Award from the Veteran’s Administration (1 I01 BX004495). M.G., Y.E.M., D.T.M. and R.L.K. were supported by the National Cancer Institute (NCI) RO1 CA219893. E.J.E.J. was supported by a NCI Ruth L. Kirschstein National Research Service Award T32-CA190216 and the Blumenthal Fellowship from the Linda Crnic Institute for Down Syndrome. C.I.T. acknowledges funding from UC Anschutz (LHNC T32CA174648). The work at the University of Colorado was also supported by NCI Cancer Center Support Grant P30CA046934. K. Litchfield is funded by the UK Medical Research Council (MR/P014712/1 and MR/V033077/1), the Rosetrees Trust and the Cotswold Trust (A2437) and Cancer Research UK (C69256/A30194). M.J.-H. is a CRUK Career Establishment Awardee has received funding from Cancer Research UK, IASLC International Lung Cancer Foundation, the National Institute for Health Research, the Rosetrees Trust, UKI NETs and the NIHR University College London Hospitals Biomedical Research Centre. C.S. is a Royal Society Napier Research Professor (RSRP\R\210001). His work is supported by the Francis Crick Institute that receives its core funding from Cancer Research UK (CC2041), the UK Medical Research Council (CC2041), and the Wellcome Trust (CC2041). For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. C.S. is funded by Cancer Research UK (TRACERx (C11496/A17786), PEACE (C416/A21999) and CRUK Cancer Immunotherapy Catalyst Network); Cancer Research UK Lung Cancer Centre of Excellence (C11496/A30025); the Rosetrees Trust, Butterfield and Stoneygate Trusts; NovoNordisk Foundation (ID16584); Royal Society Professorship Enhancement Award (RP/EA/180007); National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre; the Cancer Research UK-University College London Centre; Experimental Cancer Medicine Centre; the Breast Cancer Research Foundation (US) (BCRF-22-157); Cancer Research UK Early Detection an Diagnosis Primer Award (grant EDDPMA-Nov21/100034); and The Mark Foundation for Cancer Research Aspire Award (grant 21-029-ASP). This work was supported by a Stand Up To Cancer‐LUNGevity-American Lung Association Lung Cancer Interception Dream Team Translational Research Grant (grant number: SU2C-AACR-DT23-17 to S.M. Dubinett and A.E. Spira). Stand Up To Cancer is a division of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. C.S. is in receipt of an ERC Advanced Grant (PROTEUS) from the European Research Council under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 835297). We acknowledge the PEACE Consortium (PEACE Consortium members are named below) for their expertise and support in putting together the healthy tissue sample cohorts. We thank the clinical and administrative team of the PEACE study for their assistance in data curation (S. Shepherd, Z. Tippu, B. Shum, C. Lewis, M. O’Flaherty, A. Lucanas, E. Carlyle, L. Holt, F. Williams); nursing and biospecimen coordinators for their assistance in sample curation (K. Edmonds, L. Grostate, K. Lingard, D. Kelly, J. Korteweg, L. Terry, J. Biano, A. Murra, K. Kelly, K. Peat, N. Hunter); A. H. -K. Cheung for assistance in pathology review; J. Asklin and C. Forsberg for logistical and technical assistance; staff at the Chang Gung Memorial Hospital for providing Chang Gung Research Database (CGRD) data; staff who provided support at the Flow Cytometry Unit, the Experimental Histopathology Unit, the Advanced Light Microscopy Facility, the Advanced Sequencing Facility and the Biological Resources Unit, especially N. Chisholm and Jay O’Brien, at the Francis Crick Institute; A. Yuen, A. Azhar, K. Lau, C. Schwartz, A. Lee and C. Rider for their logistical support for the human exposure study; and staff at the Centre d’expertise et de services Génome Québec for their sequencing services and support. Data for this study are based on patient-level information collected by the NHS, as part of the care and support of cancer patients. The data are collated, maintained and quality assured by the National Cancer Registration and Analysis Service, which is part of NHS England (NHSE). We extend our thanks to the skilled Cancer Registration Officers (CROs) within the National Disease Registration Service, who abstracted and registered the English tumour and molecular testing data. For the purpose of Open Access, the author has applied for a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. PEACE Consortium members: A. Flanagan, A. Hackshaw, A. Jayaram, A. M. M. Hasan, A. Toncheva, A. Wingate, A. Bunkum, A. Sharp, A. Tookman, A. Murra, A. Magness, A. Coulton, A. M. Frankell, A. Cluroe, A. Kerr, A. Ortega-Franco, A. Lucanas, A. M. Schmitt, A. Furness, A. Rowan, A. Tutt, A. Green, A. Paterson, A.-L. Cattin, A. Fendler, A. Latifoltojar, A. Huebner, A. Thomas, B. T. Alba, B. Chain, B. Naidu, B. Shum, B. Olisemeke, B. Hampton, B. Hanley, B. Tanchel, G. Langman, C. Naceur-Lombardelli, C. Gerard, C. Caldas, C. Martínez-Ruiz, C. Dive, C. Stirling, C. Swanton, C. Ferris, C. Lewis, C. Milner-Watts, C. Spencer, C.-w. Lok, C. Bailey, C. Messiou, C. Wilson, C. Puttick, C. Lee, C. P. Marin, C. Alifrangis, C. Richard, C. T. Hiley, D. Hochhauser, D. Wetterskog, D. A. Moore, D. Deng, D. Marrone, D. Enting, D. Josephs, D. Kelly, D. A. Fennell, D. Biswas, D. Papadatos-Pastos, E. Carlyle, E. Provenzano, E. (L.) Karapanagiotou, E. Pintus, E. L. Lim, E. Beddowes, E. Colliver, E. Nye, F. Gishen, F. Gomes, F. H. Blackhall, F. Byrne, F. Athanasopoulou, G. Attard, G. Stamp, G. Middleton, G. D. Stewart, H. Feng, G. Pulman, G. Leone, H. Bridger, H. Shaw, H. Yan, H. Mudhar, H. Bancroft, H. Pallikonda, I. McNeish, I. Proctor, I. Tomlinson, I. Noorani, I. Lobon, J. Bridgewater, J. L. Reading, J. Black, J. Brenton, J. Larkin, J. Spicer, J. K. Rane, J. Biano, J. Nicod, J. Webb, J. L. Quesne, J. A. Shaw, J. Korteweg, K.-K. Shiu, K. Pearce, K. Young, K. S. S. Enfield, K. Kelly, K. Peat, K. Thol, K. G. Blyth, K. Litchfield, K. Allinson, K. Edmonds, K. Chan, K. Dijkstra, K. Grigoriadis, L. Farrelly, L. Grostate, L. Terry, L. Spain, L. Au, L. Pickering, L. Holt, L. Del Rosario, M. Jamal-Hanjani, M. Linch, M. Sivakumar, M. MacKenzie, M. Al Bakir, M. Collard, M. Forster, M. Falzon, M. Mangwende, M. Carter, M. G. Krebs, M. Emmerich, M. Akay, M. Jimenez-Linan, M. Dietzen, M. Angelova, M. Mitchison, M. O’Flaherty, N. Kanu, N. Magno, N. Yousaf, N. Wright, N. McGranahan, N. Hunter, O. Vainauskas, O. Curtis, O. Lucas, O. Pich, O. Al-Sawaf, P. Prymas, P. Roxburgh, P. Campbell, P. Oliveira, P. Cockcroft, P. Colloby, P. Ellery, P. Hill, P. Parker, P. Van Loo, P. Pawlik, P. Stone, S. Veeriah, R. Vendramin, R. Leslie, R. Fitzgerald, R. Zaidi, R. E. Hynds, R. Salgado, R. Wilson, R. Sinclair, R. Stewart, R. Mitu, S. Beck, S. K. Bola, S. Brandner, S. M. Janes, S. Lise, S. A. Quezada, S. Kuong A. Ung, S. Kadiri, S. Holden, S. Turajlic, S. Gamble, S. Jogai, S. Popat, S. Aitken, S. Benafif, J. Dransfield, S. Howlett, S. Shepherd, S. Ghosh, S. Irshad, S. Phillips-Boyd, S. Baijal, S. Zaccaria, S. Fraser, S. M. Lee, S. Hessey, Y. Ning S. Wong, S. Ward, S. Hazell, T. Enver, T. Karasaki, T. Fernandes, T. Ahmad, T. Sahwangarrom, T. Marafioti, T. B. K. Watkins, T. Maughan, U. Mahadeva, U. McGovern, V. Barbe, W. Drake, W. Hill, W. K. Liu, Y. Summers, Z. Tippu, Z. Rhodes, A. Stewart, A. Alzetani, A. J. Patel, A. Kirk, A. Kerr, A. J. Procter, A. Clipson, A. Rice, A. Bajaj, A. Devaraj, A. Grapa, A. G. Nicholson, A. Robinson, A. Leek, A. Montero, A. Karamani, A. Chaturvedi, A. Nakas, A. Nair, A. Ahmed, A. Osman, A. Sodha-Ramdeen, B. B. Campbell, C. Pilotti, C. Castignani, C. Veiga, C -A. Collins-Fekete, C. Proli, C. Lacson, C. Abbosh, C. E. Weeden, C. R. Lindsay, C. Dick, D. Kaniu, D. Chuter, D. Lawrence, D. R. Pearce, D. Patrini, D. Karagianni, D. Levi, D. G. Rothwell, E. Boleti, E. Borg, E. Kilgour, E. Smith, E. Hoxha, E. L. Cadieux, E. M. Hoogenboom, E. Lim, E. Fontaine, E. Gronroos, F. Granato, F. Galvez-Cancino, F. Monk, F. Fraioli, F. Gimeno-Valiente, G. A. Wilson, G. Royle, G. Kassiotis, G. Stavrou, G. Mastrokalos, G. Price, G. Matharu, H. Zhang, H. Zhai, H. K. Dhanda, H. Bhayani, H. Cheyne, H. Doran, H. L. Lowe, H. Shackleford, H. Chavan, H. Raubenheimer, H. J. W. L. Aerts, I. G. Matos, J. D. Hodgkinson, J. Goldman, J. R. M. Black, J. W. Holding, J. Wilson, J. F. Lester, J. Herrero, J. Richards, J. M. Lam, J. Riley, J. A. Hartley, J. Demeulemeester, J. Tugwood, J. Kisistok, J. Cave, J. Novasio, J. Choudhary, K. S. Peggs, K. Brown, K. Selvaraju, K. Gilbert, K. M. Kerr, K. Rammohan, K. Ang, K. G. Blyth, K. W. Ng, K. Chen, K. AbdulJabbar, K. Thakkar, K. Bhakhri, L. Ensell, L. Joseph, L. Robinson, L. Primrose, L. Scarlett, L. Ambrose, L. Priest, M. Djearaman, M. Hewish, M. N. Taylor, M. Shah, M. Scarci, M. V. Duran, M. Litovchenko, M. W. Sunderland, M. S. Hill, M. D. Forster, M. Hayward, M. Sokac, M. Carter, M. Thomas, M. J. Shackcloth, M. Leung, M. Escudero, M. Diossy, M. Taniƒá, M. Asif, M. Tufail, M. F. Chowdhry, M. Khalil, M. Scotland, M. Malima, N. Fernandes, N. Navani, N. Totten, N. J. Birkbak, N. Gower, N. Panagiotopoulos, N. Kostoulas, O. Ansorge, O. Chervova, P. Ingram, P. Gorman, P. Ashford, P. Bishop, P. De Sousa, P. Russell, P. Crosbie, P. Hobson, P. Shah, R. Rosenthal, R. Shah, R. Boyles, R. Khiroya, R. K. Stone, R. M. Thakrar, R. Bentham, R. C. M. Stephens, R. Bilancia, R. F. Schwarz, S. Saghafinia, S. Lopez, S. Booth, S. Danson, S. Rudman, S. Dulloo, S. Smith, S. Chee, S. Vanloo, S. Richardson, S. Austin, S. I. Buderi, S. Jordan, S. Begum, S. Rathinam, S. Boeing, S. Bandula, S. Moss, S. K. Bola, T. Denner, T. P. Mourikis, T. L. Kaufmann, T. Cruickshank, T. Clark, V. Spanswick, V. Joshi, W.-T. Lu, X. Pan, Y. Wu, Y. Yuan, Y. Naito, Z. Ramsden, Z. Szallasi, A. Dwornik, G. Langman, H. Shackleford, A. Osman, B. Naidu, K. Bowles, C. Grieco, M. L. Le, P. D. D’Arienzo and E. Turay. E.G was supported by an ERC Advanced grant (PROTEUS, grant agreement no 835297).