The evolution of lung cancer and impact of subclonal selection in TRACERx

Abstract

Lung cancer is the leading cause of cancer-associated mortality worldwide1. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource.

Metadata

Item Type:	Article
Authors/Creators:	Frankell, A.M. https://orcid.org/0000-0002-0341-7878 Dietzen, M. https://orcid.org/0000-0002-6853-7563 Al Bakir, M. https://orcid.org/0000-0002-0846-8332 Lim, E.L. Karasaki, T. https://orcid.org/0000-0001-6863-2360 Ward, S. https://orcid.org/0000-0002-6777-5279 Veeriah, S. Colliver, E. https://orcid.org/0000-0002-1497-0740 Huebner, A. https://orcid.org/0000-0001-8009-4999 Bunkum, A. https://orcid.org/0000-0002-7753-9421 Hill, M.S. https://orcid.org/0000-0003-0718-8934 Grigoriadis, K. https://orcid.org/0000-0002-8435-0176 Moore, D.A. https://orcid.org/0000-0002-6296-1312 Black, J.R.M. Liu, W.K. Thol, K. Pich, O. https://orcid.org/0000-0002-1956-1882 Watkins, T.B.K. Naceur-Lombardelli, C. Cook, D.E. https://orcid.org/0000-0003-3347-562X Salgado, R. Wilson, G.A. Bailey, C. Angelova, M. https://orcid.org/0000-0002-0495-9695 Bentham, R. Martínez-Ruiz, C. https://orcid.org/0000-0002-4817-0565 Abbosh, C. https://orcid.org/0000-0002-8983-1382 Nicholson, A.G. Le Quesne, J. https://orcid.org/0000-0003-3552-7446 Biswas, D. https://orcid.org/0000-0001-9141-5188 Rosenthal, R. Puttick, C. Hessey, S. https://orcid.org/0000-0001-9856-424X Lee, C. https://orcid.org/0000-0003-1715-2265 Prymas, P. Toncheva, A. Smith, J. Xing, W. Nicod, J. https://orcid.org/0000-0003-2459-3480 Price, G. Kerr, K.M. Naidu, B. Middleton, G. https://orcid.org/0000-0001-5695-3474 Blyth, K.G. Fennell, D.A. Forster, M.D. Lee, S.M. Falzon, M. Hewish, M. Shackcloth, M.J. Lim, E. Benafif, S. Russell, P. Boleti, E. Krebs, M.G. Lester, J.F. Papadatos-Pastos, D. Ahmad, T. Thakrar, R.M. Lawrence, D. Navani, N. Janes, S.M. Dive, C. Blackhall, F.H. Summers, Y. Cave, J. Marafioti, T. Herrero, J. https://orcid.org/0000-0001-7313-717X Quezada, S.A. https://orcid.org/0000-0002-9763-1700 Peggs, K.S. Schwarz, R.F. Van Loo, P. https://orcid.org/0000-0003-0292-1949 Miedema, D.M. Birkbak, N.J. https://orcid.org/0000-0003-1613-9587 Hiley, C.T. Hackshaw, A. https://orcid.org/0000-0002-5570-5070 Zaccaria, S. https://orcid.org/0000-0002-5265-7392 Le Quesne, J. Van Loo, P. Bajaj, A. Nakas, A. Sodha-Ramdeen, A. Ang, K. Tufail, M. Chowdhry, M.F. Scotland, M. Boyles, R. Rathinam, S. Wilson, C. Marrone, D. Dulloo, S. Matharu, G. Shaw, J.A. Riley, J. Primrose, L. Cheyne, H. Khalil, M. Richardson, S. Cruickshank, T. Gilbert, K. Patel, A.J. Osman, A. Lacson, C. Langman, G. Shackleford, H. Djearaman, M. Kadiri, S. Leek, A. Hodgkinson, J.D. Totten, N. Montero, A. Smith, E. Fontaine, E. Granato, F. Doran, H. Novasio, J. Rammohan, K. Joseph, L. Bishop, P. Shah, R. Moss, S. Joshi, V. Crosbie, P. Gomes, F. Brown, K. Carter, M. Chaturvedi, A. Priest, L. Oliveira, P. Lindsay, C.R. Clipson, A. Tugwood, J. Kerr, A. Rothwell, D.G. Kilgour, E. Aerts, H.J.W.L. Kaufmann, T.L. Szallasi, Z. Kisistok, J. Sokac, M. Diossy, M. Demeulemeester, J. Stewart, A. Magness, A. Rowan, A. Karamani, A. Chain, B. Campbell, B.B. Castignani, C. Weeden, C.E. Richard, C. Pearce, D.R. Karagianni, D. Levi, D. Hoxha, E. Larose Cadieux, E. Nye, E. Grönroos, E. Gálvez-Cancino, F. Athanasopoulou, F. Gimeno-Valiente, F. Kassiotis, G. Stavrou, G. Mastrokalos, G. Zhai, H. Lowe, H.L. Matos, I. Goldman, J. Reading, J.L. Rane, J.K. Lam, J.M. Hartley, J.A. Enfield, K.S.S. Selvaraju, K. Litchfield, K. Ng, K.W. Chen, K. Dijkstra, K. Thakkar, K. Ensell, L. Shah, M. Vasquez, M. Litovchenko, M. Werner Sunderland, M. Leung, M. Escudero, M. Tanić, M. Sivakumar, M. Kanu, N. Chervova, O. Lucas, O. Al-Sawaf, O. Hobson, P. Pawlik, P. Stone, R.K. Hynds, R.E. Vendramin, R. Saghafinia, S. López, S. Gamble, S. Ung, S.K.A. Vanloo, S. Boeing, S. Beck, S. Bola, S.K. Denner, T. Mourikis, T.P. Spanswick, V. Barbè, V. Lu, W.-T. Hill, W. Wu, Y. Naito, Y. Ramsden, Z. Veiga, C. Royle, G. Collins-Fekete, C.-A. Fraioli, F. Ashford, P. Clark, T. Borg, E. Wilson, J. Procter, A.J. Ahmed, A. Taylor, M.N. Nair, A. Patrini, D. Martinoni Hoogenboom, E. Monk, F. Holding, J.W. Choudhary, J. Bhakhri, K. Scarci, M. Hayward, M. Panagiotopoulos, N. Gorman, P. Khiroya, R. Stephens, R.C.M. Wong, Y.N.S. Bandula, S. Sharp, A. Smith, S. Gower, N. Dhanda, H.K. Chan, K. Pilotti, C. Leslie, R. Grapa, A. Zhang, H. AbdulJabbar, K. Pan, X. Yuan, Y. Chuter, D. MacKenzie, M. Chee, S. Alzetani, A. Scarlett, L. Richards, J. Ingram, P. Austin, S. De Sousa, P. Jordan, S. Rice, A. Raubenheimer, H. Bhayani, H. Ambrose, L. Devaraj, A. Chavan, H. Begum, S. Buderi, S.I. Kaniu, D. Malima, M. Booth, S. Fernandes, N. Shah, P. Proli, C. Danson, S. https://orcid.org/0000-0002-3593-2890 Robinson, L. Dick, C. Kirk, A. Asif, M. Bilancia, R. Kostoulas, N. Thomas, M. Jamal-Hanjani, M. https://orcid.org/0000-0003-1212-1259 McGranahan, N. https://orcid.org/0000-0001-9537-4045 Swanton, C. https://orcid.org/0000-0002-4299-3018
Copyright, Publisher and Additional Information:	© 2023 The Authors. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Keywords:	Humans; Adenocarcinoma of Lung; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Mutation; Neoplasm Recurrence, Local; Phylogeny; Treatment Outcome; Smoking; Mutagenesis; DNA Copy Number Variations
Dates:	Published: 20 April 2023 Published (online): 12 April 2023 Accepted: 2 February 2023
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > The Medical School (Sheffield) > Division of Genomic Medicine (Sheffield) > Department of Oncology and Metabolism (Sheffield)
Depositing User:	Symplectic Sheffield
Date Deposited:	08 Jun 2023 13:55
Last Modified:	10 Jan 2025 19:15
Published Version:	http://dx.doi.org/10.1038/s41586-023-05783-5
Status:	Published
Publisher:	Springer Science and Business Media LLC
Refereed:	Yes
Identification Number:	10.1038/s41586-023-05783-5
Related URLs:	PubMed URL Software or Code Software or Code Software or Code Software or Code Software or Code Erratum/Corrigendum
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:200023

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The evolution of lung cancer and impact of subclonal selection in TRACERx

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