Evolutionary characterization of lung adenocarcinoma morphology in TRACERx

Abstract

Lung adenocarcinomas (LUADs) display a broad histological spectrum from low-grade lepidic tumors through to mid-grade acinar and papillary and high-grade solid, cribriform and micropapillary tumors. How morphology reflects tumor evolution and disease progression is poorly understood. Whole-exome sequencing data generated from 805 primary tumor regions and 121 paired metastatic samples across 248 LUADs from the TRACERx 421 cohort, together with RNA-sequencing data from 463 primary tumor regions, were integrated with detailed whole-tumor and regional histopathological analysis. Tumors with predominantly high-grade patterns showed increased chromosomal complexity, with higher burden of loss of heterozygosity and subclonal somatic copy number alterations. Individual regions in predominantly high-grade pattern tumors exhibited higher proliferation and lower clonal diversity, potentially reflecting large recent subclonal expansions. Co-occurrence of truncal loss of chromosomes 3p and 3q was enriched in predominantly low-/mid-grade tumors, while purely undifferentiated solid-pattern tumors had a higher frequency of truncal arm or focal 3q gains and SMARCA4 gene alterations compared with mixed-pattern tumors with a solid component, suggesting distinct evolutionary trajectories. Clonal evolution analysis revealed that tumors tend to evolve toward higher-grade patterns. The presence of micropapillary pattern and ‘tumor spread through air spaces’ were associated with intrathoracic recurrence, in contrast to the presence of solid/cribriform patterns, necrosis and preoperative circulating tumor DNA detection, which were associated with extra-thoracic recurrence. These data provide insights into the relationship between LUAD morphology, the underlying evolutionary genomic landscape, and clinical and anatomical relapse risk.

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Item Type:	Article
Authors/Creators:	This paper has 291 authors. You can scroll the list below to see them all or them all. Karasaki, T. https://orcid.org/0000-0001-6863-2360 Moore, D.A. https://orcid.org/0000-0002-6296-1312 Veeriah, S. Naceur-Lombardelli, C. Toncheva, A. Magno, N. Ward, S. https://orcid.org/0000-0002-6777-5279 Bakir, M.A. https://orcid.org/0000-0002-0846-8332 Watkins, T.B.K. Grigoriadis, K. https://orcid.org/0000-0002-8435-0176 Huebner, A. https://orcid.org/0000-0001-8009-4999 Hill, M.S. https://orcid.org/0000-0003-0718-8934 Frankell, A.M. https://orcid.org/0000-0002-0341-7878 Abbosh, C. https://orcid.org/0000-0002-8983-1382 Puttick, C. Zhai, H. Gimeno-Valiente, F. Saghafinia, S. Kanu, N. Dietzen, M. https://orcid.org/0000-0002-6853-7563 Pich, O. https://orcid.org/0000-0002-1956-1882 Lim, E.L. Martínez-Ruiz, C. https://orcid.org/0000-0002-4817-0565 Black, J.R.M. Biswas, D. https://orcid.org/0000-0001-9141-5188 Campbell, B.B. Lee, C. https://orcid.org/0000-0003-1715-2265 Colliver, E. https://orcid.org/0000-0002-1497-0740 Enfield, K.S.S. https://orcid.org/0000-0002-4551-6073 Hessey, S. https://orcid.org/0000-0001-9856-424X Hiley, C.T. Zaccaria, S. https://orcid.org/0000-0002-5265-7392 Litchfield, K. Birkbak, N.J. https://orcid.org/0000-0003-1613-9587 Cadieux, E.L. Demeulemeester, J. https://orcid.org/0000-0002-2660-2478 Van Loo, P. https://orcid.org/0000-0003-0292-1949 Adusumilli, P.S. https://orcid.org/0000-0002-1699-2046 Tan, K.S. Cheema, W. https://orcid.org/0000-0002-8000-7493 Sanchez-Vega, F. https://orcid.org/0000-0002-2990-4893 Jones, D.R. https://orcid.org/0000-0002-3318-0146 Rekhtman, N. Travis, W.D. Hackshaw, A. https://orcid.org/0000-0002-5570-5070 Marafioti, T. Salgado, R. https://orcid.org/0000-0002-1110-3801 Le Quesne, J. https://orcid.org/0000-0003-3552-7446 Nicholson, A.G. Van Loo, P. Le Quesne, J. Lester, J.F. 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. Fennell, D.A. Matharu, G. Shaw, J.A. Riley, J. Primrose, L. Boleti, E. Cheyne, H. Khalil, M. Richardson, S. Cruickshank, T. Price, G. Kerr, K.M. Benafif, S. Gilbert, K. Naidu, B. Patel, A.J. Osman, A. Lacson, C. Langman, G. Shackleford, H. Djearaman, M. Kadiri, S. Middleton, G. 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. Blackhall, F.H. Krebs, M.G. Summers, Y. Clipson, A. Tugwood, J. Kerr, A. Rothwell, D.G. Kilgour, E. Dive, C. Aerts, H.J.W.L. Schwarz, R.F. Kaufmann, T.L. Wilson, G.A. Rosenthal, R. Szallasi, Z. Kisistok, J. Sokac, M. Diossy, M. Bunkum, A. Stewart, A. Magness, A. Rowan, A. Karamani, A. Chain, B. Castignani, C. Bailey, C. Weeden, C.E. Richard, C. Pearce, D.R. Karagianni, D. Levi, D. Hoxha, E. Nye, E. Grönroos, E. Gálvez-Cancino, F. Athanasopoulou, F. Kassiotis, G. Stavrou, G. Mastrokalos, G. Lowe, H.L. Matos, I.G. Goldman, J. Reading, J.L. Herrero, J. Rane, J.K. Nicod, J. Lam, J.M. Hartley, J.A. Peggs, K.S. Selvaraju, K. Thol, K. Ng, K.W. Chen, K. Dijkstra, K. Thakkar, K. Ensell, L. Shah, M. Duran, M.V. Litovchenko, M. Sunderland, M.W. Leung, M. Escudero, M. Angelova, M. Tanić, M. Sivakumar, M. Chervova, O. Lucas, O. Al-Sawaf, O. Prymas, P. Hobson, P. Pawlik, P. Stone, R.K. Bentham, R. Hynds, R.E. Vendramin, R. López, S. Gamble, S. Ung, S.K.A. Quezada, S.A. Vanloo, S. Boeing, S. Beck, S. Bola, S.K. Denner, T. Mourikis, T.P. Spanswick, V. Barbè, V. Lu, W.-T. Hill, W. Liu, W.K. Wu, Y. Naito, Y. Ramsden, Z. Veiga, C. Royle, G. Collins-Fekete, C.-A. Fraioli, F. Ashford, P. Clark, T. Forster, M.D. Lee, S.M. Borg, E. Falzon, M. Papadatos-Pastos, D. Wilson, J. Ahmad, T. Procter, A.J. Ahmed, A. Taylor, M.N. Nair, A. Lawrence, D. Patrini, D. Navani, N. Thakrar, R.M. Janes, S.M. Hoogenboom, E.M. 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. Cave, J. Scarlett, L. Richards, J. Ingram, P. Austin, S. Lim, E. 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. Hewish, M. Danson, S. https://orcid.org/0000-0002-3593-2890 Shackcloth, M.J. Robinson, L. Russell, P. Blyth, K.G. Dick, C. Kirk, A. Asif, M. Bilancia, R. Kostoulas, N. Thomas, M. McGranahan, N. https://orcid.org/0000-0001-9537-4045 Swanton, C. https://orcid.org/0000-0002-4299-3018 Jamal-Hanjani, M. https://orcid.org/0000-0003-1212-1259
Copyright, Publisher and Additional Information:	© 2023 The Author(s). Except as otherwise noted, this author-accepted version of a journal article published in Nature Medicine is made available via the University of Sheffield Research Publications and Copyright Policy under the terms of the Creative Commons Attribution 4.0 International License (CC-BY 4.0), which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/
Keywords:	Humans; Lung Neoplasms; Adenocarcinoma; Neoplasm Recurrence, Local; Adenocarcinoma of Lung; Disease Progression; DNA Helicases; Nuclear Proteins; Transcription Factors
Dates:	Published: April 2023 Published (online): 12 April 2023 Accepted: 24 January 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:	06 Jun 2023 11:52
Last Modified:	04 Sep 2023 13:12
Status:	Published
Publisher:	Springer Science and Business Media LLC
Refereed:	Yes
Identification Number:	10.1038/s41591-023-02230-w
Related URLs:	PubMed URL
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:200025

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Evolutionary characterization of lung adenocarcinoma morphology in TRACERx

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