Evolutionary characterization of lung adenocarcinoma morphology in TRACERx

Karasaki, T. et al. (2023) Evolutionary characterization of lung adenocarcinoma morphology in TRACERx. Nature Medicine, 29(4), pp. 833-845. (doi: 10.1038/s41591-023-02230-w) (PMID:37045996) (PMCID:PMC7614478)

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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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Blyth, Professor Kevin and Le Quesne, Professor John and Dick, Dr Craig
Authors: Karasaki, T., Moore, D. A., Veeriah, S., Naceur-Lombardelli, C., Toncheva, A., Magno, N., Ward, S., Bakir, M. A., Watkins, T. B. K., Grigoriadis, K., Huebner, A., Hill, M. S., Frankell, A. M., Abbosh, C., Puttick, C., Zhai, H., Gimeno-Valiente, F., Saghafinia, S., Kanu, N., Dietzen, M., Pich, O., Lim, E. L., Martínez-Ruiz, C., Black, J. R. M., Biswas, D., Campbell, B. B., Lee, C., Colliver, E., Enfield, K. S. S., Hessey, S., Hiley, C. T., Zaccaria, S., Litchfield, K., Birkbak, N. J., Cadieux, E. L., Demeulemeester, J., Van Loo, P., Adusumilli, P. S., Tan, K. S., Cheema, W., Sanchez-Vega, F., Jones, D. R., Rekhtman, N., Travis, W. D., Hackshaw, A., Marafioti, T., Salgado, R., Le Quesne, J., 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., 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., Shackcloth, M. J., Robinson, L., Russell, P., Blyth, K. G., Dick, C., Kirk, A., Asif, M., Bilancia, R., Kostoulas, N., Thomas, M., McGranahan, N., Swanton, C., and Jamal-Hanjani, M.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:Nature Medicine
Publisher:Nature Research
ISSN (Online):1546-170X
Published Online:12 April 2023
Copyright Holders:Copyright © 2023 The Authors
First Published:First published in Nature Medicine 29(4): 833-845
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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