The evolution of non-small cell lung cancer metastases in TRACERx

Al Bakir, M. et al. (2023) The evolution of non-small cell lung cancer metastases in TRACERx. Nature, 616, pp. 534-542. (doi: 10.1038/s41586-023-05729-x) (PMID:37046095) (PMCID:PMC10115651)

Abstract

Metastatic disease is responsible for the majority of cancer-related deaths. We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases diverged early, before the last clonal sweep in the primary tumour, and early divergence was enriched for patients who were smokers at the time of initial diagnosis. Simulations suggested that early metastatic divergence more frequently occurred at smaller tumour diameters (less than 8 mm). Single-region primary tumour sampling resulted in 83% of late divergence cases being misclassified as early, highlighting the importance of extensive primary tumour sampling. Polyclonal dissemination, which was associated with extrathoracic disease recurrence, was found in 32% of cases. Primary lymph node disease contributed to metastatic relapse in less than 20% of cases, representing a hallmark of metastatic potential rather than a route to subsequent recurrences/disease progression. Metastasis-seeding subclones exhibited subclonal expansions within primary tumours, probably reflecting positive selection. Our findings highlight the importance of selection in metastatic clone evolution within untreated primary tumours, the distinction between monoclonal versus polyclonal seeding in dictating site of recurrence, the limitations of current radiological screening approaches for early diverging tumours and the need to develop strategies to target metastasis-seeding subclones before relapse.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Dick, Dr Craig and Le Quesne, Professor John and Blyth, Professor Kevin
• Authors: Al Bakir, M., Huebner, A., Martínez-Ruiz, C., Grigoriadis, K., Watkins, T. B. K., Pich, O., Moore, D. A., Veeriah, S., Ward, S., Laycock, J., Johnson, D., Rowan, A., Razaq, M., Akther, M., Naceur-Lombardelli, C., Prymas, P., Toncheva, A., Hessey, S., Dietzen, M., Colliver, E., Frankell, A. M., Bunkum, A., Lim, E. L., Karasaki, T., Abbosh, C., Hiley, C. T., Hill, M. S., Cook, D. E., Wilson, G. A., Salgado, R., Nye, E., Stone, R. K., Fennell, D. A., Price, G., Kerr, K. M., Naidu, B., Middleton, G., Summers, Y., Lindsay, C. R., Blackhall, F. H., Cave, J., Blyth, K. G., Nair, A., Ahmed, A., Taylor, M. N., Procter, A. J., Falzon, M., Lawrence, D., Navani, N., Thakrar, R. M., Janes, S. M., Papadatos-Pastos, D., Forster, M. D., Lee, S. M., Ahmad, T., Quezada, S. A., Peggs, K. S., Van Loo, P., Dive, C., Hackshaw, A., Birkbak, N. J., Zaccaria, S., 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., Matharu, G., Shaw, J. A., Riley, J., Primrose, L., Boleti, E., Cheyne, H., Khalil, M., Richardson, S., Cruickshank, T., Benafif, S., 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., Krebs, M. G., Clipson, A., Tugwood, J., Kerr, A., Rothwell, D. G., Kilgour, E., Aerts, H. J. W. L., Schwarz, R. F., Kaufmann, T. L., Rosenthal, R., Szallasi, Z., Kisistok, J., Sokac, M., Diossy, M., Demeulemeester, J., Stewart, A., Magness, A., Karamani, A., Chain, B., Campbell, B. B., Castignani, C., Bailey, C., Puttick, C., Weeden, C. E., Lee, C., Richard, C., Pearce, D. R., Karagianni, D., Biswas, D., Levi, D., Hoxha, E., Larose Cadieux, 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., Black, J. R. M., Herrero, J., Rane, J. K., Nicod, J., Lam, J. M., Hartley, J. A., Enfield, K. S. S., Selvaraju, K., Thol, 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., Angelova, M., Tanić, M., Sivakumar, M., Kanu, N., Chervova, O., Lucas, O., Al-Sawaf, O., Hobson, P., Pawlik, P., Bentham, R., 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., Marafioti, 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., Borg, E., Wilson, J., 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., 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., Nicholson, A. G., Fernandes, N., Shah, P., Proli, C., Hewish, M., Danson, S., Shackcloth, M. J., Robinson, L., Russell, P., Dick, C., Le Quesne, J., Kirk, A., Asif, M., Bilancia, R., Kostoulas, N., Thomas, M., Jamal-Hanjani, M., McGranahan, N., and Swanton, C.
• 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
• Publisher: Nature Research
• ISSN: 0028-0836
• ISSN (Online): 1476-4687
• Published Online: 12 April 2023
• Copyright Holders: Copyright © 2023 The Authors
• First Published: First published in Nature 616:534–542
• Publisher Policy: Reproduced under a Creative Commons License

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• Data DOI: 10.5281/zenodo.7649257