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Nature

Publication date: 2023-04-20
Volume: 616 Pages: 534 -
Publisher: Nature Research

Author:

Al Bakir, Maise
Huebner, Ariana ; Martinez-Ruiz, Carlos ; Grigoriadis, Kristiana ; Watkins, Thomas BK ; Pich, Oriol ; Moore, David A ; Veeriah, Selvaraju ; Ward, Sophia ; Laycock, Joanne ; Johnson, Diana ; Rowan, Andrew ; Razaq, Maryam ; Akther, Mita ; Naceur-Lombardelli, Cristina ; Prymas, Paulina ; Toncheva, Antonia ; Hessey, Sonya ; Dietzen, Michelle ; Colliver, Emma ; Frankell, Alexander ; Bunkum, Abigail ; Lim, Emilia L ; Karasaki, Takahiro ; Abbosh, Christopher ; Hiley, Crispin T ; Hill, Mark S ; Cook, Daniel E ; Wilson, Gareth A ; Salgado, Roberto ; Nye, Emma ; Stone, Richard Kevin ; Fennell, Dean A ; Price, Gillian ; Kerr, Keith M ; Naidu, Babu ; Middleton, Gary ; Summers, Yvonne ; Lindsay, Colin R ; Blackhall, Fiona H ; Cave, Judith ; Blyth, Kevin G ; Nair, Arjun ; Ahmed, Asia ; Taylor, Magali N ; Procter, Alexander James ; Falzon, Mary ; Lawrence, David ; Navani, Neal ; Thakrar, Ricky M ; Janes, Sam M ; Papadatos-Pastos, Dionysis ; Forster, Martin D ; Lee, Siow Ming ; Ahmad, Tanya ; Quezada, Sergio ; Peggs, Karl S ; Van Loo, Peter ; Dive, Caroline ; Hackshaw, Allan ; Birkbak, Nicolai J ; Zaccaria, Simone ; Jamal-Hanjani, Mariam ; McGranahan, Nicholas ; Swanton, Charles ; Lester, Jason F ; Bajaj, Amrita ; Nakas, Apostolos ; Sodha-Ramdeen, Azmina ; Ang, Keng ; Tufail, Mohamad ; Chowdhry, Mohammed Fiyaz ; Scotland, Molly ; Boyles, Rebecca ; Rathinam, Sridhar ; Wilson, Claire ; Marrone, Domenic ; Dulloo, Sean ; Matharu, Gurdeep ; Shaw, Jacqui A ; Riley, Joan ; Primrose, Lindsay ; Boleti, Ekaterini ; Cheyne, Heather ; Khalil, Mohammed ; Richardson, Shirley ; Cruickshank, Tracey ; Benafif, Sarah ; Gilbert, Kayleigh ; Patel, Akshay J ; Osman, Aya ; Lacson, Christer ; Langman, Gerald ; Shackleford, Helen ; Djearaman, Madava ; Kadiri, Salma ; Leek, Angela ; Hodgkinson, Jack Davies ; Totten, Nicola ; Montero, Angeles ; Smith, Elaine ; Fontaine, Eustace ; Granato, Felice ; Doran, Helen ; Novasio, Juliette ; Rammohan, Kendadai ; Joseph, Leena ; Bishop, Paul ; Shah, Rajesh ; Moss, Stuart ; Joshi, Vijay ; Crosbie, Philip ; Gomes, Fabio ; Brown, Kate ; Carter, Mathew ; Chaturvedi, Anshuman ; Priest, Lynsey ; Oliveira, Pedro ; Krebs, Matthew G ; Clipson, Alexandra ; Tugwood, Jonathan ; Kerr, Alastair ; Rothwell, Dominic G ; Kilgour, Elaine ; Aerts, Hugo JWL ; Schwarz, Roland F ; Kaufmann, Tom L ; Rosenthal, Rachel ; Szallasi, Zoltan ; Kisistok, Judit ; Sokac, Mateo ; Diossy, Miklos ; Demeulemeester, Jonas ; Stewart, Aengus ; Magness, Alastair ; Karamani, Angeliki ; Chain, Benny ; Campbell, Brittany B ; Castignani, Carla ; Bailey, Chris ; Puttick, Clare ; Weeden, Clare E ; Lee, Claudia ; Richard, Corentin ; Pearce, David R ; Karagianni, Despoina ; Biswas, Dhruva ; Levi, Dina ; Hoxha, Elena ; Larose Cadieux, Elizabeth ; Gronroos, Eva ; Galvez-Cancino, Felip ; Athanasopoulou, Foteini ; Gimeno-Valiente, Francisco ; Kassiotis, George ; Stavrou, Georgia ; Mastrokalos, Gerasimos ; Zhai, Haoran ; Lowe, Helen L ; Matos, Ignacio ; Goldman, Jacki ; Reading, James L ; Black, James RM ; Herrero, Javier ; Rane, Jayant K ; Nicod, Jerome ; Lam, Jie Min ; Hartley, John A ; Enfield, Katey SS ; Selvaraju, Kayalvizhi ; Thol, Kerstin ; Litchfield, Kevin ; Ng, Kevin W ; Chen, Kezhong ; Dijkstra, Krijn ; Thakkar, Krupa ; Ensell, Leah ; Shah, Mansi ; Vasquez, Marcos ; Litovchenko, Maria ; Werner Sunderland, Mariana ; Leung, Michelle ; Escudero, Mickael ; Angelova, Mihaela ; Tanic, Miljana ; Sivakumar, Monica ; Kanu, Nnennaya ; Chervova, Olga ; Lucas, Olivia ; Al-Sawaf, Othman ; Hobson, Philip ; Pawlik, Piotr ; Bentham, Robert ; Hynds, Robert E ; Vendramin, Roberto ; Saghafinia, Sadegh ; Lopez, Saioa ; Gamble, Samuel ; Ung, Seng Kuong Anakin ; Vanloo, Sharon ; Boeing, Stefan ; Beck, Stephan ; Bola, Supreet Kaur ; Denner, Tamara ; Marafioti, Teresa ; Mourikis, Thanos P ; Spanswick, Victoria ; Barbe, Vittorio ; Lu, Wei-Ting ; Hill, William ; Liu, Wing Kin ; Wu, Yin ; Naito, Yutaka ; Ramsden, Zoe ; Veiga, Catarina ; Royle, Gary ; Collins-Fekete, Charles-Antoine ; Fraioli, Francesco ; Ashford, Paul ; Clark, Tristan ; Borg, Elaine ; Wilson, James ; Patrini, Davide ; Martinoni Hoogenboom, Emilie ; Monk, Fleur ; Holding, James W ; Choudhary, Junaid ; Bhakhri, Kunal ; Scarci, Marco ; Hayward, Martin ; Panagiotopoulos, Nikolaos ; Gorman, Pat ; Khiroya, Reena ; Stephens, Robert CM ; Wong, Yien Ning Sophia ; Bandula, Steve ; Sharp, Abigail ; Smith, Sean ; Gower, Nicole ; Dhanda, Harjot Kaur ; Chan, Kitty ; Pilotti, Camilla ; Leslie, Rachel ; Grapa, Anca ; Zhang, Hanyun ; AbdulJabbar, Khalid ; Pan, Xiaoxi ; Yuan, Yinyin ; Chuter, David ; MacKenzie, Mairead ; Chee, Serena ; Alzetani, Aiman ; Scarlett, Lydia ; Richards, Jennifer ; Ingram, Papawadee ; Austin, Silvia ; Lim, Eric ; De Sousa, Paulo ; Jordan, Simon ; Rice, Alexandra ; Raubenheimer, Hilgardt ; Bhayani, Harshil ; Ambrose, Lyn ; Devaraj, Anand ; Chavan, Hema ; Begum, Sofina ; Buderi, Silviu ; Kaniu, Daniel ; Malima, Mpho ; Booth, Sarah ; Nicholson, Andrew G ; Fernandes, Nadia ; Shah, Pratibha ; Proli, Chiara ; Hewish, Madeleine ; Danson, Sarah ; Shackcloth, Michael J ; Robinson, Lily ; Russell, Peter ; Dick, Craig ; Le Quesne, John ; Kirk, Alan ; Asif, Mo ; Bilancia, Rocco ; Kostoulas, Nikos ; Thomas, Mathew

Keywords:

Science & Technology, Multidisciplinary Sciences, Science & Technology - Other Topics, SOCIETY GUIDELINES, PULMONARY NODULES, TRACKING, INSTABILITY, SELECTION, ORIGINS, HISTORY, DRIVER, Humans, Carcinoma, Non-Small-Cell Lung, Clonal Evolution, Clone Cells, Cohort Studies, Disease Progression, Evolution, Molecular, Lung Neoplasms, Neoplasm Metastasis, Neoplasm Recurrence, Local, TRACERx Consortium, General Science & Technology

Abstract:

Metastatic disease is responsible for the majority of cancer-related deaths1. 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.