The evolution of non-small cell lung cancer metastases in TRACERx.
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Al Bakir Maise, Huebner Ariana, Martínez-Ruiz Carlos, Grigoriadis Kristiana, Watkins Thomas B K, 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 M, 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 A, Peggs Karl S, Van Loo Peter, Dive Caroline, Hackshaw Allan, Birkbak Nicolai J, Zaccaria Simone, TRACERx Consortium, Jamal-Hanjani Mariam, McGranahan Nicholas, Swanton Charles
Аннотация
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.