The evolution of non-small cell lung cancer metastases in TRACERx
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Maise Al Bakir Ariana Huebner Carlos Martínez-Ruiz Kristiana Grigoriadis Tom Watkins Oriol Pich David A Moore Selvaraju Veeriah Sophie Ward Joanne Laycock Diana Johnson Andrew Rowan Maryam Razaq Mita Akther Cristina Naceur-Lombardelli Paulina Prymas Antonia Toncheva Sonya Hessey Michelle Dietzen Emma Colliver Alexander Frankell Abigail Bunkum Emilia Lim Takahiro Karasaki Christopher Abbosh Crispin Hiley Mark S Hill Daniel E Cook Gareth Wilson Roberto Salgado Emma Nye Richard Stone Dean A Fennell Gillian Price Keith M Kerr Babu Naidu Gary Middleton Yvonne Summers Colin R Lindsay Fiona H Blackhall Judith Cave Kevin G Blyth Arjun Nair Asia Ahmed Magali N Taylor Alexander James Procter Mary Falzon David Lawrence Neal Navani Ricky M Thakrar Sam M Janes Dionysis Papadatos-Pastos Martin D Forster Siow Ming Lee Tanya Ahmad Sergio A Quezada Karl S Peggs Peter Van Loo Caroline Dive Allan Hackshaw Nicolai Birkbak Simone Zaccaria TRACERx Consortium Mariam Jamal-Hanjani Nicholas McGranahan Charles Swanton Toggle all authors (66)
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.
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Journal Nature
Volume 616
Issue number 7957
Pages 534-542
Available online
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Publisher website (DOI) 10.1038/s41586-023-05729-x
Europe PubMed Central 37046095
Pubmed 37046095
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