The evolution of non-small cell lung cancer metastases in TRACERx.
Creators: name: Al Bakir, Maise
name: Huebner, Ariana
name: Martínez-Ruiz, Carlos
name: Grigoriadis, Kristiana
name: Watkins, Thomas BK
name: Pich, Oriol
name: Moore, David A
name: Veeriah, Selvaraju
name: Ward, Sophia
name: Laycock, Joanne
name: Johnson, Diana
name: Rowan, Andrew
name: Razaq, Maryam
name: Akther, Mita
name: Naceur-Lombardelli, Cristina
name: Prymas, Paulina
name: Toncheva, Antonia
name: Hessey, Sonya
name: Dietzen, Michelle
name: Colliver, Emma
name: Frankell, Alexander M
name: Bunkum, Abigail
name: Lim, Emilia L
name: Karasaki, Takahiro
name: Abbosh, Christopher
name: Hiley, Crispin T
name: Hill, Mark S
name: Cook, Daniel E
name: Wilson, Gareth A
name: Salgado, Roberto
name: Nye, Emma
name: Stone, Richard Kevin
name: Fennell, Dean A
name: Price, Gillian
name: Kerr, Keith M
name: Naidu, Babu
name: Middleton, Gary
name: Summers, Yvonne
name: Lindsay, Colin R
name: Blackhall, Fiona H
name: Cave, Judith
name: Blyth, Kevin G
name: Nair, Arjun
name: Ahmed, Asia
name: Taylor, Magali N
name: Procter, Alexander James
name: Falzon, Mary
name: Lawrence, David
name: Navani, Neal
name: Thakrar, Ricky M
name: Janes, Sam M
name: Papadatos-Pastos, Dionysis
name: Forster, Martin D
name: Lee, Siow Ming
name: Ahmad, Tanya
name: Quezada, Sergio A
name: Peggs, Karl S
name: Van Loo, Peter
name: Dive, Caroline
name: Hackshaw, Allan
name: Birkbak, Nicolai J
name: Zaccaria, Simone
name: Consortium, TRACERx
name: Jamal-Hanjani, Mariam
name: McGranahan, Nicholas
name: Swanton, Charles
Publisher: name: The Francis Crick Institute
Year: 2023
Subjects: subject: Model organisms
subject: Tumour Biology
subject: Signalling &amp; Oncogenes
subject: Genetics &amp; Genomics
subject: Genome Integrity &amp; Repair
subject: Human Biology &amp; Physiology
subject: Cell Biology
subject: Cell Cycle &amp; Chromosomes
subject: Stem Cells
subject: Chemical Biology &amp; High Throughput
subject: Ecology,Evolution &amp; Ethology
subject: Immunology
subject: FOS: Clinical medicine
subject: Computational &amp; Systems Biology

description: 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.