TY - JOUR
T1 - The evolution of non-small cell lung cancer metastases in TRACERx
AU - TRACERx Consortium
AU - Al Bakir, Maise
AU - Huebner, Ariana
AU - Martínez-Ruiz, Carlos
AU - Grigoriadis, Kristiana
AU - Watkins, Thomas B.K.
AU - Pich, Oriol
AU - Moore, David A.
AU - Veeriah, Selvaraju
AU - Ward, Sophia
AU - Laycock, Joanne
AU - Johnson, Diana
AU - Rowan, Andrew
AU - Razaq, Maryam
AU - Akther, Mita
AU - Naceur-Lombardelli, Cristina
AU - Prymas, Paulina
AU - Toncheva, Antonia
AU - Hessey, Sonya
AU - Dietzen, Michelle
AU - Colliver, Emma
AU - Frankell, Alexander M.
AU - Bunkum, Abigail
AU - Lim, Emilia L.
AU - Karasaki, Takahiro
AU - Abbosh, Christopher
AU - Hiley, Crispin T.
AU - Hill, Mark S.
AU - Cook, Daniel E.
AU - Wilson, Gareth A.
AU - Salgado, Roberto
AU - Nye, Emma
AU - Stone, Richard Kevin
AU - Fennell, Dean A.
AU - Price, Gillian
AU - Kerr, Keith M.
AU - Naidu, Babu
AU - Middleton, Gary
AU - Summers, Yvonne
AU - Lindsay, Colin R.
AU - Blackhall, Fiona H.
AU - Cave, Judith
AU - Blyth, Kevin G.
AU - Nair, Arjun
AU - Ahmed, Asia
AU - Taylor, Magali N.
AU - Procter, Alexander James
AU - Falzon, Mary
AU - Van Loo, Peter
AU - Pan, Xiaoxi
AU - Yuan, Yinyin
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/4/20
Y1 - 2023/4/20
N2 - 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.
AB - 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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U2 - 10.1038/s41586-023-05729-x
DO - 10.1038/s41586-023-05729-x
M3 - Article
C2 - 37046095
AN - SCOPUS:85152472618
SN - 0028-0836
VL - 616
SP - 534
EP - 542
JO - Nature
JF - Nature
IS - 7957
ER -