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The evolution of lung cancer and impact of subclonal selection in TRACERx

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Item Type:Article
Title:The evolution of lung cancer and impact of subclonal selection in TRACERx
Creators Name:Frankell, A.M. and Dietzen, M. and Al Bakir, M. and Lim, E.L. and Karasaki, T. and Ward, S. and Veeriah, S. and Colliver, E. and Huebner, A. and Bunkum, A. and Hill, M.S. and Grigoriadis, K. and Moore, D.A. and Black, J.R.M. and Liu, W.K. and Thol, K. and Pich, O. and Watkins, T.B.K. and Naceur-Lombardelli, C. and Cook, D.E. and Salgado, R. and Wilson, G.A. and Bailey, C. and Angelova, M. and Bentham, R. and Martínez-Ruiz, C. and Abbosh, C. and Nicholson, A.G. and Le Quesne, J. and Biswas, D. and Rosenthal, R. and Puttick, C. and Hessey, S. and Lee, C. and Prymas, P. and Toncheva, A. and Smith, J. and Xing, W. and Nicod, J. and Price, G. and Kerr, K.M. and Naidu, B. and Middleton, G. and Blyth, K.G. and Fennell, D.A. and Forster, M.D. and Lee, S.M. and Falzon, M. and Hewish, M. and Shackcloth, M.J. and Lim, E. and Benafif, S. and Russell, P. and Boleti, E. and Krebs, M.G. and Lester, J.F. and Papadatos-Pastos, D. and Ahmad, T. and Thakrar, R.M. and Lawrence, D. and Navani, N. and Janes, S.M. and Dive, C. and Blackhall, F.H and Summers, Y. and Cave, J. and Marafioti, T. and Herrero, J. and Quezada, S.A. and Peggs, K.S. and Schwarz, R.F. and Van Loo, P. and Miedema, D.M. and Birkbak, N.J. and Hiley, C.T. and Hackshaw, A. and Zaccaria, S. and Jamal-Hanjani, M. and McGranahan, N. and Swanton, C.
Abstract:Lung cancer is the leading cause of cancer-associated mortality worldwide. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource.
Keywords:Genetics Research, Translational Research
Source:Nature
ISSN:0028-0836
Publisher:Nature Publishing Group
Volume:616
Number:7957
Page Range:525-533
Date:20 April 2023
Additional Information:Tom L. Kaufmann (19184) is a member of the TRACERx Consortium.
Official Publication:https://doi.org/10.1038/s41586-023-05783-5
PubMed:View item in PubMed

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