The evolution of lung cancer and impact of subclonal selection in TRACERx.
Creators: name: Frankell, Alexander M
name: Dietzen, Michelle
name: Al Bakir, Maise
name: Lim, Emilia L
name: Karasaki, Takahiro
name: Ward, Sophia
name: Veeriah, Selvaraju
name: Colliver, Emma
name: Huebner, Ariana
name: Bunkum, Abigail
name: Hill, Mark S
name: Grigoriadis, Kristiana
name: Moore, David A
name: Black, James RM
name: Liu, Wing Kin
name: Thol, Kerstin
name: Pich, Oriol
name: Watkins, Thomas BK
name: Naceur-Lombardelli, Cristina
name: Cook, Daniel E
name: Salgado, Roberto
name: Wilson, Gareth A
name: Bailey, Chris
name: Angelova, Mihaela
name: Bentham, Robert
name: Martínez-Ruiz, Carlos
name: Abbosh, Christopher
name: Nicholson, Andrew G
name: Le Quesne, John
name: Biswas, Dhruva
name: Rosenthal, Rachel
name: Puttick, Clare
name: Hessey, Sonya
name: Lee, Claudia
name: Prymas, Paulina
name: Toncheva, Antonia
name: Smith, Jon
name: Xing, Wei
name: Nicod, Jerome
name: Price, Gillian
name: Kerr, Keith M
name: Naidu, Babu
name: Middleton, Gary
name: Blyth, Kevin G
name: Fennell, Dean A
name: Forster, Martin D
name: Lee, Siow Ming
name: Falzon, Mary
name: Hewish, Madeleine
name: Shackcloth, Michael J
name: Lim, Eric
name: Benafif, Sarah
name: Russell, Peter
name: Boleti, Ekaterini
name: Krebs, Matthew G
name: Lester, Jason F
name: Papadatos-Pastos, Dionysis
name: Ahmad, Tanya
name: Thakrar, Ricky M
name: Lawrence, David
name: Navani, Neal
name: Janes, Sam M
name: Dive, Caroline
name: Blackhall, Fiona H
name: Summers, Yvonne
name: Cave, Judith
name: Marafioti, Teresa
name: Herrero, Javier
name: Quezada, Sergio A
name: Peggs, Karl S
name: Schwarz, Roland F
name: Van Loo, Peter
name: Miedema, Daniël M
name: Birkbak, Nicolai J
name: Hiley, Crispin T
name: Hackshaw, Allan
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: Lung cancer is the leading cause of cancer-associated mortality worldwide1. 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.