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Lung cancer is the leading cause of cancer-associated mortality worldwide 1 . 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.

Titel:	The evolution of lung cancer and impact of subclonal selection in TRACERx.
Autor/in / Beteiligte Person:	Frankell, AM ; Dietzen, M ; Al Bakir, M ; Lim, EL ; Karasaki, T ; Ward, S ; Veeriah, S ; Colliver, E ; Huebner, A ; Bunkum, A ; Hill, MS ; Grigoriadis, K ; Moore, DA ; Black, JRM ; Liu, WK ; Thol, K ; Pich, O ; Watkins, TBK ; Naceur-Lombardelli, C ; Cook, DE ; Salgado, R ; Wilson, GA ; Bailey, C ; Angelova, M ; Bentham, R ; Martínez-Ruiz, C ; Abbosh, C ; Nicholson, AG ; Le Quesne, J ; Biswas, D ; Rosenthal, R ; Puttick, C ; Hessey, S ; Lee, C ; Prymas, P ; Toncheva, A ; Smith, J ; Xing, W ; Nicod, J ; Price, G ; Kerr, KM ; Naidu, B ; Middleton, G ; Blyth, KG ; Fennell, DA ; Forster, MD ; Lee, SM ; Falzon, M ; Hewish, M ; Shackcloth, MJ ; Lim, E ; Benafif, S ; Russell, P ; Boleti, E ; Krebs, MG ; Lester, JF ; Papadatos-Pastos, D ; Ahmad, T ; Thakrar, RM ; Lawrence, D ; Navani, N ; Janes, SM ; Dive, C ; Blackhall, FH ; Summers, Y ; Cave, J ; Marafioti, T ; Herrero, J ; Quezada, SA ; Peggs, KS ; Schwarz, RF ; Van Loo, P ; Miedema, DM ; Birkbak, NJ ; Hiley, CT ; Hackshaw, A ; Zaccaria, S ; Jamal-Hanjani, M ; McGranahan, N ; Swanton, C
Link:	Zum Volltext
Zeitschrift:	Nature, Jg. 616 (2023-04-01), Heft 7957, S. 525-533
Veröffentlichung:	Basingstoke : Nature Publishing Group ; <i>Original Publication</i>: London, Macmillan Journals ltd., 2023
Medientyp:	academicJournal
ISSN:	1476-4687 (electronic)
DOI:	10.1038/s41586-023-05783-5
Schlagwort:	Humans Adenocarcinoma of Lung etiology Adenocarcinoma of Lung genetics Adenocarcinoma of Lung pathology Mutation Neoplasm Recurrence, Local genetics Phylogeny Treatment Outcome Smoking genetics Smoking physiopathology Mutagenesis DNA Copy Number Variations Carcinoma, Non-Small-Cell Lung etiology Carcinoma, Non-Small-Cell Lung genetics Carcinoma, Non-Small-Cell Lung pathology Lung Neoplasms etiology Lung Neoplasms genetics Lung Neoplasms pathology
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Corporate Authors: TRACERx Consortium Publication Type: Journal Article; Research Support, Non-U.S. Gov't Language: English [Nature] 2023 Apr; Vol. 616 (7957), pp. 525-533. <i>Date of Electronic Publication: </i>2023 Apr 12. MeSH Terms: Carcinoma, Non-Small-Cell Lung* / etiology ; Carcinoma, Non-Small-Cell Lung* / genetics ; Carcinoma, Non-Small-Cell Lung* / pathology ; Lung Neoplasms* / etiology ; Lung Neoplasms* / genetics ; Lung Neoplasms* / pathology ; Humans ; Adenocarcinoma of Lung / etiology ; Adenocarcinoma of Lung / genetics ; Adenocarcinoma of Lung / pathology ; Mutation ; Neoplasm Recurrence, Local / genetics ; Phylogeny ; Treatment Outcome ; Smoking / genetics ; Smoking / physiopathology ; Mutagenesis ; DNA Copy Number Variations Comments: Comment in: Nature. 2023 Apr;616(7957):435-436. (PMID: 37045956) References: Sung, H. et al. 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(PMID: 2978816710.1093/annonc/mdy075) Grant Information: 25354 United Kingdom CRUK_ Cancer Research UK; CTRNBC-2022/100001 United Kingdom CRUK_ Cancer Research UK; 21999 United Kingdom CRUK_ Cancer Research UK; 24956 United Kingdom CRUK_ Cancer Research UK; United Kingdom WT_ Wellcome Trust; 17786 United Kingdom CRUK_ Cancer Research UK; CC2008 United Kingdom ARC_ Arthritis Research UK; MR/V033077/1 United Kingdom MRC_ Medical Research Council; CC2041 United Kingdom ARC_ Arthritis Research UK; 29569 United Kingdom CRUK_ Cancer Research UK; 30025 United Kingdom CRUK_ Cancer Research UK Contributed Indexing: Investigator: J Le Quesne; P Van Loo; A Bajaj; A Nakas; A Sodha-Ramdeen; K Ang; M Tufail; MF Chowdhry; M Scotland; R Boyles; S Rathinam; C Wilson; D Marrone; S Dulloo; G Matharu; JA Shaw; J Riley; L Primrose; H Cheyne; M Khalil; S Richardson; T Cruickshank; K Gilbert; AJ Patel; A Osman; C Lacson; G Langman; H Shackleford; M Djearaman; S Kadiri; A Leek; JD Hodgkinson; N Totten; A Montero; E Smith; E Fontaine; F Granato; H Doran; J Novasio; K Rammohan; L Joseph; P Bishop; R Shah; S Moss; V Joshi; P Crosbie; F Gomes; K Brown; M Carter; A Chaturvedi; L Priest; P Oliveira; CR Lindsay; A Clipson; J Tugwood; A Kerr; DG Rothwell; E Kilgour; HJWL Aerts; TL Kaufmann; Z Szallasi; J Kisistok; M Sokac; M Diossy; J Demeulemeester; A Stewart; A Magness; A Rowan; A Karamani; B Chain; BB Campbell; C Castignani; CE Weeden; C Richard; DR Pearce; D Karagianni; D Levi; E Hoxha; E Larose Cadieux; E Nye; E Grönroos; F Gálvez-Cancino; F Athanasopoulou; F Gimeno-Valiente; G Kassiotis; G Stavrou; G Mastrokalos; H Zhai; HL Lowe; I Matos; J Goldman; JL Reading; JK Rane; JM Lam; JA Hartley; KSS Enfield; K Selvaraju; K Litchfield; KW Ng; K Chen; K Dijkstra; K Thakkar; L Ensell; M Shah; M Vasquez; M Litovchenko; M Werner Sunderland; M Leung; M Escudero; M Tanić; M Sivakumar; N Kanu; O Chervova; O Lucas; O Al-Sawaf; P Hobson; P Pawlik; RK Stone; RE Hynds; R Vendramin; S Saghafinia; S López; S Gamble; SKA Ung; S Vanloo; S Boeing; S Beck; SK Bola; T Denner; TP Mourikis; V Spanswick; V Barbè; WT Lu; W Hill; Y Wu; Y Naito; Z Ramsden; C Veiga; G Royle; CA Collins-Fekete; F Fraioli; P Ashford; T Clark; E Borg; J Wilson; AJ Procter; A Ahmed; MN Taylor; A Nair; D Patrini; E Martinoni Hoogenboom; F Monk; JW Holding; J Choudhary; K Bhakhri; M Scarci; M Hayward; N Panagiotopoulos; P Gorman; R Khiroya; RC Stephens; YNS Wong; S Bandula; A Sharp; S Smith; N Gower; HK Dhanda; K Chan; C Pilotti; R Leslie; A Grapa; H Zhang; K AbdulJabbar; X Pan; Y Yuan; D Chuter; M MacKenzie; S Chee; A Alzetani; L Scarlett; J Richards; P Ingram; S Austin; P De Sousa; S Jordan; A Rice; H Raubenheimer; H Bhayani; L Ambrose; A Devaraj; H Chavan; S Begum; SI Buderi; D Kaniu; M Malima; S Booth; N Fernandes; P Shah; C Proli; S Danson; L Robinson; C Dick; A Kirk; M Asif; R Bilancia; N Kostoulas; M Thomas Molecular Sequence: ClinicalTrials.gov NCT01888601 Substance Nomenclature: EC 2.7.10.1 (ROS1 protein, human) ; EC 2.7.10.1 (RET protein, human) ; EC 2.7.10.1 (ALK protein, human) ; EC 2.7.10.1 (MET protein, human) ; EC 2.7.10.1 (EGFR protein, human) Entry Date(s): Date Created: 20230412 Date Completed: 20230512 Latest Revision: 20240320 Update Code: 20240320 PubMed Central ID: PMC10115649

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