{"entity":{"id":"paper-tracerx-evolution-nature-2023","kind":"paper","name":"TRACERx 421: the full-cohort picture of how lung cancer evolves and which subclones drive relapse","aka":[],"tldr":"Analysis of 1,644 tumour regions from 421 patients confirmed that subclonal expansions and whole-genome doubling predict relapse, mapped which drivers are selected late, and showed that the metastasising subclone is often a minor population in the primary.","summary":"The full TRACERx 421 cohort report was published as a set of Nature papers in April 2023. Frankell and colleagues analysed 1,644 regions from 421 early-stage NSCLC tumours with whole-exome sequencing and phylogenetic reconstruction.\n\nSubclonal selection was pervasive, with evidence of positive selection acting on late-arising drivers such as those in the PI3K pathway and chromatin modifiers; subclonal expansions (a large subclone dominating a region) and whole-genome doubling were associated with worse disease-free survival. Companion papers showed that the metastasis-seeding clone was frequently a minor subclone in the primary (Al Bakir), that ctDNA at surgery and subclonal copy-number alterations predicted outcome (Abbosh), and that a mutation-independent mechanism by which air pollution promotes EGFR-mutant lung cancer (Hill) operates through inflammation acting on pre-existing mutant cells.\n\nTRACERx is the largest longitudinal tumour-evolution dataset and the model for evolutionary studies in other cancers.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1038/s41586-023-05783-5"},{"label":"TRACERx Nature collection 2023","url":"https://www.nature.com/collections/tracerx"}],"tags":[],"related":["paper-tracerx-100-nejm-2017","whole-genome-doubling","idea-prev-clean-air-never-smoker-endpoints","idea-bio1-clonal-clearance-endpoint"],"cancers":["nsclc"],"sections":["diagnostics"],"technologies":["wes-wgs","liquid-biopsy","mrd-testing"],"targets":[],"drugs":[],"companies":[],"institutions":["francis-crick","cruk"],"pathways":["clonal-evolution","chromosomal-instability","inflammation-nfkb"],"terms":["ctdna","mrd"],"trials":[],"people":["charles-swanton"],"bottlenecks":["b-tumor-heterogeneity","b-metastasis-biology","b-dormancy-mrd"],"keyPapers":[],"journals":["nature"],"dependsOn":[],"notes":[],"journal":"Nature","year":2023,"doi":"10.1038/s41586-023-05783-5","pmid":"37046096","authors":"Frankell AM, Dietzen M, Al Bakir M, et al. (TRACERx Consortium)","paperType":"translational","findings":["1,644 regions from 421 tumours; subclonal expansions and recent whole-genome doubling associated with shorter disease-free survival","Positive selection detected on subclonal drivers, including in the PI3K pathway and chromatin regulators, meaning late drivers are not merely passengers","Companion paper: metastases frequently seeded by minor subclones of the primary, and by polyclonal seeding in a substantial fraction","Companion paper: air pollutant PM2.5 promotes lung cancer in EGFR-mutant cells via IL-1beta-driven inflammation without new mutations","Companion paper: preoperative ctDNA detection and its dynamics predicted relapse"],"whatItMeans":"Relapse after surgery is driven by particular subclones that can be identified in the primary tumour and tracked in blood, which argues for evolution-aware adjuvant strategies. The pollution finding reframes carcinogenesis: some agents promote already-mutant cells rather than causing mutations.","caveats":["Observational and correlative; interventions based on evolutionary metrics have not been tested","Whole-exome data limits detection of structural and non-coding events","Predominantly UK patients with resectable disease; evolutionary dynamics in advanced and treated disease differ","Cost and complexity of multi-region sequencing preclude routine clinical use"],"changedPractice":false,"participants":421},"route":"/key-papers/paper-tracerx-evolution-nature-2023/","neighbours":{"paper":[{"id":"paper-tracerx-100-nejm-2017","kind":"paper","name":"TRACERx first 100: tracking how lung cancers evolve, and how chromosomal chaos predicts relapse","route":"/key-papers/paper-tracerx-100-nejm-2017/"}],"term":[{"id":"ctdna","kind":"term","name":"Circulating tumour DNA (ctDNA)","route":"/terms/ctdna/"},{"id":"mrd","kind":"term","name":"Minimal / molecular residual disease (MRD)","route":"/terms/mrd/"},{"id":"whole-genome-doubling","kind":"term","name":"Whole-genome doubling (WGD)","route":"/terms/whole-genome-doubling/"}],"idea":[{"id":"idea-prev-clean-air-never-smoker-endpoints","kind":"idea","name":"Evaluate clean-air policies using lung cancer in never-smokers","route":"/ideas/idea-prev-clean-air-never-smoker-endpoints/"},{"id":"idea-bio1-clonal-clearance-endpoint","kind":"idea","name":"Make clonal clearance, not tumour shrinkage, a trial endpoint","route":"/ideas/idea-bio1-clonal-clearance-endpoint/"}],"cancer":[{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"}],"section":[{"id":"diagnostics","kind":"section","name":"Diagnostics & Biomarkers","route":"/fronts/diagnostics/"}],"technology":[{"id":"liquid-biopsy","kind":"technology","name":"Liquid biopsy (ctDNA)","route":"/technologies/liquid-biopsy/"},{"id":"mrd-testing","kind":"technology","name":"MRD / molecular residual disease testing","route":"/technologies/mrd-testing/"},{"id":"wes-wgs","kind":"technology","name":"Whole-exome & whole-genome sequencing","route":"/technologies/wes-wgs/"}],"institution":[{"id":"cruk","kind":"institution","name":"Cancer Research UK","route":"/institutions/cruk/"},{"id":"francis-crick","kind":"institution","name":"The Francis Crick Institute","route":"/institutions/francis-crick/"}],"pathway":[{"id":"chromosomal-instability","kind":"pathway","name":"Chromosomal instability & aneuploidy","route":"/pathways/chromosomal-instability/"},{"id":"clonal-evolution","kind":"pathway","name":"Clonal evolution & minimal residual disease","route":"/pathways/clonal-evolution/"},{"id":"inflammation-nfkb","kind":"pathway","name":"Inflammation & NF-κB","route":"/pathways/inflammation-nfkb/"}],"person":[{"id":"charles-swanton","kind":"person","name":"Charles Swanton","route":"/people/charles-swanton/"}],"bottleneck":[{"id":"b-dormancy-mrd","kind":"bottleneck","name":"Dormant cells and minimal residual disease","route":"/bottlenecks/b-dormancy-mrd/"},{"id":"b-metastasis-biology","kind":"bottleneck","name":"Metastasis is understood least and studied last","route":"/bottlenecks/b-metastasis-biology/"},{"id":"b-tumor-heterogeneity","kind":"bottleneck","name":"Tumour heterogeneity and clonal evolution","route":"/bottlenecks/b-tumor-heterogeneity/"}],"journal":[{"id":"nature","kind":"journal","name":"Nature","route":"/journals/nature/"}]}}