# TRACERx 421: the full-cohort picture of how lung cancer evolves and which subclones drive relapse

Source: https://onco.cc/key-papers/paper-tracerx-evolution-nature-2023/  
OnCo record `paper-tracerx-evolution-nature-2023` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

Subclonal 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.

TRACERx is the largest longitudinal tumour-evolution dataset and the model for evolutionary studies in other cancers.

## Fields

- Kind: Key paper
- Last checked: 2026-09-08
- Journal: Nature
- Year: 2023
- DOI: 10.1038/s41586-023-05783-5
- Authors: Frankell AM, Dietzen M, Al Bakir M, et al. (TRACERx Consortium)
- 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
- What it means: 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

## Sources

- DOI: https://doi.org/10.1038/s41586-023-05783-5
- TRACERx Nature collection 2023: https://www.nature.com/collections/tracerx

## Connected records

- key papers: [TRACERx first 100: tracking how lung cancers evolve, and how chromosomal chaos predicts relapse](https://onco.cc/key-papers/paper-tracerx-100-nejm-2017/)
- terms: [Circulating tumour DNA (ctDNA)](https://onco.cc/terms/ctdna/), [Minimal / molecular residual disease (MRD)](https://onco.cc/terms/mrd/), [Whole-genome doubling (WGD)](https://onco.cc/terms/whole-genome-doubling/)
- ideas: [Evaluate clean-air policies using lung cancer in never-smokers](https://onco.cc/ideas/idea-prev-clean-air-never-smoker-endpoints/), [Make clonal clearance, not tumour shrinkage, a trial endpoint](https://onco.cc/ideas/idea-bio1-clonal-clearance-endpoint/)
- cancers: [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/)
- fronts: [Diagnostics & Biomarkers](https://onco.cc/fronts/diagnostics/)
- technologies: [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/), [MRD / molecular residual disease testing](https://onco.cc/technologies/mrd-testing/), [Whole-exome & whole-genome sequencing](https://onco.cc/technologies/wes-wgs/)
- institutions: [Cancer Research UK](https://onco.cc/institutions/cruk/), [The Francis Crick Institute](https://onco.cc/institutions/francis-crick/)
- pathways: [Chromosomal instability & aneuploidy](https://onco.cc/pathways/chromosomal-instability/), [Clonal evolution & minimal residual disease](https://onco.cc/pathways/clonal-evolution/), [Inflammation & NF-κB](https://onco.cc/pathways/inflammation-nfkb/)
- people: [Charles Swanton](https://onco.cc/people/charles-swanton/)
- bottlenecks: [Dormant cells and minimal residual disease](https://onco.cc/bottlenecks/b-dormancy-mrd/), [Metastasis is understood least and studied last](https://onco.cc/bottlenecks/b-metastasis-biology/), [Tumour heterogeneity and clonal evolution](https://onco.cc/bottlenecks/b-tumor-heterogeneity/)
- journals: [Nature](https://onco.cc/journals/nature/)

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