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