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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.
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.
Shares Charles Swanton, TRACERx first 100: tracking how lung cancers evolve, and how chromosomal chaos predicts relapse, The Francis Crick Institute, Clonal evolution & minimal residual disease.
Shares Charles Swanton, TRACERx first 100: tracking how lung cancers evolve, and how chromosomal chaos predicts relapse, The Francis Crick Institute, Clonal evolution & minimal residual disease.
Shares Evaluate clean-air policies using lung cancer in never-smokers, Charles Swanton, TRACERx first 100: tracking how lung cancers evolve, and how chromosomal chaos predicts relapse, The Francis Crick Institute.
Shares The Francis Crick Institute, Metastasis is understood least and studied last, Tumour heterogeneity and clonal evolution, Cancer Research UK.
Shares Whole-genome doubling (WGD), Chromosomal instability & aneuploidy, Clonal evolution & minimal residual disease, Nature.
Shares The Francis Crick Institute, Tumour heterogeneity and clonal evolution, Cancer Research UK, Whole-exome & whole-genome sequencing.
Shares Metastasis is understood least and studied last, Dormant cells and minimal residual disease, Minimal / molecular residual disease (MRD), MRD / molecular residual disease testing.
Shares Dormant cells and minimal residual disease, Minimal / molecular residual disease (MRD), Circulating tumour DNA (ctDNA), MRD / molecular residual disease testing.