Abstract

Spatial and temporal dissection of the genomic changes occurring during the evolution of human non-small cell lung cancer (NSCLC) may help elucidate the basis for its dismal prognosis. We sequenced 25 spatially distinct tumour regions from seven operable NSCLCs and found evidence of branched tumour evolution in all cases, with driver mutations arising before and after subclonal diversification. There was pronounced intra-tumour heterogeneity in copy number alterations, translocations, and mutations associated with APOBEC cytidine deaminase activity. Despite maintained carcinogen exposure, tumours from smokers showed a relative decrease in smoking-related mutations over time, accompanied by an increase in APOBEC-associated mutations. In tumours from ex-smokers, genome-doubling occurred within a smoking-signature context before subclonal diversification, suggesting that a long period of tumour latency may have preceded clinical detection. The presence of regionally separated driver mutations, coupled with the relentless and heterogeneous nature of the genome instability processes are likely to confound treatment success in NSCLC.