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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 regions from seven operable NSCLCs and found evidence of branched evolution, with driver mutations arising before and after subclonal diversification. There was pronounced intratumor heterogeneity in copy number alterations, translocations, and mutations associated with APOBEC cytidine deaminase activity. Despite maintained carcinogen exposure, tumors from smokers showed a relative decrease in smoking-related mutations over time, accompanied by an increase in APOBEC-associated mutations. In tumors from former smokers, genome-doubling occurred within a smoking-signature context before subclonal diversification, which suggested that a long period of tumor latency had preceded clinical detection. The regionally separated driver mutations, coupled with the relentless and heterogeneous nature of the genome instability processes, are likely to confound treatment success in NSCLC.

Original publication

DOI

10.1126/science.1253462

Type

Journal article

Journal

Science (new york, n.y.)

Publication Date

10/2014

Volume

346

Pages

251 - 256

Addresses

Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6BT, UK.

Keywords

Tumor Cells, Cultured, Humans, Carcinoma, Non-Small-Cell Lung, Lung Neoplasms, Neoplasm Recurrence, Local, Translocation, Genetic, Genomic Instability, Cytidine Deaminase, Carcinogens, Prognosis, Smoking, Evolution, Molecular, Gene Dosage, Genetic Heterogeneity, Mutation, APOBEC-1 Deaminase