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Spatial and temporal diversity in genomic instability processes defines lung cancer evolution.

Accepted version
Peer-reviewed

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Authors

de Bruin, Elza C 
McGranahan, Nicholas 
Mitter, Richard 
Salm, Max 
Wedge, David C 

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 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.

Description

Keywords

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

Journal Title

Science

Conference Name

Journal ISSN

0036-8075
1095-9203

Volume Title

346

Publisher

American Association for the Advancement of Science (AAAS)
Sponsorship
Cancer Research UK (17001)