10.17863/CAM.39697
de Bruin, Elza C
McGranahan, Nicholas
Mitter, Richard
Salm, Max
Wedge, David C
Yates, Lucy
Jamal-Hanjani, Mariam
Shafi, Seema
Murugaesu, Nirupa
Rowan, Andrew J
Grönroos, Eva
Muhammad, Madiha A
Horswell, Stuart
Gerlinger, Marco
Varela, Ignacio
Jones, David
Marshall, John
Voet, Thierry
Van Loo, Peter
Rassl, Doris M
Rintoul, Robert C
Janes, Sam M
Lee, Siow-Ming
Forster, Martin
Ahmad, Tanya
Lawrence, David
Falzon, Mary
Capitanio, Arrigo
Harkins, Timothy T
Lee, Clarence C
Tom, Warren
Teefe, Enock
Chen, Shann-Ching
Begum, Sharmin
Rabinowitz, Adam
Phillimore, Benjamin
Spencer-Dene, Bradley
Stamp, Gordon
Szallasi, Zoltan
Matthews, Nik
Stewart, Aengus
Campbell, Peter
Swanton, Charles
Spatial and temporal diversity in genomic instability processes defines lung cancer evolution.
American Association for the Advancement of Science (AAAS)
2014
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
Apollo - University of Cambridge Repository
University of Cambridge
013meh722
2019-05-08
2019-05-08
2014-10-10
eng
Article
https://www.repository.cam.ac.uk/handle/1810/292538
10.1126/science.1253462
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.
Cancer Research UK
17001