Spatial and temporal diversity in genomic instability processes defines lung cancer evolution
Authors listElza C de Bruin Nicholas McGranahan Richard Mitter Max Salm David C Wedge Lucy Yates Mariam Jamal-Hanjani Seema Shafi Nirupa Murugaesu Andrew Rowan Eva Gronroos Madiha A Muhammad Stuart Horswell Marco Gerlinger Ignacio Varela David Jones John Marshall Thierry Voet Peter Van Loo Doris M Rassl Robert C Rintoul Sam M Janes Siow-Ming Lee Martin Forster Tanya Ahmad David Lawrence Mary Falzon Arrigo Capitanio Timothy T Harkins Clarence C Lee Warren Tom Enock Teefe Shann-Ching Chen Sharmin Begum Adam Rabinowitz Benjamin Phillimore Bradley Spencer-Dene Gordon Stamp Zoltan Szallasi Nik Matthews Aengus Stewart Peter Campbell Charles Swanton
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.