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

• DOI: 10.1126/science.1253462
• Publication Date: 2014-10-09T18:17:20Z
• Authors: Elza C. de Bruin; Nicholas McGranahan; Richard Mitter; Max Salm; David C. Wedge; Lucy Yates; Mariam Jamal-Hanjani; Seema Shafi; Nirupa Murugaesu; Andrew J. Rowan; Eva Grönroos; 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
• Keywords: APOBEC

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