EGAGenomicsCharles Swantonhttps://ega-archive.org/dacs/EGAC00001000198EGAEGA DAC EGAC00001000198EGACharles.Swanton@crick.ac.ukSpatial 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.<h4>Background</h4>Analysis of somatic mutations provides insight into the mutational processes that have shaped the cancer genome, but such analysis currently requires large cohorts. We develop deconstructSigs, which allows the identification of mutational signatures within a single tumor sample.<h4>Results</h4>Application of deconstructSigs identifies samples with DNA repair deficiencies and reveals distinct and dynamic mutational processes molding the cancer genome in esophageal adenocarcinoma compared to squamous cell carcinomas.<h4>Conclusions</h4>deconstructSigs confers the ability to define mutational processes driven by environmental exposures, DNA repair abnormalities, and mutagenic processes in individual tumors with implications for precision cancer medicine.DeconstructSigs: delineating mutational processes in single tumors distinguishes DNA repair deficiencies and patterns of carcinoma evolution.Spatial and temporal diversity in genomic instability processes defines lung cancer evolution.Rosenthal Rachel R, McGranahan Nicholas N, Herrero Javier J, Taylor Barry S BS, Swanton Charles Cde Bruin Elza C EC, McGranahan Nicholas N, Mitter Richard R, Salm Max M, Wedge David C DC, Yates Lucy L, Jamal-Hanjani Mariam M, Shafi Seema S, Murugaesu Nirupa N, Rowan Andrew J AJ, Grönroos Eva E, Muhammad Madiha A MA, Horswell Stuart S, Gerlinger Marco M, Varela Ignacio I, Jones David D, Marshall John J, Voet Thierry T, Van Loo Peter P, Rassl Doris M DM, Rintoul Robert C RC, Janes Sam M SM, Lee Siow-Ming SM, Forster Martin M, Ahmad Tanya T, Lawrence David D, Falzon Mary M, Capitanio Arrigo A, Harkins Timothy T TT, Lee Clarence C CC, Tom Warren W, Teefe Enock E, Chen Shann-Ching SC, Begum Sharmin S, Rabinowitz Adam A, Phillimore Benjamin B, Spencer-Dene Bradley B, Stamp Gordon G, Szallasi Zoltan Z, Matthews Nik N, Stewart Aengus A, Campbell Peter P, Swanton Charles CPilot, Studies, Study, Project, Pilot Project, Projects, Pilot Study., Pilot StudiesCarcinoma, anatomical protrusion, Malignant Neoplasm, Undifferentiated Carcinoma, epithelioma, Neoplasms, Benign Neoplasm, "carcinoma" EXACT [CSP2005:2000-1867], Spindle-Cell., Malignant Epithelial Tumors, "carcinoma, Tumor, Malignant, Epithelial Tumors, Anaplastic, protrusion, Undifferentiated Carcinomas, Benign, "epithelial carcinoma" EXACT [NCI2004_11_17:C2916], epithelial cancer, Epitheliomas, "carcinoma NOS (morphologic abnormality)" EXACT [SNOMEDCT_2005_07_31:189549006], Neoplasm, DNA Damage Response, Spindle-Cell Carcinomas, Malignant Epithelial Neoplasms, no subtype (morphologic abnormality)" EXACT [SNOMEDCT_2005_07_31:68453008], Malignant Epithelial, Epithelioma, Carcinomatosis, Carcinomatoses, Carcinomas, Anaplastic Carcinoma, Spindle-Cell Carcinoma, Undifferentiated, Spindle Cell, Malignancy, Epithelial Neoplasms, Benign Neoplasms, Cancers, Epithelial Neoplasm, Malignant Neoplasms, Neoplasias, spine, Malignant Epithelial Neoplasm, Malignancies, Anaplastic Carcinomas, malignant Epithelioma, Malignant Epithelial Tumor, Epithelial Tumor, Neoplasia, Cancer, Tumorshuman being, Effects, non-small cell lung carcinoma, Smoking Behavior, deoxycytidine deaminase activity, Vapers, Neoplasms, number, Benign Neoplasm, Non-Tobacco Products Smoker, Non-Small Cell Lung Cancer, Prognostic Factors, Non-Small-Cell Lung, APOBEC, cytosine nucleoside deaminase activity, non-small cell carcinoma of the lung, Tumor, Malignant, presence, temporal, Long Term, Human, protrusion, Mutations, non-small cell cancer of the lung, Lung Carcinomas, Smokers, Homo sapiens, Genetic heterogeneity, Promoters, Non-Small-Cell Lung Carcinoma, Tobacco, Tumor Initiator, NSCLC - non-small cell lung cancer, ramiform, Non-Small Cell Lung Carcinoma, Tumor Promoter, Effect, Separated, Man, treatment, Divorced, Prognoses, Man (Taxonomy), Malignancy, Genomes, Longterm, long, Promoter, apoB mRNA editing enzyme complex, Non-Small Cell Lung, Divorces, ramified, Long-Term, Non Small Cell Lung Carcinoma, Tobacco Smokers, Lung Carcinoma, Neoplasias, NSCLC, Non-Tobacco Products Smokers, Smoking Habits, heterogeneity, Nonsmall Cell Lung Cancer, disease management, Habit, Therapies, Malignancies, Long-Term Effect, associated, Non-Tobacco Products, Behaviors, Non-Small-Cell Lung Carcinomas, Long-Term Effects, incidence, Cancer, Tumors, Dissections, Therapy, Carcinoma, Initiators, anatomical protrusion, Malignant Neoplasm, Modern, Tobacco Smoker, Longterm Effect, Initiator, Non Tobacco Products, Factor, non-small cell lung carcinoma., Vaper, Behavior, non-small cell lung cancer, Menstruation, count in organism, Benign, Period, Oncogen, Smoking Habit, Long Term Effects, Neoplasm, cytidine aminohydrolase activity, Non-small cell lung cancer, carcinogenic agent, non-small cell lung carcinoma (disease), Smoking, Carcinomas, Separation, tobacco use disorder, Factors, distinct, Prognostic, Separations, Tumor Promoters, Heterogeneity, Benign Neoplasms, Smoker, Cancers, smoking, whole genome, Treatments, human, Non Small Cell Lung, Longterm Effects, Malignant Neoplasms, non-small cell carcinoma of lung, Tumor Initiators, Oncogens, Therapeutic, spine, Modern Man, cardinality, Smoking Behaviors, Carcinogen, Treatment, non-small cell cancer of lung, other neoplasm, Neoplasia, Habits, Non-Small-Cell, Prognostic FactorfalseTRACERx Pilot Study Data Access CommitteeData Access Committee EGAC00001000198EGAC0000100019896062530163026899170EGAS00001000809EGAD00001000900EGAD00001001918