EGAGenomicsCharles Swantonhttps://ega-archive.org/dacs/EGAC00001000340EGAEGA DAC EGAC00001000340EGACharles.Swanton@crick.ac.uk<h4>Unlabelled</h4>Esophageal adenocarcinomas are associated with a dismal prognosis. Deciphering the evolutionary history of this disease may shed light on therapeutically tractable targets and reveal dynamic mutational processes during the disease course and following neoadjuvant chemotherapy (NAC). We exome sequenced 40 tumor regions from 8 patients with operable esophageal adenocarcinomas, before and after platinum-containing NAC. This revealed the evolutionary genomic landscape of esophageal adenocarcinomas with the presence of heterogeneous driver mutations, parallel evolution, early genome-doubling events, and an association between high intratumor heterogeneity and poor response to NAC. Multiregion sequencing demonstrated a significant reduction in thymine to guanine mutations within a CpTpT context when comparing early and late mutational processes and the presence of a platinum signature with enrichment of cytosine to adenine mutations within a CpC context following NAC. Esophageal adenocarcinomas are characterized by early chromosomal instability leading to amplifications containing targetable oncogenes persisting through chemotherapy, providing a rationale for future therapeutic approaches.<h4>Significance</h4>This work illustrates dynamic mutational processes occurring during esophageal adenocarcinoma evolution and following selective pressures of platinum exposure, emphasizing the iatrogenic impact of therapy on cancer evolution. Identification of amplifications encoding targetable oncogenes maintained through NAC suggests the presence of stable vulnerabilities, unimpeded by cytotoxics, suitable for therapeutic intervention.Tracking the genomic evolution of esophageal adenocarcinoma through neoadjuvant chemotherapy.Murugaesu Nirupa N, Wilson Gareth A GA, Birkbak Nicolai J NJ, Watkins Thomas T, McGranahan Nicholas N, Kumar Sacheen S, Abbassi-Ghadi Nima N, Salm Max M, Mitter Richard R, Horswell Stuart S, Rowan Andrew A, Phillimore Benjamin B, Biggs Jennifer J, Begum Sharmin S, Matthews Nik N, Hochhauser Daniel D, Hanna George B GB, Swanton Charles CDrug, Therapy, oesophageal adenocarcinoma, EAC, esophagus adenocarcinoma, oesophagus adenocarcinoma, Pharmacotherapy, adenocarcinoma of oesophagus, chemotherapy, Therapies, Chemotherapies., Chemotherapy, adenocarcinoma of the oesophagus, esophageal adenocarcinoma, pharmacologic therapy, pharmacotherapy, Pharmacotherapies, adenocarcinoma of the esophagus, Drug Therapies, adenocarcinoma - esophagus, adenocarcinoma of esophagus, adenocarcinoma - oesophagusadenocarcinoma of the oesophagus, esophageal adenocarcinoma, oesophageal adenocarcinoma, EAC, esophagus adenocarcinoma, oesophagus adenocarcinoma, adenocarcinoma - oesophagus., adenocarcinoma of the esophagus, adenocarcinoma - esophagus, adenocarcinoma of oesophagus, adenocarcinoma of esophagusNalp1, Adenomas, N-acetylcysteine, CG8759, SLEV1, Visible Light, mercapturic acid, Platin, Tumor, ADNOS, DEFCAP-L/S, Mutations, 5-Methyluracil, Pt, diseases, 4-dihydroxy-5-methylpyrimidine, Associations, Granular Cell Adenocarcinoma, 2, Tubular Carcinoma, diseases and disorders, 4, Transforming, Chromosomal Stabilities, Fs(3)Hor, Cribriform Carcinoma, KIAA0926, Chromosome Instabilities, imprinted and ancient gene protein, A, treatment, C, human disease, DmelCG2684, Prognoses, G, esophagus adenocarcinoma, 5-methyl-2, Genomes, Adenoma, Granular Cell Carcinoma, T, 4-amino-2(1H)-pyrimidinone, 1H-Purin-6-amine, Tubular Carcinomas, Histories, NTef2, 7-dihydro-, DEFCAP, 5 Methyluracil, Chromosomal Stability, TNFSF14, Thy, Transforming Genes, malignant neoplasm, 3H)-Pyrimidinedione, CIDED, disease management, Therapies, Homo sapiens disease, Malignancies, XKR1, Zytosin, adenocarcinoma of esophagus, CLR17.1, Tumors, Therapy, NACalpha, close to, Carcinoma, Ade, Thymin, 4-amino-, Radiation, anatomical protrusion, alpha-NAC, UNQ391/PRO726, Light, 6H-Purin-6-one, Procedure, historical aspects, Adenocarcinomas, 2-Amino-6-hydroxypurine, Fs(3)Sz11, Cyt, DmelCG8759, Tubular, LIGHT, Benign, Malignant Adenoma, alphaNAC, Chromosome Instability, Diseases, Chemotherapy, X1k, esophageal adenocarcinoma, Basal Cell Adenocarcinoma, (2R)-2-acetylamino-3-sulfanylpropanoic acid, Carcinomas, Visible Radiations, 2(1H)-Pyrimidinone, platine, Visible Radiation, Factors, Vitamin, HVEML, Pharmacotherapy, platino, Adenin, chromosomal passenger complex, adenocarcinoma of oesophagus, Prognostic, Heterogeneity, Exomes, Cribriform, Benign Neoplasms, 5-methyluracil, whole genome, MCLDS, 3H)-pyrimidinedione, adenocarcinoma of the esophagus, 78Pt, Treatments, Tubular Adenocarcinomas, early, Malignant Neoplasms, disease, Oncogene, oesophageal adenocarcinoma, CARD7, Patient, Chromosome, spine, Horka, historical notes, 2-amino-1, acetilcisteina, CG2684, NAC, Fs(3)Horka, NALP1, adenocarcinoma of the oesophagus, Cytosin, other neoplasm, E430016J11Rik, Prognostic Factor, Adenocarcinoma, other disease, whole exome, 5-methylpyrimidine-2, Aspect, chemotherapy, Neoplasms, Oxyphilic Adenocarcinoma, Benign Neoplasm, number, Vitamin B 4, Gua, Gene, Prognostic Factors, pharmacotherapy, Vitamin B, Pharmacotherapies, Malignant, l(2)04329, Ximpact, presence, Chemotherapies, adenocarcinoma - oesophagus, Granular Cell Adenocarcinomas, Ly113, protrusion, Intervention or Procedure, Stability, EAC, Instabilities, Genetic heterogeneity, disease or disorder, DmF2, Basal Cell Adenocarcinomas, aic, Chromosomal Instabilities, Drug Therapies, lod, Chromosome Stabilities, oesophagus adenocarcinoma, Transforming Gene, Malignancy, interventionDescription, Tubular Adenocarcinoma, Interventional, CpC, Visible, Cribriform Carcinomas, 3H)-dione, cytidine-3'-phosphate-5'-cytidine, non-neoplastic, L-acetylcysteine, Neoplasias, Platinum Black, Granular Cell Carcinomas, Nlrp1, N-acetyl-L-(+)-cysteine, SURGICAL AND MEDICAL PROCEDURES., (R)-2-acetylamino-3-mercaptopropanoic acid, Clients, KX, heterogeneity, disorder, TR2, NACA, CPC, adenocarcinoma - esophagus, Cancer, CPC complex, Intervention Strategies, Oxyphilic, Nalp1a, VAMAS1, Gm14, Acetylcysteine, Malignant Neoplasm, Gm15, Basal Cell, disorders, Factor, medical condition, Chromosome Stability, Historical Aspects, CD258, Historical Aspect, Client, impact-a, Chromosomal, Stabilities, near to, L-alpha-acetamido-beta-mercaptopropionic acid, count in organism, 6-Aminopurine, MT, 2-amino-6-oxopurine, DEFCAP-L|S, Neoplasm, condition, imprinted and ancient gene protein homolog, IMPACT, NA, 4(1H, Granular Cell, Oxyphilic Adenocarcinomas, Radiations, Intervention, primary cancer, Genes, HVEM-L, Photoradiation, B 4, Cancers, Lds, malignant tumor, Malignant Adenomas, PP1044, LTg, Drug, 5-methyl-, Photoradiations, 4-amino-2-hydroxypyrimidine, Pressures, Therapeutic, (R)-mercapturic acid, approaches, vicinity of, Treatment, pharmacologic therapy, acetylcysteinum, Aspects, Instability, Neoplasia, RWDD5, HistoricalfalseTRACERx esophageal adenocarcinomaData Access Committee EGAC00001000340EGAC00001000340960626003801EGAS00001001254EGAD00001001364