EGAGenomicsN/Ahttps://ega-archive.org/datasets/EGAD000010007040EGA dataset EGAD00001000704EGACancer genome sequencing studies have identified numerous driver genes, but the relative timing of mutations in carcinogenesis remains unclear. The gradual progression from premalignant Barrett's esophagus to esophageal adenocarcinoma (EAC) provides an ideal model to study the ordering of somatic mutations. We identified recurrently mutated genes and assessed clonal structure using whole-genome sequencing and amplicon resequencing of 112 EACs. We next screened a cohort of 109 biopsies from 2 key transition points in the development of malignancy: benign metaplastic never-dysplastic Barrett's esophagus (NDBE; n=66) and high-grade dysplasia (HGD; n=43). Unexpectedly, the majority of recurrently mutated genes in EAC were also mutated in NDBE. Only TP53 and SMAD4 mutations occurred in a stage-specific manner, confined to HGD and EAC, respectively. Finally, we applied this knowledge to identify high-risk Barrett's esophagus in a new non-endoscopic test. In conclusion, mutations in EAC driver genes generally occur exceptionally early in disease development with profound implications for diagnostic and therapeutic strategies.Ordering of mutations in preinvasive disease stages of esophageal carcinogenesis.Weaver Jamie M J JMJ, Ross-Innes Caryn S CS, Shannon Nicholas N, Lynch Andy G AG, Forshew Tim T, Barbera Mariagnese M, Murtaza Muhammed M, Ong Chin-Ann J CJ, Lao-Sirieix Pierre P, Dunning Mark J MJ, Smith Laura L, Smith Mike L ML, Anderson Charlotte L CL, Carvalho Benilton B, O'Donovan Maria M, Underwood Timothy J TJ, May Andrew P AP, Grehan Nicola N, Hardwick Richard R, Davies Jim J, Oloumi Arusha A, Aparicio Sam S, Caldas Carlos C, Eldridge Matthew D MD, Edwards Paul A W PAW, Rosenfeld Nitzan N, Tavaré Simon S, Fitzgerald Rebecca C RCPilot, F23A5_3., PRE, PhrB photolyase activity, deoxyribonucleic cyclobutane dipyrimidine photolyase activity, PILOT, photoreactivating enzyme activity, pigmented epithelium, adenocarcinoma - oesophagus, MODIFIER OF SNC1, EAC, retinal pigment, Aviators, deoxyribonucleic photolyase activity, dipyrimidine photolyase (photosensitive), Co-Pilot, 3, esophageal adenocarcinoma, stratum pigmentosa retinae, NUP96, epithelium, retinal pigment layer, Co-Pilots, average, MOS3, RPE, esophagus adenocarcinoma, oesophagus adenocarcinoma, deoxyribocyclobutadipyrimidine pyrimidine-lyase activity, PRECOCIOUS, photolyase activity, Aviator, adenocarcinoma of oesophagus, pigmented retina, F23A5.3, adenocarcinoma of the esophagus, DNA cyclobutane dipyrimidine photolyase activity, SUPPRESSOR OF AUXIN RESISTANCE 3, p. pigmentosa retinae, phr A photolyase activity, oesophageal adenocarcinoma, DNA-photoreactivating enzyme, Oesophageal adenocarcinoma, Co Pilot, adenocarcinoma of the oesophagus, deoxyribonucleate pyrimidine dimer lyase (photosensitive), EGR-3, adenocarcinoma - esophagus, adenocarcinoma of esophagusDesc, Description, Descriptive, Provide., Supplied, Supply, Descriptor, description, Provided, Product Description/Appearance, DESCRnon-neoplastic, Mutations, other disease, disease, Tumorigenesis., human disease, Tumorigeneses, diseases, Oncogenesis, Diseases, disease or disorder, disorders, Carcinogeneses, condition, disorder, diseases and disorders, Homo sapiens disease, Oncogeneses, medical conditionMetaplasias, other disease, HgD, SMAD family member 4, Tumorigeneses, Materials, postnatal development., single-organism developmental process, DmelCG1775, conformation, (S)-2-hydroxymethylglutarate:NAD+ oxidoreductase activity, Neoplasms, postnatal development, p53, developmental stage, dysplasia, jip, Benign Neoplasm, Gene, Barretts Esophagus, growth and development, Barrett Metaplasia, Tumor, Malignant, LFS1, Tp53, adenocarcinoma - oesophagus, Mutations, Relative, EAC, diseases, SMAD 4, bbl, l(3)SG36, Barrett's epithelium, HGO, Hgo, madh4, disease or disorder, diseases and disorders, DmF2, 2010013M14Rik, Fs(3)Hor, Barrett, Barrett's Syndrome, MYHRS, Barrett Epithelium, lod, CYLDI, study, hSMAD4, DmelCG2684, human disease, esophagus adenocarcinoma, oesophagus adenocarcinoma, MADH4, medea, Genetic, XSmad4alpha, Biopsies, Malignancy, Genomes, Barrett esophagus, BCC7, dyscrasia, smad4, Oncogeneses, NTef2, CYLD1, E(zen)3, non-neoplastic, Neoplasias, Barretts Syndrome, SMAD4, reaction, Barrett metaplasia, Trp53, MAD homolog 4, anon-EST:Posey121, Mothers against DPP homolog 4, malignant neoplasm, AKU, Barrett Syndrome, Barretts syndrome, Deletion target in pancreatic carcinoma 4 homolog, disorder, Smad4, Homo sapiens disease, Malignancies, stage, TRP53, adenocarcinoma - esophagus, adenocarcinoma of esophagus, Cancer, Tumors, l(3)12m-137, C130039D01Rik, Barretts esophagus, Malignant Neoplasm, aku, (S)-2-hydroxymethylglutarate - NAD+ oxidoreductase activity, USPL2, disorders, MFT1, dpc4, l(3)11m-254, Madh4, medical condition, Tumorigenesis, D18Wsu70e, Cistrons, Xp53, Fs(3)Sz11, dysplastic, development, 2900009M21Rik, MT, Benign, Epithelium, MED, Relative Risks, Esophagus, BRSS, mKIAA0849, Diseases, Neoplasm, Metaplasia, Genetic Materials, Barrett's oesophagus, condition, esophageal adenocarcinoma, bfy, xsmad4a, dSmad4, Genetic Material, CG1775, Relative Risk, Epistemology, primary cancer, Risk, adenocarcinoma of oesophagus, Xsmad4, med, Risks, Carcinogeneses, postnatal growth, Benign Neoplasms, Cancers, whole genome, CDMT, Barretts oesophagus, l(3)SG70, Barrett's, adenocarcinoma of the esophagus, MFT, Lds, malignant tumor, early, Malignant Neoplasms, AW743858, disease, Barrett's Esophagus, SBS, Deletion target in pancreatic carcinoma 4, oesophageal adenocarcinoma, Oncogenesis, Material, Horka, P53, JIP, CG2684, p44, Fs(3)Horka, bhy, Cistron, adenocarcinoma of the oesophagus, Barrett Metaplasias, growth, l(3)XIIm137, Neoplasia, TEM, DPC4falseICGC Oesophageal Adenocarcinoma sequence data - pilot normal and pre-chemo - samplesDescription not provided2023-08-02 12:38:22EGAD00001000704960624952744EGAC00001000010EGAS00001000559