title: Tracking the genomic evolution of esophageal adenocarcinoma through neoadjuvant chemotherapy.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: UCL Cancer Institute, London, UK.
authors.forename: Nirupa
authors.initials: N
authors.lastname: Murugaesu
authors.affiliation: The Francis Crick Institute, 44 Lincoln's Inn Fields, London, UK.|UCL Cancer Institute, CRUK Lung Cancer Centre of Excellence, London, UK.
authors.forename: Gareth A
authors.initials: GA
authors.lastname: Wilson
authors.affiliation: The Francis Crick Institute, 44 Lincoln's Inn Fields, London, UK.|UCL Cancer Institute, CRUK Lung Cancer Centre of Excellence, London, UK.
authors.forename: Nicolai J
authors.initials: NJ
authors.lastname: Birkbak
authors.affiliation: The Francis Crick Institute, 44 Lincoln's Inn Fields, London, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Watkins
authors.affiliation: The Francis Crick Institute, 44 Lincoln's Inn Fields, London, UK.|Centre for Mathematics & Physics in the Life Science & Experimental Biology (CoMPLEX), UCL, London, UK.
authors.forename: Nicholas
authors.initials: N
authors.lastname: McGranahan
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Sacheen
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Nima
authors.initials: N
authors.lastname: Abbassi-Ghadi
authors.affiliation: The Francis Crick Institute, 44 Lincoln's Inn Fields, London, UK.
authors.forename: Max
authors.initials: M
authors.lastname: Salm
authors.affiliation: The Francis Crick Institute, 44 Lincoln's Inn Fields, London, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Mitter
authors.affiliation: The Francis Crick Institute, 44 Lincoln's Inn Fields, London, UK.
authors.forename: Stuart
authors.initials: S
authors.lastname: Horswell
authors.affiliation: The Francis Crick Institute, 44 Lincoln's Inn Fields, London, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Rowan
authors.affiliation: The Francis Crick Institute, 44 Lincoln's Inn Fields, London, UK.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Phillimore
authors.affiliation: The Francis Crick Institute, 44 Lincoln's Inn Fields, London, UK.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Biggs
authors.affiliation: The Francis Crick Institute, 44 Lincoln's Inn Fields, London, UK.
authors.forename: Sharmin
authors.initials: S
authors.lastname: Begum
authors.affiliation: The Francis Crick Institute, 44 Lincoln's Inn Fields, London, UK.
authors.forename: Nik
authors.initials: N
authors.lastname: Matthews
authors.affiliation: UCL Cancer Institute, London, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Hochhauser
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: George B
authors.initials: GB
authors.lastname: Hanna
authors.affiliation: The Francis Crick Institute, 44 Lincoln's Inn Fields, London, UK.|UCL Cancer Institute, CRUK Lung Cancer Centre of Excellence, London, UK.
authors.forename: Charles
authors.initials: C
authors.lastname: Swanton
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D060965:Clonal Evolution; D019295:Computational Biology; D056915:DNA Copy Number Variations; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D019143:Evolution, Molecular; D059472:Exome; D005784:Gene Amplification; D014644:Genetic Variation; D015894:Genome, Human; D042822:Genomic Instability; D023281:Genomics / Q000379:methods; D006801:Humans; D009154:Mutation; D020360:Neoadjuvant Therapy; D010984:Platinum / Q000008:administration & dosage
chemical_list: D010984:Platinum