title: Whole-genome sequencing provides new insights into the clonal architecture of Barrett's esophagus and esophageal adenocarcinoma.
abstract: The molecular genetic relationship between esophageal adenocarcinoma (EAC) and its precursor lesion, Barrett's esophagus, is poorly understood. Using whole-genome sequencing on 23 paired Barrett's esophagus and EAC samples, together with one in-depth Barrett's esophagus case study sampled over time and space, we have provided the following new insights: (i) Barrett's esophagus is polyclonal and highly mutated even in the absence of dysplasia; (ii) when cancer develops, copy number increases and heterogeneity persists such that the spectrum of mutations often shows surprisingly little overlap between EAC and adjacent Barrett's esophagus; and (iii) despite differences in specific coding mutations, the mutational context suggests a common causative insult underlying these two conditions. From a clinical perspective, the histopathological assessment of dysplasia appears to be a poor reflection of the molecular disarray within the Barrett's epithelium, and a molecular Cytosponge technique overcomes sampling bias and has the capacity to reflect the entire clonal architecture.
authors.affiliation: Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, UK.
authors.forename: Caryn S
authors.initials: CS
authors.lastname: Ross-Innes
authors.affiliation: Illumina, Chesterford Research Park, Little Chesterford, UK.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Becq
authors.affiliation: Illumina, Chesterford Research Park, Little Chesterford, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Warren
authors.affiliation: Illumina, Chesterford Research Park, Little Chesterford, UK.
authors.forename: R Keira
authors.initials: RK
authors.lastname: Cheetham
authors.affiliation: Illumina, Chesterford Research Park, Little Chesterford, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Northen
authors.affiliation: Department of Histopathology, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: O'Donovan
authors.affiliation: Department of Histopathology, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Shalini
authors.initials: S
authors.lastname: Malhotra
authors.affiliation: Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, UK.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: di Pietro
authors.affiliation: Illumina, Chesterford Research Park, Little Chesterford, UK.
authors.forename: Sergii
authors.initials: S
authors.lastname: Ivakhno
authors.affiliation: Illumina, Chesterford Research Park, Little Chesterford, UK.
authors.forename: Miao
authors.initials: M
authors.lastname: He
authors.affiliation: Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, UK.
authors.forename: Jamie M J
authors.initials: JMJ
authors.lastname: Weaver
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
authors.forename: Andy G
authors.initials: AG
authors.lastname: Lynch
authors.affiliation: Illumina, Chesterford Research Park, Little Chesterford, UK.
authors.forename: Zoya
authors.initials: Z
authors.lastname: Kingsbury
authors.affiliation: Illumina, Chesterford Research Park, Little Chesterford, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Ross
authors.affiliation: Illumina, Chesterford Research Park, Little Chesterford, UK.
authors.forename: Sean
authors.initials: S
authors.lastname: Humphray
authors.affiliation: Illumina, Chesterford Research Park, Little Chesterford, UK.
authors.forename: David
authors.initials: D
authors.lastname: Bentley
authors.affiliation: Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, UK.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Fitzgerald
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000368:Aged; D001471:Barrett Esophagus / Q000235:genetics*; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000235:genetics*; D005260:Female; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide