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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.

Original publication

DOI

10.1038/ng.3357

Type

Journal article

Journal

Nature genetics

Publication Date

09/2015

Volume

47

Pages

1038 - 1046

Addresses

Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, UK.

Keywords

Humans, Adenocarcinoma, Esophageal Neoplasms, Barrett Esophagus, Disease Progression, DNA Mutational Analysis, Polymorphism, Single Nucleotide, Genome, Human, Aged, Middle Aged, Female, Male, Genome-Wide Association Study, DNA Copy Number Variations