Cancer 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.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Whole-genome sequencing of EAC is part of the International Cancer Genome Consortium (ICGC) through the Esophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium and is funded by Cancer Research UK. We thank the ICGC members for their input on verification standards as part of the benchmarking exercise. Cytosponge samples were collected as part of the Cancer Research UK–funded BEST2 trial. We thank M. Griffin, L. Lovat and K. Ragunath for their contribution to Cytosponge collection. The MRC developed the Cytosponge and also funded laboratory work through a program grant to R.C.F. J.M.J.W. was funded by a Wellcome Trust Translational Medicine and Therapeutics grant. R.C.F. and C.C. are supported by additional clinical research infrastructure funding from the NHS National Institute for Health Research (NIHR), the Experimental Cancer Medicine Centre Network and the NIHR Cambridge Biomedical Research Centre. Bioinformatics work was also supported by a Cancer Research UK program grant to S.T.
We thank the Genomics Core at the Cancer Research UK Cambridge Institute for their help with processing some of the Access Array experiments as well as for running the targeted resequencing experiments. We thank the IT department at the Cancer Research UK Cambridge Institute for their support. We thank F. Marass for assistance with data analysis. We thank the Human Research Tissue Bank, supported by the NIHR Cambridge Biomedical Research Centre, from Addenbrooke's Hospital as well as the University Hospital of Southampton Trust and the Southampton Experimental Cancer Medicine Centre. We are grateful to all patients who provided written consent for participation in this study, and the staff at Addenbrooke's and the University of Southampton Tissue Bank.
Integrated supplementary information
Supplementary Note, Supplementary Figures 1–4 and Supplementary Tables 1–17
About this article
Experimental and Molecular Pathology (2019)