Journal
NATURE GENETICS
Volume 46, Issue 8, Pages 837-843Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.3013
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Funding
- Cancer Research UK
- BEST2 trial
- program grant
- Wellcome Trust Translational Medicine and Therapeutics grant
- NHS National Institute for Health Research (NIHR)
- Experimental Cancer Medicine Centre Network
- NIHR Cambridge Biomedical Research Centre
- Cancer Research UK program grant
- IT department at the Cancer Research UK Cambridge Institute
- NIHR Cambridge Biomedical Research Centre, from Addenbrooke's Hospital
- University Hospital of Southampton Trust
- Southampton Experimental Cancer Medicine Centre
- MRC [G1002565, MC_UU_12022/2, MC_U105365007] Funding Source: UKRI
- Cancer Research UK [14545, 15874, 11906, 20240, 19556, 16942, 22310, 12088] Funding Source: researchfish
- Medical Research Council [MC_UU_12022/2, 1390282, MC_U105365007, G1002565] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0611-10154, NIHR-RP-02-12-011, 05/12/01, NF-SI-0611-10065] Funding Source: researchfish
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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.
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