Nat Genet. 2014 Jun 22. doi: 10.1038/ng.3013. [Epub ahead of print]
Ordering of mutations in preinvasive disease stages of esophageal carcinogenesis.
Weaver JM1, Ross-Innes CS1, Shannon N2, Lynch AG2, Forshew T3, Barbera M4, Murtaza M3, Ong CA4, Lao-Sirieix P4, Dunning MJ3, Smith L4, Smith ML3,Anderson CL3, Carvalho B3, O'Donovan M5, Underwood TJ6, May AP7, Grehan N4, Hardwick R8, Davies J9, Oloumi A10, Aparicio S10, Caldas C3, Eldridge MD3,Edwards PA11, Rosenfeld N3, Tavaré S3, Fitzgerald RC4; the OCCAMS Consortium.
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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