title: Ordering of mutations in preinvasive disease stages of esophageal carcinogenesis.
abstract: 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.
authors: MRC Cancer Unit, University of Cambridge, Cambridge, UK.
authors: Jamie M J
authors: JMJ
authors: Weaver
authors: MRC Cancer Unit, University of Cambridge, Cambridge, UK.
authors: Caryn S
authors: CS
authors: Ross-Innes
authors: CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.
authors: Nicholas
authors: N
authors: Shannon
authors: CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.
authors: Andy G
authors: AG
authors: Lynch
authors: CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.
authors: Tim
authors: T
authors: Forshew
authors: MRC Cancer Unit, University of Cambridge, Cambridge, UK.
authors: Mariagnese
authors: M
authors: Barbera
authors: CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.
authors: Muhammed
authors: M
authors: Murtaza
authors: MRC Cancer Unit, University of Cambridge, Cambridge, UK.
authors: Chin-Ann J
authors: CJ
authors: Ong
authors: MRC Cancer Unit, University of Cambridge, Cambridge, UK.
authors: Pierre
authors: P
authors: Lao-Sirieix
authors: CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.
authors: Mark J
authors: MJ
authors: Dunning
authors: MRC Cancer Unit, University of Cambridge, Cambridge, UK.
authors: Laura
authors: L
authors: Smith
authors: CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.
authors: Mike L
authors: ML
authors: Smith
authors: CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.
authors: Charlotte L
authors: CL
authors: Anderson
authors: CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.
authors: Benilton
authors: B
authors: Carvalho
authors: Department of Histopathology, Addenbrooke's Hospital, Cambridge, UK.
authors: Maria
authors: M
authors: O'Donovan
authors: Cancer Sciences Division, University of Southampton, Southampton, UK.
authors: Timothy J
authors: TJ
authors: Underwood
authors: Fluidigm Corporation, South San Francisco, California, USA.
authors: Andrew P
authors: AP
authors: May
authors: MRC Cancer Unit, University of Cambridge, Cambridge, UK.
authors: Nicola
authors: N
authors: Grehan
authors: Oesophago-Gastric Unit, Addenbrooke's Hospital, Cambridge, UK.
authors: Richard
authors: R
authors: Hardwick
authors: Oxford ComLab, University of Oxford, UK.
authors: Jim
authors: J
authors: Davies
authors: British Columbia Cancer Research Centre, Cancer Agency Research Centre, Canada.
authors: Arusha
authors: A
authors: Oloumi
authors: British Columbia Cancer Research Centre, Cancer Agency Research Centre, Canada.
authors: Sam
authors: S
authors: Aparicio
authors: CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.
authors: Carlos
authors: C
authors: Caldas
authors: CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.
authors: Matthew D
authors: MD
authors: Eldridge
authors: Department of Pathology, University of Cambridge, Cambridge, UK.
authors: Paul A W
authors: PAW
authors: Edwards
authors: CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.
authors: Nitzan
authors: N
authors: Rosenfeld
authors: CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.
authors: Simon
authors: S
authors: Tavaré
authors: MRC Cancer Unit, University of Cambridge, Cambridge, UK.
authors: Rebecca C
authors: RC
authors: Fitzgerald
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001471:Barrett Esophagus / Q000235:genetics / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics*; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011230:Precancerous Conditions / Q000235:genetics* / Q000473:pathology; D017422:Sequence Analysis, DNA / Q000379:methods