Truncated Caveolin-3 Mutation In Familial Barrett’s Esophagus

ABSTRACT Objective Barrett’s esophagus and esophageal adenocarcinoma demonstrate familial aggregation. The goal was to identify a segregating genetic variant in an large family and subsequently localize esophageal gene expression. Methods Whole exome sequencing of genomic DNA from affected members of a large family with Barrett’s esophagus and esophageal adenocarcinoma was analyzed to identify rare coding variants in genes segregating with disease. Histopathological assessment of archived formalin fixed esophageal human and porcine tissues to localize expression of identified genes in esophagus. Results A segregating nonsense mutation in the gene Caveolin-3 ( CAV3 ) was identified. Esophageal CAV3 localized to myoepithelial cells around esophageal submucosal glands. Histologic examination of a formalin fixed paraffin embedded esophagectomy specimen from an individual carrying the CAV3 null mutation revealed submucosal glands demonstrating atypical acinar metaplasia with absence of myoepithelial cells and no CAV3+ cells. Conclusions Submucosal glands contribute to healing of injured squamous esophagus. We theorize the truncating nonsense CAV3 mutation disrupts normal squamous healing and the organization of submucosal glands, making affected family members susceptible to the proliferation and development of metaplastic columnar Barrett’s esophagus.