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Brief Report
October 2016

Association Between Germline Mutation in VSIG10L and Familial Barrett Neoplasia

Author Affiliations
  • 1Department of Pathology, Case Medical Center, Case Western Reserve University, Cleveland, Ohio
  • 2Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia
  • 3Division of Gastroenterology and Liver Disease, Department of Medicine, Case Medical Center, Cleveland, Ohio
  • 4Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio
  • 5Electron Microscopy Facility, Case Western Reserve University, Cleveland, Ohio
  • 6Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio
  • 7Division of Hematology-Oncology, Department of Medicine, Case Western Reserve University, Cleveland, Ohio
  • 8Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio
  • 9Division of General Medical Sciences-Oncology, Case Western Reserve University, Cleveland, Ohio
JAMA Oncol. 2016;2(10):1333-1339. doi:10.1001/jamaoncol.2016.2054
Key Points

Question  Do germline DNA mutations underlie susceptibility to familial Barrett esophagus, familial aggregation of Barrett esophagus, and esophageal adenocarcinoma?

Findings  In this genetic study of a multigenerational family with 14 affected individuals, a rare variant in the uncharacterized gene VSIG10L was associated with susceptibility to Barrett esophagus and esophageal adenocarcinoma. Functional studies revealed this germline mutation in VSIG10L disrupts esophageal epithelial maturation.

Meaning  This discovery of the first susceptibility variant in familial Barrett esophagus reveals novel biology in disease pathogenesis and indicates early screening and close clinical monitoring for individuals harboring the germline variant.


Importance  Esophageal adenocarcinoma and its precursor lesion Barrett esophagus have seen a dramatic increase in incidence over the past 4 decades yet marked genetic heterogeneity of this disease has precluded advances in understanding its pathogenesis and improving treatment.

Objective  To identify novel disease susceptibility variants in a familial syndrome of esophageal adenocarcinoma and Barrett esophagus, termed familial Barrett esophagus, by using high-throughput sequencing in affected individuals from a large, multigenerational family.

Design, Setting, and Participants  We performed whole exome sequencing (WES) from peripheral lymphocyte DNA on 4 distant relatives from our multiplex, multigenerational familial Barrett esophagus family to identify candidate disease susceptibility variants. Gene variants were filtered, verified, and segregation analysis performed to identify a single candidate variant. Gene expression analysis was done with both quantitative real-time polymerase chain reaction and in situ RNA hybridization. A 3-dimensional organotypic cell culture model of esophageal maturation was utilized to determine the phenotypic effects of our gene variant. We used electron microscopy on esophageal mucosa from an affected family member carrying the gene variant to assess ultrastructural changes.

Main Outcomes and Measures  Identification of a novel, germline disease susceptibility variant in a previously uncharacterized gene.

Results  A multiplex, multigenerational family with 14 members affected (3 members with esophageal adenocarcinoma and 11 with Barrett esophagus) was identified, and whole-exome sequencing identified a germline mutation (S631G) at a highly conserved serine residue in the uncharacterized gene VSIG10L that segregated in affected members. Transfection of S631G variant into a 3-dimensional organotypic culture model of normal esophageal squamous cells dramatically inhibited epithelial maturation compared with the wild-type. VSIG10L exhibited high expression in normal squamous esophagus with marked loss of expression in Barrett-associated lesions. Electron microscopy of squamous esophageal mucosa harboring the S631G variant revealed dilated intercellular spaces and reduced desmosomes.

Conclusions and Relevance  This study presents VSIG10L as a candidate familial Barrett esophagus susceptibility gene, with a putative role in maintaining normal esophageal homeostasis. Further research assessing VSIG10L function may reveal pathways important for esophageal maturation and the pathogenesis of Barrett esophagus and esophageal adenocarcinoma.