Skip to main content
Premium Trial:

Request an Annual Quote

Barrett Esophagus Risk Gene Detected in Large Esophageal Cancer-Prone Family

NEW YORK (GenomeWeb) – A study published online in JAMA Oncology today suggests germline mutations in the VSIG10L gene may increase the risk of familial Barrett esophagus, a complication of gastroesophageal reflux disease that can lead to esophageal cancer.

Researchers from Case Western Reserve University and elsewhere did exome sequencing on four members of a multigenerational family with familial Barrett esophagus and elevated esophageal cancer risk. The search led to a rare germline mutation in VSIG10L, a yet-to-be-characterized gene that appears to contribute to susceptibility to Barrett neoplasias and esophageal adenocarcinoma in the family.

Beyond its role in esophageal cancer risk in the affected family, the team believes a more detailed examination of VSIG10L could contribute to a better understanding of Barrett esophagus and esophageal adenocarcinoma biology. Though the mutation identified in the study appeared to be restricted to one family, it noted that the variant may offer a means of identifying members of that family who are most prone to esophageal disease.

"This is a step forward in combating this deadly disease as we discovered a new way to categorize those at risk for esophageal adenocarcinoma," corresponding author Amitabh Chak, a gastroenterology researcher at Case Western, said in a statement.

Prompted by rising esophageal adenocarcinoma rates and poor survival outcomes in those with esophageal cancer, the team set out to find new genetic contributors to familial Barrett esophagus — an inherited, autosomal dominant condition implicated in roughly 7 percent of Barrett esophagus cases. The researchers focused on individuals from a five-generation family affected by familial Barrett esophagus. Of the more than four-dozen family members considered, 11 had developed Barrett esophagus and three had been diagnosed with esophageal adenocarcinoma.

When the team scrutinized protein-coding sequences from four affected family members selected for exome sequencing, it saw a rare, missense, germline mutation in VSIG10L — a mutation that subsequently turned up in eight of 10 affected family members.

The VSIG10L alteration was also present in three of nine unaffected family members tested, the researchers noted, pointing to incomplete penetrance for the apparently risky mutation. Still, the gene's enhanced expression in squamous cells from normal esophageal tissue, coupled with diminished expression in dysplastic or cancerous esophageal samples, suggests the alteration could conceivably contribute to Barrett esophagus and esophageal cancer risk.

Using Sanger sequencing, Chak and his colleagues assessed the VSIG10L gene in germline samples from individuals in 35 more familial Barrett esophagus-affected families and in biopsy samples from 19 esophageal adenocarcinoma samples, uncovering a somatic missense mutation in VSIG10L in one of the cancer biopsies.

"Our finding of a private variant in VSIG10L in [one] unique family … suggests marked genetic heterogeneity of [familial Barrett esophagus," the authors wrote, though "discovery of this novel gene opens avenues of translational research for elucidating the function of VSIG10L in [Barrett esophagus] pathogenesis, prevention, and treatment."

Further research on the gene variant itself, Chak added, "may reveal pathways important for the pathogenesis of [Barrett esophagus] and esophageal adenocarcinoma, leading to earlier detection and better treatment options."