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Rare genetic variant may predict Barrett esophagus, esophageal cancer
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Mutations in the VSIG1OL gene appeared associated with susceptibility to familial Barrett esophagus and esophageal cancer, according to study results published in JAMA Oncology.
“Instances of esophageal cancer are on the rise, and the disease has a poor 5-year survival rate of less than 15%,” Amitabh Chak, MD, professor of medicine at Case Western Reserve University School of Medicine and gastroenterologist at University Hospitals Case Medical Center’s Seidman Cancer Center, said in a press release. “However, early detection through screening can prevent the development of esophageal cancer.”
Research into genetic variants that may contribute to early detection of esophageal cancer and its precursor lesion, Barrett esophagus, has been hampered by the disease’s genetic heterogeneity.
Chak and colleagues sought to identify novel disease susceptibility variants in familial Barrett esophagus and esophageal cancer.
The researchers performed high-throughput sequencing on a multigenerational family with 14 affected members (esophageal cancer, n = 3; Barrett esophagus, n = 11).
Whole-exome sequencing was performed from peripheral lymphocyte DNA in four distant relatives of the study family to identify candidate disease susceptibility variants. The sequencing identified a germline mutation — S631G — present in highly conserved serine residue in the uncharacterized gene VSIG10L.
VSIG10L sequencing in 19 family members (affected, n = 10; unaffected, n = 9) revealed that the mutation appeared in 11 individuals (affected, n = 8; unaffected, n = 3).
However, germline DNA sequencing of VSIG10L in 35 similarly affected families did not identify any similar private variants.
The researchers used a 3-dimensional organotypic cell culture model to assess the phenotypic effects of the S631G variant, which showed that S631G expression noticeably disrupted cellular organization and was characterized by epithelial dysmaturation.
High VSIG10L expression occurred in normal squamous esophagus and showed a marked loss of expression in Barrett-associated lesions.
The use of transmission electron microscopy found that the proximal esophageal epithelium from an individual carrying the S631G variant exhibited pronounced dilation of the intercellular space and reduced desmosome formation compared with an individual without the S631G variant.
These discoveries may allow researchers and clinicians to identify and monitor individuals at risk for Barrett esophagus and esophageal cancer, according to Chak.
“This is a step forward in combating this deadly disease, as we discovered a new way to categorize those at risk for esophageal adenocarcinoma,” Chak said. – by Cameron Kelsall
Disclosure: The researchers report no relevant financial disclosures.
Perspective
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Jimmy J. Hwang
The paper by Fecteau and colleagues represents a tremendous amount of work by a dedicated group of researchers who investigated the impact of a germline variation of the gene VSIG10L on the risk for development of familial Barrett esophagus. However, the identification of this gene variant is derived from one family, and from individuals who had Barrett esophagus but not adenocarcinoma, which may limit the applicability of these results to the less prevalent, more lethal disease. In addition, this variant has not been identified in other families in which it was investigated. This may indicate that this mutational variant is of low frequency and therefore limited generalizability as a specific test.
Subsequent correlative studies that Fecteau and colleagues performed suggest that this gene encodes an epithelial protein that is involved in cellular maturation and organization. The S631G variant that was identified appears to result in the disruption of these processes, potentially leading to Barrett esophagus. Although these results provide a reasonable theoretical basis for this mutation resulting in Barrett esophagus, any subsequent link to esophageal adenocarcinoma remains unclear. The import of other mutations or environmental influences remains undefined, and crucial, especially because Barrett esophagus is not the sole precursor to esophageal adenocarcinoma, and the vast majority of patients who have Barrett esophagus do not develop adenocarcinoma.
Therefore, although the identification of this heretofore unrecognized gene and variation has the potential to be an important tool in selected families, it does not appear to be broadly generalizable as a test, and may be more important as a proof-of-concept model for the identification of future mutations and tests for other populations.
Reference:
Gregson EM, et al. Br J Cancer. 2016;doi:10.1038/bjc.2016.219.
Disclosure: Hwang reports no relevant financial disclosures.
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