Genetic variants A1826H and D2937Y in GAG-beta domain of versican influence susceptibility to intestinal-type gastric cancer

Abstract

Versican regulates adhesion, migration, proliferation, and survival of cells, and plays an important role in cancer development. A case-control association study was performed to test genetic association of versican polymorphisms with susceptibility to gastric cancer. In this study, 1,101 unrelated Korean subjects including 612 gastric cancer patients and 489 healthy controls were genotyped for all 21 exonic polymorphisms in the versican gene (VCAN) encoding amino acid changes in versican. Cancer susceptibility associations with the polymorphisms were assessed using multivariate logistic regression analysis with adjustment for age and gender and with control for multiple testing. Two amino acid changes in GAG-beta domain of versican encoded by two almost fully correlated (r (2) = 0.97) nonsynonymous single-nucleotide polymorphisms in VCAN were associated with gastric cancer. The association was evident in intestinal-type but not in diffuse-type gastric cancer. The minor-allele homozygote of rs188703 (G > A, R1826H) or rs160277 (G > T, D2937Y) was significantly associated with a twofold decreased susceptibility to intestinal-type gastric cancer when compared with the other genotypes (adjusted odds ratio = 0.52 or 0.51, P = 0.0098 or 0.0087, respectively). The intestinal-type gastric cancer susceptibility is associated with two amino acid changes of versican in the GAG-beta domain, which is critical for enhancement of cell proliferation and activation of EGFR signal pathway by versican, and changes from the major to minor alleles may impair the function to decrease susceptibility to cancer.