Abstract
The purpose of this study was to identify functional genetic variants in the promoter of tumor necrosis factor superfamily member 15 (TNFSF15) and evaluate their effects on the risk of developing gastric adenocarcinoma. Forty DNA samples from healthy volunteers were sequenced to identify single nucleotide polymorphisms (SNPs) in the TNFSF15 promoter. Two TNFSF15 SNPs (−358T>C and −638A>G) were identified by direct sequencing. Next, genotypes and haplotypes of 470 gastric adenocarcinoma patients and 470 cancer-free controls were analyzed. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression. Serologic tests for Helicobacter pylori infection were measured by enzyme-linked immuno-sorbent assay (ELISA). Subjects carrying the TNFSF15 −358CC genotype were at an elevated risk for developing gastric adenocarcinoma, compared with those with the −358TT genotype (OR 1.42, 95% CI, 1.10 to 2.03). H. pylori infection was a risk factor for developing gastric adenocarcinoma (OR 2.31, 95% CI, 1.76 to 3.04). In the H. pylori infected group, subjects with TNFSF15 −358CC genotype were at higher risks for gastric adenocarcinoma compared with those carrying −358TT genotype (OR: 2.01, 95%CI: 1.65 to 4.25), indicating that H. pylori infection further influenced gastric adenocarcinoma susceptibility. The −358 T>C polymorphism eliminates a nuclear factor Y (NF-Y) binding site and the −358C containing haplotypes showed significantly decreased luciferase expression compared with −358T containing haplotypes. Collectively these findings indicate that functional genetic variants in TNFSF15 may play a role in increasing susceptibility to gastric adenocarcinoma.
Highlights
Gastric cancer is one of the most common cancers worldwide
By re-sequencing the Tumor necrosis factor superfamily member 15 (TNFSF15) promoter of 40 healthy subjects, we identified two genetic variants (2358 T.C, rs6478109 and 2638 A.G, rs7848647), which were located at 2358 bp and 2638 bp upstream of the translation start site, ATG
Identification of single nucleotide polymorphisms (SNPs) in the TNFSF15 promoter By resequencing the TNFSF15 promoter of 40 healthy subjects, we identified two genetic variants (2358 T.C, rs6478109 and 2638 A.G, rs7848647), which were located at 2358 bp and 2638 bp upstream of the translation start site, ATG
Summary
Gastric cancer is one of the most common cancers worldwide. According to the GLOBOCAN project, 952 000 new gastric cancer cases were estimated to have occurred in 2012, which attributed to 6.8% of newly diagnosed cancers [1]. The mechanism underlying the development and progression of gastric cancer influenced by H. pylori infection is still unclear. It has been suggested that inflammation is an important mediator of gastric cancer induced by H. Pylori and tumor necrosis factors (TNFs) is a key regulator of inflammation and has been indicated as a contributing factor for the development and progression of tumors [5,6,7,8]. Tumor necrosis factor superfamily member 15 (TNFSF15), known as vascular endothelial growth inhibitor (VEGI) or TNF ligand related molecule 1 (TL1), is a unique cytokine that functions as a modulator of vascular homeostasis and inflammation [9,10,11,12]. TNFSF15 was recognized as a valuable potential therapeutic target for cancer therapy [21,22]
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