Abstract
Chronic inflammation due to H. pylori infection is the risk factor of gastric cancer (GC). Through its receptor (TNFR1), TNF-α plays a fundamental role in inflammatory, infectious, and tumor processes. Dysregulation of TNFR1 gene expression could impact many biological processes that can lead to cancer. This study is aimed at evaluating the association of TNFR1 promoter gene polymorphisms (-580 A/G and -609 G/T) and TNFR1 serum levels with GC and precancerous lesion susceptibility. Patients suffering from gastric lesions (65 chronic gastritis, 50 precancerous lesions, and 40 GC) related to H. pylori infection and 63 healthy controls (HC) were involved in this study. Individuals are genotyped by TNFR1 gene promoter sequencing, and TNFR1 serum levels were measured by the ELISA quantitative method. Concerning TNFR1 -609 G/T locus, we noticed that the T allele was associated with an attenuated susceptibility to GC (OR = 0.4; p value = 0.02). At the genotypic level and under the recessive model, the TNFR1 -609 TT genotype showed a decreased risk of GC (OR = 0.3, p value = 0.03) compared to the combined (GG/GT) genotypes. TNFR1 serum levels have been increased together with gastric lesion severity (p value < 0.05). The TNFR1 -609 TT genotype seemed linked to a low level of sTNFR1 compared to GT and GG genotypes (p value = 0.07). Concerning TNFR1 -580 A/G locus, no significant relation was noticed between this polymorphism and GC susceptibility, as well as with the TNFR1 serum level. Our results suggest that the TNFR1 -609 T allele appears to have a protective effect against GC. High levels of TNFR1 serum levels seemed to be associated with the aggressiveness of gastric lesions. Therefore, our results suggest that TNFR1 -609 T/G polymorphism and the TNFR1 serum levels may be related to GC susceptibility.
Highlights
Gastric cancer is one of the most aggressive neoplasms
Gastric cancer is a multistep process, starting by Helicobacter pylori- (H. pylori-) driven inflammation, which leads to chronic gastritis, atrophic gastritis, intestinal metaplasia, and dysplasia which can progress to an adenocarcinoma [2]
While under the recessive model, we noticed a significantly reduced risk for gastric cancer (OR = 0:3, 95% confidence intervals (CI) 0.09-0.9, p value = 0.03) in subjects with the TNFR1 -609 TT genotype compared to the combined genotypes (GG+GT)
Summary
Gastric cancer is one of the most aggressive neoplasms. It is ranked among the fourth most diagnosed cancers and the second leading cause of death worldwide [1]. Gastric cancer is a multistep process, starting by Helicobacter pylori- (H. pylori-) driven inflammation, which leads to chronic gastritis, atrophic gastritis, intestinal metaplasia, and dysplasia which can progress to an adenocarcinoma [2]. Chronic inflammation related to H. pylori infection is believed to be a critical step in gastric carcinogenesis [3]. Tumor Necrosis Factor-alpha (TNF-α) is known as a principal mediator of inflammation and host response to H. pylori infection, and it is closely related to gastric epithelial injury [4, 5]. TNF-α elicits its pleiotropic cellular effects through interaction with its two cell surface receptors TNFR1 and TNFR2. TNFR1 represents the primary receptor for TNF-α due to its ubiquitous expression and its enrolling in several biological effects [8]
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