Associations of the -238(G/A) and -308(G/A) TNF-α Promoter Polymorphisms and TNF-α Serum Levels with the Susceptibility to Gastric Precancerous Lesions and Gastric Cancer Related to Helicobacter pylori Infection in a Moroccan Population

Abstract

Objective: Helicobacter pylori (H. pylori) induces the production of tumor necrosis factor-alpha (TNF-α), which is closely related to a gastric epithelial injury. TNF-α gene polymorphism and TNF-α serum levels are associated with various malignant conditions. Identification of the ideal marker for gastric cancer (GC) is still the leading aim of several trials. Physio-pathological considerations of GC led us to investigate the association of two TNF-α promoter polymorphisms (-308G>A and -238G>A), and TNF-α serum levels with the susceptibility to gastric precancerous (PL) and GC. Methods: Patients suffering from gastric lesions (65 chronic gastritis, 50 PL, 40 GC) related to H. pylori ‎infection , and 63 healthy controls (HC) were involved in this study. Individuals are genotyped by TNF-α gene promoter sequencing and TNF-α serum levels are measured by ELISA quantitative method. Results: Regarding TNF-α-308 G/A locus, we noticed higher risk for GC (OR=4.3, CI 1.5-11.9, p-value=0.005) and PL (OR=3.4, CI 1.2-9.2, p-value=0.01) for individuals with AA/GA genotypes compared to GG genotype. Concerning TNF-α-238 G/A locus, we noticed higher risk for GC (OR=5.9, CI 1.2-27.5, p-value=0.01) and PL (OR=4.8, CI 1.3-18, p-value=0.01) for individuals with GG genotype compared to AA/GA genotypes. We noticed that TNF-α serum levels have been increased together with gastric lesions severity. Moreover, TNF-α-308 and TNF-α-238 A alleles seemed to, respectively, upregulate and downregulate TNF-α serum levels. Conclusion: The TNF-α -308 A allele has a promotive effect for GC progression, whereas the TNF-α -238 A allele has a protective function against GC progression. High levels of TNF-α seemed to be associated with the aggressiveness of gastric lesions. TNF-α gene polymorphisms and TNF-α serum levels might be helpful to select those patients who are at high risk for GC.

Alteration in Serum Levels of Tumor Necrosis Factor Alpha is associated with Histopathologic Progression of Gastric Cancer

“…Combining the NM and CG groups also revealed a lower TNF-α level in patients with FHGC than those without (12.5 ± 14.2 vs. 31.0 ± 36.3 pg/ml; p = 0.003). According to the herein performed extensive literature review (Supplementary Table 1), our results are not in line with many studies [ 5 – 7 ] which have reported relatively higher serum levels of TNF-α in GC patients, as compared to healthy controls. However, our results are consistent with two other studies indicating a lower concentration of TNF-α in GC patients [ 8 , 9 ] .…”

Influence of Cytokine Gene Polymorphisms on the Risk of Gastric Disorders in H. pylori Infected Patients

“…Several studies on Moroccan and Brazilian patients found no association between this polymorphism and gastric pathologies, which is consistent with our data [42,43]. On the other hand, TNF-α-308 polymorphism was considered a risk factor for GC in Caucasians and western populations [44,45].…”

Association of Tumor Necrosis Factor Receptor 1 Promoter Gene Polymorphisms (-580 A/G and -609 G/T) and TNFR1 Serum Levels with the Susceptibility to Gastric Precancerous Lesions and Gastric Cancer Related to H. pylori Infection in a Moroccan Population

“…The genetic predisposition to cancers has been demonstrated through several studies and is still a subject of interest and scientific research [ 11 , 13 , 19 ]. Serum levels of sTNFR1 are used as a predictive marker of multifactorial inflammatory disorders and cancers [ 12 , 17 , 20 , 21 ].…”

“…The PCR products were checked out in 1.5% agarose gel electrophoresis and purified using 1 μ L of exonuclease (Thermo Scientific), 1 μ L of alkaline phosphatase (Promega), and 5 μ L of PCR product and incubated at 37°C for 15 minutes and 80°C for 15 minutes. The DNA sequencing conditions were carried out based on the method as previously described [ 19 ]. The DNA sequences were read by an Applied Biosystems 377 DNA sequencer and analyzed using the BIOEDIT software package.…”

“…sTNFR1 can also function as a ligand for tmTNF- α and induce intracellular messages via reverse signaling [ 16 ]. The serum levels of sTNFR1 and its ligand TNF- α are highly regulated in diverse human cancers and are suggested to be an important determinant of growth and cancer progression [ 7 , 15 , 17 – 19 ].…”