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HLA-G 3'UTR Polymorphisms Are Linked to Susceptibility and Survival in Spanish Gastric Adenocarcinoma Patients.

ABSTRACT: HLA-G is a non-classical class I HLA molecule that induces tolerance by acting on receptors of both innate and adaptive immune cells. When overexpressed in tumors, limits surveillance by the immune system. The HLA-G gene shows several polymorphisms involved in mRNA and protein levels. We decided to study the implication of two polymorphisms (rs371194629; 14bp INS/DEL and rs1063320; +3142 C/G) in paired tissue samples (tumoral and non-tumoral) from 107 Spanish patients with gastric adenocarcinoma and 58 healthy control individuals, to assess the possible association of the HLA-G gene with gastric adenocarcinoma susceptibility, disease progression and survival. The presence of somatic mutations involving these polymorphisms was also analyzed. The frequency of the 14bp DEL allele was increased in patients (70.0%) compared to controls (57.0%, p=0.025). In addition, the haplotype formed by the combination of the 14bp DEL/+3142 C variants is also increased in patients (54.1% vs 44.4%, p=0.034, OR=1.74 CI95% 1.05-2.89). Kaplan-Meier analysis revealed that 14bp DEL/DEL patients showed lower 5-year life-expectancy than INS/DEL or INS/INS (p=0.041). Adjusting for TNM staging (Cox regression analysis) disclosed a significant difference in death risk (p=0.03) with an expected hazard 2.6 times higher. Finally, no somatic mutations were found when comparing these polymorphisms in tumoral vs non-tumoral tissues, which indicates that this is a preexisting condition in patients and not a de novo, tumor-restricted, event. In conclusion, the variants predominant in patients were those increasing HLA-G mRNA stability and HLA-G expression, clearly involving this molecule in gastric adenocarcinoma susceptibility, disease progression and survival and making it a potential target for immunotherapeutic approaches.

SUBMITTER: Vaquero-Yuste C

PROVIDER: S-EPMC8453083 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB, AKT)/mammalian target of rapamycin (mTOR) signaling pathway plays a critical role in angiogenesis and cell growth, proliferation, metabolism, migration, differentiation, and apoptosis. Genetic diversity in key factors of this pathway may influence protein function and signal transduction, contributing to disease initiation and progression. Studies suggest that MTOR rs1064261 and AKT rs1130233 polymorphisms are associated with risk and/or prognosis of multiple cancer types. However, this relationship with gastric cancer (GC) remains unclear. The aim of this study was to investigate the role of MTOR and AKT polymorphisms in the risk and prognosis of GC.MethodsThe Sequenom MassARRAY platform was used to genotype 1842 individuals for MTOR rs1064261 T→C and AKT rs1130233 G→A polymorphisms. ELISA was used to detect Helicobacter pylori antibodies in serum. Immunohistochemical analysis was used to detect total and phosphorylated MTOR and AKT proteins.ResultsThe MTOR rs1064261 (TC+CC) genotype and the AKT rs1130233 (GA+AA) genotype were associated with increased risk of GC in men (P = 0.049, P = 0.030). In H. pylori-negative individuals, the AKT rs1130233 GA and (GA+AA) genotypes were related to increased risk of atrophic gastritis (AG; P = 0.012, P = 0.024). Notably, the AKT rs1130233 (GA+AA) genotype demonstrated significant interactions with H. pylori in disease progression from healthy controls (CON) to AG (P = 0.013) and from AG to GC (P = 0.049). Additionally, for individuals with the AKT rs1130233 variant, those in the H. pylori-positive group had higher levels of phosphorylated AKT (p-AKT) expression. The AKT rs1130233 genotype was found to be associated with clinicopathological parameters including lymph node metastasis and alcohol drinking (P<0.05).ConclusionMTOR rs1064261and AKT rs1130233 polymorphisms were associated with increased GC risk in males and increased AG risk in H. pylori-negative individuals. A significant interaction existed between the AKT rs1130233 genotype and H. pylori infection in CON→AG→GC disease progression. The AKT rs1130233 genotype influenced p-AKT protein expression in H. pylori-infected individuals.

Project description:Objective:To reveal the distribution signature of cancer susceptibility genes in patients with gastric adenocarcinoma, offering a diagnostic and prognostic surrogate for disease risk management and therapeutic decisions. Methods:A total of 282 patients with gastric adenocarcinoma (182 males and 100 females) were enrolled in this study, with peripheral blood genomic DNA extracted. Mutations of 69 canonical cancer susceptibility genes or presumably tumor-related genes were analyzed by targeted capture-based high-throughput sequencing. Candidate mutations were particularly selected for discussion on tumor pathogenesis according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Results:In this study, 7.1% (20/282) of patients with gastric adenocarcinoma were found to harbor mutations of canonical or presumable cancer susceptibility genes. The detection rate in male patients (3.8%, 7/182) was significantly lower than that in female patients (13%, 13/100) (P=0.004). The most recurrent mutations were in A-T mutated (ATM) (1.1%, 3/282), followed by BRCA1, BRIP1 and RAD51D, all showed a detection rate of 0.7% (2/282). Mutations in three genes associated with hereditary gastric cancer syndromes were detected, namely, PMS2 and EPCAM associated with Lynch syndrome and CDH1 associated with hereditary diffuse gastric cancer. The detection frequencies were all 0.4% (1/282). Notwithstanding no significant difference observed, the age of patients with pathogenic mutations or likely pathogenic mutations is slightly younger than that of non-carriers (median age: 58.5 vs. 60.5 years old), while the age of patients with ATM mutations was the youngest overall (median age: 49.3 years old). Conclusions:Our study shed more light on the distribution signature and pathogenesis of mutations in gastric cancer susceptibility genes, and found the detection rate of pathogenic and likely pathogenic mutations in male patients was significantly lower than that in female patients. Some known and unidentified mutations were found in gastric cancer, which allowed us to gain more insight into the hereditary gastric cancer syndromes from the molecular perspective.

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HLA-G 3'UTR Polymorphisms Are Linked to Susceptibility and Survival in Spanish Gastric Adenocarcinoma Patients.

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