Abstract
The chronic inflammatory microenvironment and immune cell dysfunction have been described as critical components for gastric tumor initiation and progression. The diffuse subtype is related to poor clinical outcomes, pronounced inflammation, and the worst prognosis. We investigated the association of polymorphisms in inflammatory response-related genes (COX-2, OGG1, TNFB, TNFA, HSPA1L, HSPA1B, VEGFA, IL17F, LGALS3, PHB, and TP53) with gastric cancer susceptibility, progression and prognosis in a Brazilian sample, focusing on the diffuse subtype. We also performed the analysis regarding the total sample of cases (not stratified for tumor subtypes), allowing the comparison between the findings. We further investigated the polymorphisms in linkage disequilibrium and performed haplotype association analyses. In the case-control study, rs1042522 (TP53) was associated with a stronger risk for developing gastric cancer in the sample stratified for diffuse subtype patients when compared to the risk observed for the total cases; CTC haplotype (rs699947/rs833061/rs2010963 VEGFA) was associated with risk while rs699947 was associated with protection for gastric malignancy in the total sample. Regarding the associations with the clinicopathological features of gastric cancer, for the diffuse subtype we found that rs699947 and rs833061 (VEGFA) were associated with outcomes related to a worse progression while rs5275 (COX-2), rs909253 (TNFB), and rs2227956 (HSPA1L) were associated to a better progression of the disease. In the total sample, rs699947 and rs833061 (VEGFA), rs4644 (LGALS3), and rs1042522 (TP53) were able to predict a worse progression while rs5275 (COX-2), rs2227956 (HSPA1L), and rs3025039 (VEGFA) a better progression. Besides, rs909253 (TNFB) predicted protection for the overall and disease-free survivals for gastric cancer. In conclusion, these results helped us to clarify the potential role of these polymorphisms in genes involved in the modulation of the inflammatory response in the pathogenesis of gastric cancer.
Highlights
Gastric cancer is the fifth most common malignancy and the third leading cause of death due to cancer worldwide [1]
All the association analyses were carried out considering the sample stratified for the diffuse subtype and were compared to the results regarding the total sample of cases (N = 178)
Results of Hardy-Weinberg Equilibrium (HWE) deviation and the genotypic and allelic frequency distributions of the 16 studied genetic variants are presented in Table 1, together with the detailed description of the polymorphisms and their corresponding genes, including other nomenclatures, genomic coordinate, amino acid change, genotypes, Minor allele frequency (MAF) described in 1000 Genome Project, and Exome Aggregation Consortium (ExAC) databases
Summary
Gastric cancer is the fifth most common malignancy and the third leading cause of death due to cancer worldwide [1]. In Brazil, the National Cancer Institute (INCA) estimated around 21,290 new cases for 2018–2019 [2]. This disease has multifactorial etiology and molecular complexity, including. Gastric tumors are mostly adenocarcinomas and present high heterogeneity, which is mainly due to architecture and growth, cell differentiation, histogenesis, and molecular pathogenesis [4]. The most common histopathological classification widely used in clinical practice distinguishes two main subtypes of gastric adenocarcinoma: Diffuse and intestinal subtypes of Lauren [5]. The diffuse subtype is poorly differentiated, characterized by the lack of tumor cellular cohesion in the absence of gland formation [4]
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