Genetic Variations in Prostaglandin E2 Pathway Identified as Susceptibility Biomarkers for Gastric Cancer in an Intermediate Risk European Country

Abstract

The cyclooxygenase-2 (COX-2)/prostaglandin E₂ (PGE₂) pathway exerts deleterious pleiotropic effects in inflammation-induced gastric carcinogenesis. We aimed to assess the association of genetic variants in prostaglandin-endoperoxide synthase 2 (PTGS2), ATP binding cassette subfamily C member 4 (ABCC4), hydroxyprostaglandin dehydrogenase 15-(NAD) (HPGD), and solute carrier organic anion transporter family member 2A1 (SLCO2A1) PGE₂ pathway-related genes with gastric cancer (GC) risk in a European Caucasian population. A hospital-based case-control study gathering 260 GC cases and 476 cancer-free controls was implemented. Using a tagSNP approach, 51 single nucleotide polymorphisms (SNPs) were genotyped through MassARRAY^® iPLEX Gold Technology or allelic discrimination by real-time polymerase chain reaction (PCR). Homozygous carriers of the minor allele for both rs689466 and rs10935090 SNPs were associated with a 2.98 and 4.30-fold increased risk for GC, respectively (95% confidence interval (CI): 1.14-7.74, p = 0.027; 95% CI: 1.22-15.16, p = 0.026), with the latter also being associated with an anticipated diagnosis age. A multifactor dimensionality reduction analysis identified an overall three-factor best interactive model composed of age, rs689466, and rs1678374 that was associated with a 17.6-fold GC increased risk (95% CI: 11.67-26.48, p < 0.0001, (cross-validation) CV consistency of 8/10 and accuracy of 0.807). In this preliminary study, several tagSNPs in PGE₂ pathway-related genes were identified as risk biomarkers for GC development. This approach may help to identify higher-risk individuals and may contribute to the tailoring screening of GC in intermediate-risk European countries.

Keywords: ATP binding cassette subfamily C member 4; gastric cancer; genetic susceptibility; hydroxyprostaglandin dehydrogenase 15-(NAD); prostaglandin E2; prostaglandin-endoperoxide synthase 2; solute carrier organic anion transporter family member 2A1.

Figure 1

(A) Hydroxyprostaglandin dehydrogenase 15-(NAD) (HPGD) mRNA relative expression considering the genotypes of the rs2303520 G>A polymorphism. In “normal”-appearing mucosa, the GA genotype is associated with HPGD mRNA downregulation by a mean factor of 0.67. Lines represent median values of expression. (B) Solute carrier organic anion transporter family member 2A1 (SLCO2A1) mRNA relative expression considering the genotypes of the rs11915399 C > T polymorphism. In “normal”-appearing mucosa, the TT genotype is associated with SLCO2A1 mRNA upregulation compared to the CC genotype and the carriers of the C allele by a mean factor of 1.63 and 1.67, respectively. Lines represent median values of expression. * p < 0.05; ** p < 0.01.