PGC TagSNP and Its Interaction with H. pylori and Relation with Gene Expression in Susceptibility to Gastric Carcinogenesis

Abstract

BackgroundPepsinogen C (PGC) plays an important role in sustaining the cellular differentiation during the process of gastric carcinogenesis. This study aimed to assess the role of PGC tagSNPs and their interactions with Helicobacter pylori (H. pylori) in the development of gastric cancer and its precursor, atrophic gastritis.MethodsFour PGC tagSNPs (rs6941539, rs6912200, rs3789210 and rs6939861) were genotyped by Sequenom MassARRAY platform in a total of 2311 subjects consisting of 642 gastric cancer, 774 atrophic gastritis, and 895 healthy control subjects. The mRNA and protein expression levels of PGC in gastric tissues and in serum were respectively measured by quantitative reverse transcriptase–polymerase chain reaction (qRT-PCR), immunohistochemistry, and Eenzyme-linked immunoabsorbent assay (ELISA).ResultsWe found associations between PGC rs3789210 CG/GG genotypes and reduced gastric cancer risk and between PGC rs6939861 A variant allele and increased risks of both gastric cancer and atrophic gastritis. As for the haplotypes of PGC rs6941539-rs6912200-rs3789210-rs6939861 loci, the TTCA and TTGG haplotypes were respectively associated with increased and reduced risks of both gastric cancer and atrophic gastritis; additionally, the CTCA haplotype was associated with increased atrophic gastritis risk. Very interestingly, rs6912200 CT/TT genotypes had a positive interaction with H. pylori, synergistically elevating the gastric cancer risk. Moreover, healthy subjects who carried rs6912200 CT, TT and CT/TT variant genotypes had lower histological and serum expression levels of PGC protein.ConclusionsOur findings highlight an important role of PGC rs3789210 and rs6939861 in altering susceptibility to atrophic gastritis and/or gastric cancer. Moreover, people who carry rs6912200 variant genotypes exhibit higher gastric cancer risk in case of getting H. pylori infection, which strongly suggest a necessity of preventing and/or eliminating H. pylori infection in those individuals.

Association of Polymorphisms in three pri-miRNAs that Target Pepsinogen C with the Risk and Prognosis of Gastric Cancer

“…The expression of PGC protein decreased gradually with gastric disease progression11. Our previous studies showed that a PGC polymorphism was also associated with gastric cancer and atrophic gastritis293031. It is well accepted that gene–gene interactions are more important than single genes in promoting cancer susceptibility323334.…”

“…After admission, endoscopic biopsy and tissue pathology diagnosis were carried out. Patient data (including age, gender, smoking and drinking habits) were recorded and have been published previously29. For the prognosis study, we selected subjects who underwent surgical treatment and were subjected to regular follow-up; ultimately, 357 gastric cancer patients with complete clinical pathology data were studied.…”

“…DNA was extracted from the patients’ venous blood, and Sequenom’s MassArray system was used to conduct polymorphism typing in all cases29. Repeated verification (Sequenom’s MassArray system) was performed for 10% of cases and the repetition rate was >99%.…”

SNP interactions of PGC with its neighbor lncRNAs enhance the susceptibility to gastric cancer/atrophic gastritis and influence the expression of involved molecules

“…First, a two‐step approach was employed to select tagSNPs for PGC, which was described in our previous studies . Then, we focused on the lncRNA genes nearby PGC using Ensembl genome browser, approximately encompassing 3 Mb of upstream and downstream flanking sequences of PGC.…”

“…PGC protein, encoded by the pepsinogen C (PGC) gene, is a specific marker in the terminal differentiation of gastric mucosa, of which the aberrant expression occurs in many gastric diseases . Our research group previously found PGC polymorphisms could affect the susceptibility to atrophic gastritis (AG) and gastric cancer (GC) . Interestingly, several SNPs in long noncoding RNA (lncRNA) genes, just adjacent to PGC, were found to be associated with AG risk and GC prognosis afterward .…”