Genetic factors related to gastric cancer susceptibility identified using a genome-wide association study

Abstract

Gastric cancer (GC) is one of the major malignant diseases worldwide, especially in Asia, where Japan and Korea have the highest incidence in the world. Gastric cancer is classified into intestinal and diffuse types. While the former is almost absolutely caused by Helicobacter pylori infection as the initial insult, the latter seems to include cases in which the role of infection is limited, if any, and a contribution of genetic factors is anticipated. Previously, we performed a genome-wide association study (GWAS) on diffuse-type GC by using single nucleotide polymorphisms (SNP) catalogued for Japanese population (JSNP), and identified a prostate stem cell antigen (PSCA) gene encoding a glycosylphosphatidylinositol-anchored cell surface antigen as a GC susceptibility gene. From the second candidate locus identified using the GWAS, 1q22, we found the Mucin 1 (MUC1) gene encoding a cell membrane-bound mucin protein as another gene related to diffuse-type GC. A two-allele analysis based on risk genotypes of the two genes revealed approximately 95% of Japanese population have at least one of the two risk genotypes, and approximately 56% of the population have both risk genotypes. The two-SNP genotype might offer ample room to further stratify a high GC risk subpopulation in Japan and Asia by adding another genetic and/or non-genetic factor. Recently, a GWAS on the Chinese population disclosed an additional three GC susceptibility loci: 3q13.31, 5p13.1 and 10q23.

Figure 1

Prostate stem cell antigen (PSCA) and Mucin 1 (MUC1) genotypes are associated with risk for diffuse‐type gastric cancer (DGC). Association studies were performed with a distinct model for each risk allele's effect, dominant for rs2294008 (risk genotype: TT and TC; protective genotype: CC) and recessive for rs4072037 (risk genotype: AA; protective genotype: GG and GA), using genotype data of rs2294008 in PSCA and rs4072037 in MUC1 (Japanese 605 DGC cases and 1264 controls). Bar, upper bound of 95% confidence interval.

Figure 2

Prostate stem cell antigen (PSCA) regulates proliferation of pre‐pit cells in gastric epithelium? (a) PSCA is mainly expressed in the epithelium in the middle portion, the isthmus and neck regions, of the gastric gland (immunohistochemical double stain; blue for PSCA and brown for proliferating cell nuclear antigen). Together the two regions are called the isthmus/neck region as the boundary between the two regions is often ambiguous. Weak PSCA expression is also observed in the epithelium of the pit region. (b) The isthmus/neck region harbors pre‐pit cells, a precursor of pit cells, which are rapidly proliferating to compensate for rapid turnover of pit cells. It is hypothesized that PSCA regulates proliferation of pre‐pit cells, which also contributes to prevention of carcinogenesis in the epithelium.

Figure 3

Single nucleotide polymorphism (SNP) rs4072037 determines the major splicing variants expressed in the gastric mucosa. In the gastric mucosa, major splicing forms were variant 2 (NM_001018016) and variant 3 (NM_001018017). The allele of SNP rs4072037 is related to the splicing acceptor site selection in the second exon (upper panel). Nucleotide sequences of the first/second exon boundary of Mucin 1 (MUC1) variants 2 and 3 revealed using RNA ligase‐mediated rapid amplification of the 5′ cDNA end on RNA samples from normal stomach and gastric cancer cell lines (lower panel).13 In the present study, all variant 2 transcripts containing the first 27 bp of the second exon (double‐headed red arrow) had a G allele at rs4072037, while all variant 3 lacking the 27 bp had A allele. This result is concordant with a previous report.55 It is anticipated that deletion of the 27 bp, corresponding to nine amino acids, changes cleavage sites (green arrows) of the signal peptide among the variants. One‐letter amino acid abbreviation is shown just below or above the second nucleotide of each codon.