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 diffusetype 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 membranebound 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. (Cancer Sci 2013; 104: 1-8) G astric cancer (GC) is one of the major malignant diseases and the second causal of cancer death worldwide.(1) It is usually classified into two types, intestinal and diffuse, a classification which was originally based on histological observation but is recently thought to reflect its pathogenesis.(2) The majority of intestinal-type GC (IGC) arises in the sequence of inflammatory change of the gastric epithelium resulting from bacterial infection; Helicobacter pylori (HP) infectionchronic inflammation -intestinal metaplasia -dysplasia -adenocarcinoma. In contrast, de novo diffuse-type GC (DGC) is thought to emerge in a histologically almost normal epithelium as a consequence of some genetic change that occurred in gastric stem cells and/or epithelial precursor cells, although some cases with DGC might represent dedifferentiated stages of IGC, and a contribution of HP is also suggested.(3) In other words, it is apparent that the pathogenesis of IGC is initiated by HP infection, a class I carcinogen acknowledged by WHO, and therefore IGC is essentially a preventable disease by eradicating HP infection. However, DGC might develop earlier in life than IGC, (4) and no definite DGC-specific environmental risk factor has been established. Therefore, so far we have neither solid strategy nor promising theory to envision a consistent diminution of the incidence of DGC.The incidence of GC has strong geographical and ethnical characteristics. For example, it is one of the rare cancers in North America and Europe, while its incidence is s...

rs2294008T, a risk allele for gastric and gallbladder cancers, suppresses the PSCA promoter by recruiting the transcription factor YY1

“…In the Japanese and Korean populations, both of which have the highest incidence of GC in the world, T is the major allele, whereas it is a minor allele in other ethnic populations (Sakamoto et al 2008;Song et al 2011). The results of our previous study suggest that PSCA has a tumor-suppressive function in the pre-pit cells in the gastric epithelium, which are transit-amplifying cells that are highly proliferative for renewal of superficial mucous-secreting pit cells and the presumed origin of DGC (Sakamoto et al 2008;Saeki et al 2013). Our previous study also showed that rs2294008 is a functional SNP that influences the transcriptional activity of the PSCA promoter: The T allele significantly suppresses its transcriptional activity (Sakamoto et al 2008).…”

“…The T allele is a risk allele for GC and GBC in which PSCA is down-regulated rs2294008T was previously shown to be associated with GC and GBC (Sakamoto et al 2008;Matsuo et al 2009;Wu et al 2009;Lu et al 2010;Ou et al 2010;Lochhead et al 2011;Song et al 2011;Zeng et al 2011;Sala et al 2012;Rai et al 2013;Saeki et al 2013). In the Japanese and Korean populations, both of which have the highest incidence of GC in the world, T is the major allele, whereas it is a minor allele in other ethnic populations (Sakamoto et al 2008;Song et al 2011).…”

“…Moreover, the T allele is a major allele of rs2294008 in Japanese and Korean populations (Sakamoto et al 2008;Song et al 2011), which have a high incidence of GC, and is a minor allele in most other countries (Sakamoto et al 2008;Saeki et al 2013). More importantly, the association between the T allele and GC was showed in other studies and in other ethnic populations including Caucasians (Matsuo et al 2009;Wu et al 2009;Lu et al 2010;Ou et al 2010;Lochhead et al 2011;Song et al 2011;Zeng et al 2011;Sala et al 2012;Saeki et al 2013). These findings suggest that PSCA has tumor suppressor activity and that the T allele predisposes people to DGC development as a consequence of suppression of PSCA expression by the allele.…”

Macrophage-secreted Exosomes Delivering miRNA-21 Inhibitor can Regulate BGC-823 Cell Proliferation

“…Gastric cancer is a major malignant tumor type, representing the second most common cancer and the leading cause of cancer mortality worldwide. This is especially the case in Asia, with the highest incidence being found in China, Japan, and Korea (Ferlay et al, 2010;Saeki et al, 2013), and about 1,000,000 new cases every year (Yang, 2006). There is increased expression of miR-421, miR-21, miR-221/222, and miR-106a in gastric cancer, while the expression of miR-124a, miR-128b, miR-148, and miR-129 is reduced (Guo et al, 2009;Konishi et al, 2012).…”

MiR-421 Regulates Apoptosis of BGC-823 Gastric Cancer Cells by Targeting Caspase-3

“…However, it is estimated that 50% of gastric cancer cases especially in Asia, where China, Japan and Korea have the highest incidence in the world (Ferlay et al, 2010). (Saeki et al, 2013) revealed prostate stem cell antigen (PSCA) gene and Mucin 1 (MUC1) gene were related to human gastric cancer, additionally certain strains of H. pylori assisted by some of its virulence factors also play a critical role in gastric cancer development, which influence cellular proliferation signaling, the expression of cell proliferation regulating genes or the progression of gastric cancer (Kim et al, 2011), but successful therapeutic targets are limited. Thus, the molecular mechanisms of gastric cancer are of great importance and remain to be elucidated.…”