Search

The present study was conducted to clarify the cooperative significance of epigenomic and genomic abnormalities during gastric carcinogenesis. Using 21 samples of normal control gastric mucosa (C), 109 samples of non-cancerous gastric mucosa (N) and 105 samples of cancerous tissue (T) from 109 patients with primary gastric adenocarcinomas, genome-wide DNA methylation analysis was performed using Infinium assay. Among these samples, 66 paired N and corresponding T samples were subjected to whole-exome and single nucleotide polymorphism array analyses. As had been shown in our previous study, 109 patients were clustered clinicopathologically into least aggressive Cluster A (n = 20), most aggressive Cluster B1 (n = 20) and Cluster B2 (n = 69). Most DNA methylation alterations in each cluster had already occurred even in N samples compared with C samples, and DNA methylation alterations at the precancerous N stage were inherited by the established cancers themselves. Recurrent single nucleotide variants and insertions/deletions resulting in functional disruption of the proteins encoded by the ABCA10, BNC2, CDH1, CTNNB1, SMAD4 and VAV2 genes were specific to Cluster B1, whereas those of the APC, EGFR, ERBB2, ERBB3, MLH1 and MUC6 genes were specific to Cluster A. MetaCore pathway analysis revealed that the epigenomically affected TWIST1 gene and genomically affected CDH1, CTNNB1, MMP9, TLN2, ROCK1 and SMAD4 genes were accumulated in signaling pathways related to cell adhesion, cytoskeleton remodeling and epithelial-mesenchymal transition in Cluster B1. These data indicate that epigenomic alterations at the precancerous stage are important in gastric carcinogenesis and that epigenomic and genomic alterations cooperatively underlie the aggressiveness of gastric adenocarcinomas., (© The Author(s) 2020. Published by Oxford University Press.)

Background & Aims: Two major types of gastric cancer, intestinal and diffuse, develop through distinct mechanisms; the diffuse type is considered to be more influenced by genetic factors, although the mechanism is unknown. Our previous genome-wide association study associated 3 single nucleotide polymorphisms (SNPs) with diffuse-type gastric cancer (DGC); 1 was a functional SNP (rs2294008) in prostate stem cell antigen (PSCA), but the loci of the other 2 were not investigated., Methods: We performed high-density mapping to explore a linkage disequilibrium status of the 2 SNPs at chromosome 1q22. A DGC case-control study was conducted using DNA from 606 cases and 1264 controls (all Japanese individuals) and validated using DNA from Japanese (304 cases, 1465 controls) and Korean (452 cases, 372 controls) individuals. The effects of SNPs on function were analyzed by reporter assays and analyses of splice variants., Results: A region of a strong linkage disequilibrium with the 2 SNPs contained mucin 1 (MUC1) and other 4 genes and SNPs significantly associated with DGC (rs2070803: P = 4.33 × 10(-13); odds ratio [OR], 1.71 by meta-analysis of the studies on the 3 panels) but not with intestinal-type gastric cancer. Functional studies demonstrated that rs4072037 (P = 1.43 × 10(-11); OR, 1.66 by meta-analysis) in MUC1 affects promoter activity and determines the major splicing variants of MUC1 in the gastric epithelium. Individuals that carry both SNPs rs2294008 in PSCA and rs4072037 in MUC1 have a high risk for developing DGC (OR, 8.38)., Conclusions: MUC1 is the second major DGC susceptibility gene identified. The SNPs rs2070803 and rs4072037 in MUC1 might be used to identify individuals at risk for this type of gastric cancer., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Gastric cancer is classified into intestinal and diffuse types, the latter including a highly malignant form, linitis plastica. A two-stage genome-wide association study (stage 1: 85,576 SNPs on 188 cases and 752 references; stage 2: 2,753 SNPs on 749 cases and 750 controls) in Japan identified a significant association between an intronic SNP (rs2976392) in PSCA (prostate stem cell antigen) and diffuse-type gastric cancer (allele-specific odds ratio (OR) = 1.62, 95% CI = 1.38-1.89, P = 1.11 x 10(-9)). The association was far less significant in intestinal-type gastric cancer. We found that PSCA is expressed in differentiating gastric epithelial cells, has a cell-proliferation inhibition activity in vitro and is frequently silenced in gastric cancer. Substitution of the C allele with the risk allele T at a SNP in the first exon (rs2294008, which has r(2) = 0.995, D' = 0.999 with rs2976392) reduces transcriptional activity of an upstream fragment of the gene. The same risk allele was also significantly associated with diffuse-type gastric cancer in 457 cases and 390 controls in Korea (allele-specific OR = 1.90, 95% CI = 1.56-2.33, P = 8.01 x 10(-11)). The polymorphism of the PSCA gene, which is possibly involved in regulating gastric epithelial-cell proliferation, influences susceptibility to diffuse-type gastric cancer.