Genes associated with susceptibility to gastric cancer

Abstract

A case-control association study based on candidate gene approaches was performed to search for gastric cancer genes. The 524 SNPs selected from 98 candidate genes were initially genotyped with pooled DNA and 62 SNPs with 5\%-point allele frequency difference or more between cases and controls were identified. Then the subsequent individual genotyping with 430 unrelated gastric cancer patients and 406 healthy controls revealed two genes significantly associated with susceptibility to gastric cancer. The rs869736 located at position -309 of the PTPRCAP promoter was associated with susceptibility to diffuse-type gastric cancer. The minor allele homozygote was significantly associated with a 2.5-fold increased susceptibility to diffuse-type gastric cancer (P = 0.0021, n = 252), but not to intestinal-type (P = 0.30, n = 178), versus the major allele homozygote. Nine other SNPs were in nearly perfect linkage disequilibrium ($r^2$ ≥ 0.97) with rs869736, exhibiting the same association, and spread out for 26 kb on 11q13 covering PTPRCAP, RPS6KB2, CORO1B, and GPR152. Among the four genes, however, only PTPRCAP expression was affected by haplotypes of the 10 SNPs. Endogenous transcript levels of PTPRCAP were linearly correlated with copy numbers (zero, one, and two) of the risk-haplotype (P = 0.0060) in 12 lymphoblastoid cells derived from blood samples, but those of the other three genes were not. Furthermore, the cancer-risk, minor allele T of rs869736 increased both promoter activity and specific nuclear protein-binding affinity than the nonrisk, major allele G in luciferase reporter and electrophoretic mobility shift assays, respectively. Accordingly, the minor allele of rs869736 in the PTPRCAP promoter is associated with increased susceptibility to diffuse-type gastric cancer by increasing PTPRCAP expression, possibly leading to activation of the oncogenic Src family kinases. On the other hand, SNPs in VCAN were specifically associated with intestinal-type gas...