Assosiation Between Methylation Status in Gastric Mucosa and Gastric Cancer Development and Progression

Introduction: CpG island hyper methylation (CIHM) status provides a distinct clinicopathological feature of gastric cancer (GC). We investigated the association between the CIHM of four highly susceptible loci and GC. Methods: Paired samples of GC tissues and adjacent normal mucosa in GC patients as well as control samples from 180 non-GC subjects were obtained. CIHM of p14, p16, CDH1 and DAP-kinase (DAPK) genes were determined by Methylation Specific PCR. CIHM high was defined as when three or all CpG islands methylated. Result: Rates of CIHM of p14, CDH1, DAPK, and high CIHM in non-cancer mucosa were significantly higher in GC patients than in non-GC patients (p14: 32.2 vs. 50.4%; OR: 1.70, 95% CI 1.03-2.80, CDH1: 36.1 vs. 84.0%; OR: 8.65, 95% CI 14.74-15.77, DAPK: 42.2 vs. 83.2%; OR: 5.98, 95% CI 3.37-10.62 and high CIHM: 44.4 vs. 80.8%; OR: 4.40, 95% CI 2.51-7.72). CIHM in CDH1 and DAPK were associated with a greater risk of GC including all of its different subtypes. In comparison of a paired sample in GC patients, frequencies of CIHM of p16, CDH1, and high CIHM were decreased in cancer tissues than in normal mucosa. Mean methylation number in the cancer tissue was also decreased. Decreased CIHM of p14, CDH1, and high CIHM were associated with advanced stage, lymphatic invasion, venous invasion, lymph node metastasis, peritoneal dissemination and distant metastasis. When dividing GC by mean methylation number into Type A (increased methylation number in GC tissues), Type B (no change in methylation number) and Type C (decreased methylation number in GC tissues), aggressive phenotypes of GCs presented lower prevalence of Type A, and higher prevalence of Type B and C. Conclusion: CIHM in non-neoplastic mucosa corresponded to a risk of GC, while it is suggested that CIHM may occur earlier in the gastric mucosa, then decrease during GC development and progression.