Abstract
BackgroundEpigenetics, particularly DNA methylation, has recently been elucidated as important in gastric cancer (GC) initiation and progression. We investigated the clinical and prognostic importance of whole blood global and site-specific DNA methylation in GC.MethodsGenomic DNA was extracted from the peripheral blood of 105 Omani GC patients at diagnosis. DNA methylation was quantified by pyrosequencing of global DNA and specific gene promoter regions at 5 CpG sites for CDH1, 7 CpG sites for p16, 4 CpG sites for p53, and 3 CpG sites for RUNX3. DNA methylation levels in patients were categorized into low, medium, and high tertiles. Associations between methylation level category and clinicopathological features were evaluated using χ2 tests. Survival analyses were carried out using the Kaplan-Meier method and log rank test. A backward conditional Cox proportional hazards regression model was used to identify independent predictors of survival.ResultsOlder GC patients had increased methylation levels at specific CpG sites within the CDH1, p53, and RUNX-3 promoters. Male gender was significantly associated with reduced global and increased site-specific DNA methylation levels in CDH1, p16, and p53 promoters. Global DNA low methylation level was associated with better survival on univariate analysis. Patients with high and medium methylation vs. low methylation levels across p16 promoter CpG sites, site 2 in particular, had better survival. Multivariate analysis showed that global DNA hypermethylation was a significant independent predictor of worse survival (hazard ratio (HR) = 2.0, 95% CI: 1.1–3.8; p = 0.02) and high methylation mean values across p16 promoter sites 1–7 were associated with better survival with HR of 0.3 (95% CI, 0.1–0.8; p = 0.02) respectively.ConclusionsAnalysis of global and site-specific DNA methylation in peripheral blood by pyrosequencing provides quantitative DNA methylation values that may serve as important prognostic indicators.
Highlights
Gastric cancer (GC) is a common malignancy that is a leading cause of cancer mortality worldwide [1]
Studies have recently begun to elucidate the role of epigenetics, in particular DNA methylation, in gastric cancer (GC) initiation and progression [9,10,11]
CDH1 promoter hypermethylation frequently occurs in gastric carcinomas with a diffuse histotype and is significantly associated with down-regulated E-cadherin expression [15]
Summary
Gastric cancer (GC) is a common malignancy that is a leading cause of cancer mortality worldwide [1]. GC has been linked to Helicobacter infection and environmental exposures including: smoking, salted fish, and low intake of fruit and vegetables [2,3,4,5] While these exposures are very common, very few exposed individuals develop GC. Global DNA hypomethylation is associated with genomic instability, while DNA hypermethylation at CpG islands in or near gene promoter regions is associated with gene ‘‘silencing’’ [10,12,13]. Global genomic DNA methylation in cancerous gastric tissues has been found to be significantly lower than in non-cancerous tissues and shows a gradual increase in hypomethylation from normal gastric mucosa to chronic atrophic gastritis, severe, and intestinal metaplasia [10,12,13]. Epigenetics, DNA methylation, has recently been elucidated as important in gastric cancer (GC) initiation and progression.
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