Abstract
Promoter methylation (PM) of RING-finger protein (RNF) 180 affects gastric cancer (GC) prognosis, but its association with risk of GC or atrophic gastritis (AG) is unclear. We investigated relationships between RNF180 PM and GC or AG, and the effects of Helicobactor pylori (H.pylori) infection on RNF180 PM. This study included 513 subjects (159 with GC, 186 with AG, and 168 healthy controls [CON]) for RNF180 PM analysis, and another 55 GC patients for RNF180 gene expression analysis. Methylation was quantified using average methylation rates (AMR), methylated CpG site counts (MSC) and hypermethylated CpG site counts (HSC). RNF180 promoter AMR and MSC increased with disease severity. Optimal cut-offs were GC + AG: AMR > 0.153, MSC > 4 or HSC > 1; GC: AMR > 0.316, MSC > 15 and HSC > 6. Hypermethylation at 5 CpG sites differed significantly between GC/AG and CON groups, and was more common in GC patients than AG and CON groups for 2 other CpG sites. The expression of RNF180 mRNA levels in tumor were significantly lower than those in non-tumor, with the same as in hypermethylation than hypomethylation group. H.pylori infection increased methylation in normal tissue or mild gastritis, and increased hypermethylation risk at 3 CpG sites in AG. In conclusion, higher AMR, MSC and HSC levels could identify AG + GC or GC. Some RNF180 promoter CpG sites could identify precancerous or early-stage GC. H.pylori affects RNF180 PM in normal tissue or mild gastritis, and increases hypermethylation in 3 CpG sites in AG.
Highlights
Aberrant CpG island methylation, especially in promoter regions of tumor suppressor genes, is related to tumorigenesis
The results show average methylation rates (AMR) in the RNF180 promoter to increase with disease severity, such that control group (CON) < atrophic gastritis (AG) < gastric cancer (GC) (GC vs. AG: P < 0.021; AG vs. CON: P < 0.001; Figure 1A)
We evaluated the validity of RNF180 promoter area AMR in distinguishing AG or GC from controls, by Receiver operating characteristic (ROC) curves
Summary
Aberrant CpG island methylation, especially in promoter regions of tumor suppressor genes, is related to tumorigenesis. RUNX3 promoter methylation (PM) is related to esophageal squamous cell carcinoma [1]. Relationships between the PM of tumor suppressor genes and carcinoma risk have attracted much attention in methylation research [6, 7]. Interesting, new gene (RING) Finger (RNF) is a family of ubiquitin ligases that function as tumor suppressors [8,9,10]. The PM status of RNF180 is known to affect GC prognosis [12,13,14]; its effect on risk of GC, or on its most important precancerous state, atrophic gastritis (AG), remain unclear
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