Abstract
BackgroundMeasuring the DNA methylome may offer the opportunity to identify novel disease biomarkers and insights into disease mechanisms. Although aberrant DNA methylation has been investigated in many human cancers and precancerous lesions, the DNA methylation landscape of gastric cardiac intestinal metaplasia (IM) remains unknown. Therefore, we aimed to investigate the genome-wide DNA methylation landscape and to search for potential epigenetic biomarkers of gastric cardiac IM.MethodsHistopathologic profiling was performed on a total of 118 gastric cardiac biopsies from cancer-free individuals. Genome-wide DNA methylation analysis was performed on 11 gastric cardiac mucosal biopsies (IM = 7; normal = 4) using Illumina 850K microarrays. Transcriptional relevance of any candidate epigenetic biomarker was validated by qRT-PCR.ResultsThe detection rate of gastric cardiac IM was 23% (27/118) in cancer-free individuals. Genome-wide DNA methylation profiling showed a global decrease in methylation in IM compared with normal tissues (median methylation = 0.64 and 0.70 for gastric cardiac IM and normal tissues, respectively). Differential methylation analysis between gastric cardiac IM and normal tissues identified 38,237 differentially methylated probes (DMPs) with a majority of sites showing hypermethylation in IM compared with normal tissues (56.3% vs. 43.7%). Subsequent analysis revealed a significant enrichment of hypermethylated DMPs in promoter and CpG islands (p < 0.001 for both, Pearson χ2 test). For DMPs located in promoter CpG islands showing extreme hypermethylation, the candidate gene with the largest number of DMPs (n = 7) was mapped to HOXA5. Accordingly, mRNA expression of HOXA5 was significantly reduced in IM compared to normal tissue.ConclusionsOur results suggest the implication of alterations in DNA methylation in gastric cardiac IM and highlight that HOXA5 hypermethylation may be a promising epigenetic biomarker, emphasizing the role of aberrant HOXA5 expression in the pathogenesis of gastric cardiac IM.
Highlights
Measuring the DNA methylome may offer the opportunity to identify novel disease biomarkers and insights into disease mechanisms
By comparing with normal tissue, we found that the HOXA5 gene exhibited both promoter hypermethylation and reduced mRNA expression in gastric cardiac intestinal metaplasia (IM)
Detection rate of gastric cardiac IM in cancer‐free individuals According to the overall study design (Fig. 1a), histologic studies were conducted in a total of 118 gastric cardiac mucosal biopsies from cancer-free individuals
Summary
Measuring the DNA methylome may offer the opportunity to identify novel disease biomarkers and insights into disease mechanisms. Aberrant DNA methylation has been investigated in many human cancers and precancerous lesions, the DNA methylation landscape of gastric cardiac intestinal metaplasia (IM) remains unknown. We aimed to investigate the genome-wide DNA methylation landscape and to search for potential epigenetic biomarkers of gastric cardiac IM. There is some controversy about this, the precancerous nature of IM is suggested by the observation that patients affected by IM have a higher risk of developing gastric cancer (GC) than those without IM. Barrett’s esophagus (BE), an intestinal metaplasia of the distal esophagus, has been reported to be a premalignant condition conferring an 11.3-fold (95% CI 8.8–14.4) increased risk for esophageal adenocarcinoma (EAC) [3]. Current knowledge of the underlying causes of IM is still incomplete
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