Abstract
BackgroundTelomere length shortening in Helicobacter pylori (H. pylori) infected gastric mucosa constitutes the earliest steps toward neoplastic transformation. In addition to this genotoxic changes, epigenetic changes such as promoter CpG island (PCGI) methylation are frequently occurred in H. pylori infected gastric mucosa. The aim of this study was to investigate a potential link between H. pylori related PCGI methylation and telomere length shortening in the human gastric mucosa.MethodsTelomere length was measured in non-neoplastic gastric mucosa from 106 cancer-free subjects. To identify H. pylori related PCGI methylation, bisulfite pyrosequencing was used to quantify the methylation of 49 PCGIs from 47 genes and LINE1 repetitive elementResultsWe identified five PCGIs (IGF2, SLC16A12, SOX11, P2RX7 and MYOD1), which the methylation is closely associated with H. pylori infection. Hypermethylation of all these PCGIs was associated with development of pathological state from normal to mild, active, and atrophic gastritis (P<0.001) and lower pepsinogen I/II ratio (P<0.05), an indicator for gastric mucosal atrophy. Telomere shortening was significantly associated with mean Z score methylation of five PCGIs (R=−0.39, P<0.0001) and four of these locus (IGF2: R=−0.35, P=0.0003, SLC16A12: R=−0.35, P=0.0002, P2RX7: R=−0.29, P=0.003, and MYOD1: R=−0.33, P=0.0005). Multivariate analysis revealed that telomere shortening held an increased risk for hypermethylation (odds ratio: 1.71, 95% confidence interval: 1.11-2.63, P=0.016).ConclusionPotential link between H. pylori related PCGI methylation and telomere shortening emphasize the importance of genotoxic-epigenetic interaction in the pathological state of H. pylori infected gastric mucosa.
Highlights
Telomeres consist of repetitive nucleotide sequences and an associated terminal protein complex that help avoid loss of chromosomal integrity [1]
Helicobacter pylori (H. pylori) infected gastric mucosa is characterized as chronic inflammation [11, 12], which is closely linked with telomere length shortening [13, 14]
To explore hyper methylated promoter CpG island (PCGI) in H. pylori positive gastric mucosa, we initially performed unsupervised hierarchical clustering analysis of 49 PCGIs and LINE1 among six H. pylori negative and six positive cases (Figure 1). This analysis showed that all H. pylori positive gastric mucosa was clearly clustered as hyper methylated samples compared with the H. pylori negative mucosa
Summary
Telomeres consist of repetitive nucleotide sequences and an associated terminal protein complex that help avoid loss of chromosomal integrity [1]. Helicobacter pylori (H. pylori) infected gastric mucosa is characterized as chronic inflammation [11, 12], which is closely linked with telomere length shortening [13, 14]. These facts suggest that shortened telomere constitutes the earliest steps toward neoplastic transformation relevant to gastric cancer predisposition. Telomere length shortening in Helicobacter pylori (H. pylori) infected gastric mucosa constitutes the earliest steps toward neoplastic transformation In addition to this genotoxic changes, epigenetic changes such as promoter CpG island (PCGI) methylation are frequently occurred in H. pylori infected gastric mucosa. The aim of this study was to investigate a potential link between H. pylori related PCGI methylation and telomere length shortening in the human gastric mucosa
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