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. 2016 Jul 12;7(28):43989-43996.
doi: 10.18632/oncotarget.9764.

Demonstration of potential link between Helicobacter pylori related promoter CpG island methylation and telomere shortening in human gastric mucosa

Tomomitsu Tahara  1 , Tomoyuki Shibata  1 , Masaaki Okubo  1 , Tomohiko Kawamura  1 , Noriyuki Horiguchi  1 , Takamitsu Ishizuka  1 , Naoko Nakano  1 , Mitsuo Nagasaka  1 , Yoshihito Nakagawa  1 , Naoki Ohmiya  1
Affiliations

Demonstration of potential link between Helicobacter pylori related promoter CpG island methylation and telomere shortening in human gastric mucosa

Tomomitsu Tahara et al. Oncotarget. .

Abstract

Background: 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.

Methods: Telomere 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 elementResults: We 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).

Conclusion: Potential 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.

Keywords: DNA methylation; H. pylori; gastric mucosa; gastritis; telomere length.

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Conflict of interest statement

We declare that we have no conflicts of interest.

Figures

Figure 1
Figure 1. Unsupervised hierarchical clustering analysis of 49 PCGIs and LINE1 repetitive element among six H. pylori negative (blue boxes) and six positive cases (red boxes)
Numbers listed above the blue and red boxes indicates sample ID.
Figure 2
Figure 2. Methylation status of five PCGIs (IGF2, SLC16A12, SOX11, P2RX7 and MYOD1) among all subjects with or without H. pylori infection
Horizontal bars represents mean methylation percentage. The statistical analysis was performed using Student's t-Test.
Figure 3
Figure 3. Association between telomere shortening and mean Z score methylation of five PCGIs (left) and methylation of LINE 1 repetitive element (right)
Statistical analysis was performed using the Spearman correlation analysis.
Figure 4
Figure 4. Association between telomere shortening and methylation status of five PCGIs (IGF2, SLC16A12, SOX11, P2RX7 and MYOD1) Statistical analysis was performed using the Spearman correlation analysis
See this image and copyright information in PMC

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