Promising aberrant DNA methylation marker to predict gastric cancer development in individuals with family history and long-term effects of H. pylori eradication on DNA methylation

Kim, Hee Jin; Kim, Nayoung; Kim, Hyung Woo; Park, Ji Hyun; Shin, Cheol Min; Lee, Dong Hoon

doi:10.1007/s10120-020-01117-w

Cited by 21 publications

(16 citation statements)

References 33 publications

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“…The relationship between H.pylori infection and methylation alterations can be further confirmed by anti-H.pylori intervention in addition to the case-control study. Some specific methylation changes (such as CDH1, COX-2, and LOX) were already reported in gastric mucosa after H.pylori eradication [23][24][25], which may be involved in gastric carcinogenesis. While no methylation alterations before and after eradication have been systemically evaluated both in gastric mucosa and in blood leukocyte.…”

Section: Discussionmentioning

confidence: 93%

Helicobacter pylori associated aberrant methylation genes in blood leukocyte and gastric mucosa

Zhang¹,

Chen²,

Ma³

et al. 2021

J. Cancer

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Background and Aim: Methylation alterations may be involved in Helicobacter pylori -associated gastric carcinogenesis. This study aims to explore the potential H.pylori- associated methylation biomarkers in blood leukocyte and gastric mucosa. Methods: Five candidate H.pylori -associated aberrant methylation genes were selected from the previous genome-wide profiling panels and validated in blood leukocyte and gastric mucosa in multi-stages (case-control validation between H.pylori positive and negative subjects and self-control validation before and after anti- H.pylori treatment). Results: GNAS methylation level was decreased in blood leukocyte (62.07% v.s. 46.33%, p <0.001) and gastric mucosa (56.30% v.s. 32.42%, p <0.001) of H.pylori positive subjects compared to negative controls. While, MTERF1 methylation level was increased significantly in blood leukocyte (29.57% v.s. 56.02%, p <0.001) and gastric mucosa (31.10% v.s. 47.50%, p <0.001) of positive subjects compared to controls. After successful H.pylori eradication, the methylation levels were increased from 44.87% to 60.88% ( p <0.001) for GNAS and decreased from 46.19% to 34.56% ( p <0.001) for MTERF1 in blood leukocyte. Similar increasing and decreasing methylation alterations were also found for the two genes after successful eradication in paired gastric mucosa. In TCGA database, an inverse relationship was found between GNAS methylation and mRNA expression ( r =-0.12, p =0.027). The GC cases with higher GNAS expression levels showed significantly worse survival (HR, 2.09, 95%CI, 1.22-3.57, p =0.007) compared to lower expression subjects. Conclusions: GNAS and MTERF1 methylation levels may be affected by H.pylori infection in gastric mucosa and blood leukocyte. GNAS may be involved in advanced stage of GC development, although the possible mechanism still needs further study in precancerous lesions.

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Section: Discussionmentioning

confidence: 93%

Helicobacter pylori associated aberrant methylation genes in blood leukocyte and gastric mucosa

Zhang¹,

Chen²,

Ma³

et al. 2021

J. Cancer

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“…Even if many methylated cells are shed after H. pylori eradication because cell differentiation from methylated stem cells continues, it is possible that the methylation level does not improve after eradication. Additionally, there may be other factors besides H. pylori that increase methylation levels in gastric mucosa, such as age, familial history, and smoking 43–45 …”

Section: Discussionmentioning

confidence: 99%

“…Additionally, there may be other factors besides H. pylori that increase methylation levels in gastric mucosa, such as age, familial history, and smoking. [43][44][45] F I G U R E 3 Changes in DNA methylation levels in patients with repeated metachronous cancer In the MGC group, six patients had repeated metachronous gastric cancer (MGC) more than twice after eradication. Methylation levels before eradication and when MGCs were detected after eradication were plotted for each of the six Aberrant methylation in all three genes seemed to accumulate over time after eradication.…”

Section: Discussionmentioning

confidence: 99%

Long‐term changes in aberrant DNA methylation and gastritis after Helicobacter pylori eradication focused on metachronous gastric cancer

et al. 2022

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BackgroundA persistently high methylation level in gastric mucosa after Helicobacter pylori (H. pylori) eradication is presumed to be a risk for metachronous gastric cancer (MGC); however, long-term changes in aberrant DNA methylation and histological gastritis have been unclear. Our aim was to examine changes in DNA methylation and histological gastritis according to the occurrence of MGC. MethodsSubjects were classi ed into 3 groups: 25 patients in whom metachronous gastric cancers occurred after the initial endoscopic resection (ER) for early gastric cancer and H. pylori eradication (MGC group), 17 patients in whom MGC did not occur for more than 5 years after initial ER and H. pylori eradication (non-MGC group) and 29 patients without a history of gastric cancer who succeeded in eradication more than 5 years ago (HP group). Aberrance of DNA methylation in 3 genes (miR-124a-3, EMX1, NKX6-1) and histological score of atrophy and intestinal metaplasia (IM) were evaluated using biopsy samples before and more than a mean of 5 years after H. pylori eradication. ResultsThe methylation level of miR-124a-3 in the HP group and non-MGC group and that of EMX1 in the HP group signi cantly decreased in the long term after eradication. In the MGC group, H. pylori eradication did not improve aberrant methylation, and the Z-score signi cantly increased. There were signi cant positive correlations between methylation levels in miR-124a-3 and EMX1 and histological ndings after eradication. ConclusionsA persistently high methylation level after H. pylori eradication re ected precancerous mucosal conditions and led to long-term MGC.

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“…Genomic DNA was extracted directly from noncancerous antral biopsy specimens using sodium bisulfite. The methodology was reported previously [ 19 ]. Briefly, specimens were homogenized in proteinase K solution (20 mmol/L Tris–HCl [pH 8.0], 10 mmol/L ethylenediaminetetraacetic acid, 0.5% sodium dodecyl sulfate, and 10 mg/mL proteinase K) using a sterile micropestle, followed by incubation for 3 hours at 52°C.…”

Section: Methodsmentioning

confidence: 99%

Aberrant DNA Methylation Maker for Predicting Metachronous Recurrence After Endoscopic Resection of Gastric Neoplasms

et al. 2022

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To investigate whether MOS methylation can be useful for the prediction of metachronous recurrence after endoscopic resection of gastric neoplasms. Materials and MethodsFrom 2012 to 2017, 294 patients were prospectively enrolled after endoscopic resection of gastric dysplasia (n=171) or early gastric cancer (n=123). When H. pylori was positive, eradication therapy was performed. Among them, 124 patients completed the study protocol (follow-up duration > 3 years or development of metachronous recurrence during the followup). Methylation levels of MOS were measured at baseline using quantitative MethyLight assay from the antrum. ResultsMedian follow-up duration was 49.9 months. MOS methylation levels at baseline were not different by age, sex, and current H. pylori infection, but they showed a weak correlation with operative link on gastritis assessment (OLGA) or operative link on gastric intestinal metaplasia assessment (OLGIM) stages (Spearman's ρ = 0.240 and 0.174, respectively, p < 0.05). During the follow-up, a total of 20 metachronous gastric neoplasms (13 adenomas and 7 adenocarcinomas) were developed. Either OLGA or OLGIM stage was not useful in predicting the risk for metachronous recurrence. In contrast, MOS methylation high group (≥ 34.82 %) had a significantly increased risk for metachronous recurrence compared to MOS methylation low group (adjusted hazard ratio [95% confidence interval]. 4.76 [1.54,14.79], p=0.007). ConclusionMOS methylation can be a promising marker for predicting metachronous recurrence after endoscopic resection of gastric neoplasms. To confirm the usefulness of MOS methylation, validation studies are warranted in the future. (ClinicalTrials No.: NCT04830618)

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Promising aberrant DNA methylation marker to predict gastric cancer development in individuals with family history and long-term effects of H. pylori eradication on DNA methylation

Cited by 21 publications

References 33 publications

Helicobacter pylori associated aberrant methylation genes in blood leukocyte and gastric mucosa

Helicobacter pylori associated aberrant methylation genes in blood leukocyte and gastric mucosa

Long‐term changes in aberrant DNA methylation and gastritis after Helicobacter pylori eradication focused on metachronous gastric cancer

Aberrant DNA Methylation Maker for Predicting Metachronous Recurrence After Endoscopic Resection of Gastric Neoplasms

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