DNA methylation silencing of microRNA gene methylator in the precancerous background mucosa with and without gastric cancer: Analysis of the effects of H. pylori eradication and long-term aspirin use

The risk of gastric cancer (GC) declines after Helicobacter pylori (H. pylori) eradication and long-term aspirin use. We evaluated the effects of H. pylori eradication (Cohort 1) and aspirin use (Cohort 2) on the methylation of microRNAs (miRNAs) such as miR-34c, miR-124a-3, miR-129-2, and miR-137 in the gastric mucosa with and without GC, i.e., atrophic mucosa (AM) and intestinal metaplasia (IM). DNA was isolated from AM and IM separately using laser caption microdissection. In Cohort 1, H. pylori eradication was associated with a significant reduction of miR-124a-3 methylation only in AM, but not in IM. miR-129-2 methylation in AM may be a surrogate marker of GC in H. pylori-infected patients. In Cohort 2, aspirin did not reverse miRNA methylation in either AM or IM irrespective of H. pylori infection. miR-129-2 methylation in AM was an independent predictive marker of GC in H. pylori-infected but not -eradicated patients. These results indicate that H. pylori eradication and aspirin use were less effective in improving methylation in IM compared with AM; thus, these interventions are recommended at an early stage prior to the development of IM to prevent GC development.

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Long-term Changes In Aberrant DNA Methylation And Gastritis After Helicobacter Pylori Eradication Focused On Metachronous Gastric Cancer

10.21203/rs.3.rs-1187733/v1 ◽

2021 ◽

Author(s):

Ikko Tanaka ◽

Shoko Ono ◽

Yoshiyuki Watanabe ◽

Hiroyuki Yamamoto ◽

Ritsuko Oikawa ◽

...

Keyword(s):

Gastric Cancer ◽

Dna Methylation ◽

Helicobacter Pylori ◽

Methylation Level ◽

Aberrant Methylation ◽

Long Term Changes ◽

Metachronous Gastric Cancer ◽

Aberrant Dna Methylation ◽

H Pylori

Abstract 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 classified 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 significantly decreased in the long term after eradication. In the MGC group, H. pylori eradication did not improve aberrant methylation, and the Z-score significantly increased. There were significant positive correlations between methylation levels in miR-124a-3 and EMX1 and histological findings after eradication.ConclusionsA persistently high methylation level after H. pylori eradication reflected precancerous mucosal conditions and led to long-term MGC.

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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

Gastric Cancer ◽

10.1007/s10120-020-01117-w ◽

2020 ◽

Author(s):

Hee Jin Kim ◽

Nayoung Kim ◽

Hyoung Woo Kim ◽

Ji Hyun Park ◽

Cheol Min Shin ◽

...

Keyword(s):

Gastric Cancer ◽

Dna Methylation ◽

Family History ◽

Cancer Development ◽

Long Term Effects ◽

Methylation Marker ◽

Aberrant Dna Methylation ◽

H Pylori

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Study of Incidence of Gastric Cancer After H. pylori Eradication in Patients With Long-Term Administration of Low-Dose Aspirin

The American Journal of Gastroenterology ◽

10.14309/00000434-201810001-02892 ◽

2018 ◽

Vol 113 (Supplement) ◽

pp. S1595

Author(s):

Koji Takahashi ◽

Takashi Kawai ◽

Yuki Aoki ◽

Akihiko Sugimoto ◽

Shinʼichi Takahashi

Keyword(s):

Gastric Cancer ◽

Low Dose ◽

Dose Aspirin ◽

Low Dose Aspirin ◽

Term Administration ◽

H Pylori

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Long-term use of proton-pump inhibitors and risk of gastric cancer: a review of the current evidence

Therapeutic Advances in Gastroenterology ◽

10.1177/1756284819834511 ◽

2019 ◽

Vol 12 ◽

pp. 175628481983451 ◽

Cited By ~ 26

Author(s):

Ka Shing Cheung ◽

Wai K. Leung

Keyword(s):

Gastric Cancer ◽

Proton Pump Inhibitors ◽

Proton Pump ◽

Randomized Clinical Trials ◽

Bacterial Overgrowth ◽

Current Evidence ◽

Neoplastic Progression ◽

Increased Risk ◽

H Pylori

Gastric cancer remains one of the leading cancers in the world with a high mortality, particularly in East Asia. Helicobacter pylori infection accounts for the majority of the noncardia gastric cancers by triggering gastric inflammation and subsequent neoplastic progression. Eradication of H. pylori can reduce, but not totally eliminate, subsequent risk of developing gastric cancer. Proton-pump inhibitors (PPIs) are one of the most widely prescribed medications worldwide. With their profound gastric-acid suppression, there are concerns about a possible carcinogenic role in gastric cancer, due to induced hypergastrinemia, gastric atrophy and bacterial overgrowth in the stomach. While randomized clinical trials to establish causality between long-term PPI use and gastric cancer are lacking, current evidence based on observational studies suggests PPIs are associated with an increased gastric cancer risk. However, opinions on causality remain divergent due to unmeasured and possible residual confounding in various studies. Our recent study has showed that even after H. pylori eradication, long-term PPI use is still associated with an increased risk of gastric cancer by more than twofold. Hence, long-term PPIs should be used judiciously after considering individual’s risk–benefit profile, particularly among those with history of H. pylori infection. Further well-designed prospective studies are warranted to confirm the potential role of PPIs in gastric cancer according to baseline gastric histology and its interaction with other chemopreventive agents like aspirin, statins and metformin.

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Discovery and Validation of Novel Methylation Markers in Helicobacter pylori-Associated Gastric Cancer

Disease Markers ◽

10.1155/2021/4391133 ◽

2021 ◽

Vol 2021 ◽

pp. 1-11

Author(s):

Huan Wang ◽

Nian-Shuang Li ◽

Cong He ◽

Chuan Xie ◽

Yin Zhu ◽

...

Keyword(s):

Gene Expression ◽

Gastric Cancer ◽

Dna Methylation ◽

Helicobacter Pylori ◽

Gene Expression Data ◽

Functional Enrichment ◽

Expression Data ◽

H Pylori

Previous studies have shown that abnormal methylation is an early key event in the pathogenesis of most human cancers, contributing to the development of tumors. However, little attention has been given to the potential of DNA methylation patterns as markers for Helicobacter pylori- (H. pylori-) associated gastric cancer (GC). In this study, an integrated analysis of DNA methylation and gene expression was conducted to identify some potential key epigenetic markers in H. pylori-associated GC. DNA methylation data of 28 H. pylori-positive and 168 H. pylori-negative GC samples were compared and analyzed. We also analyzed the gene expression data of 18 H. pylori-positive and 145 H. pylori-negative GC cases. Finally, the results were verified by in vitro and in vivo experiments. A total of 5609 differentially methylated regions associated with 2454 differentially methylated genes were identified. A total of 228 differentially expressed genes were identified from the gene expression data of H. pylori-positive and H. pylori-negative GC cases. The screened genes were analyzed for functional enrichment. Subsequently, we obtained 28 genes regulated by methylation through a Venn diagram, and we identified five genes (GSTO2, HUS1, INTS1, TMEM184A, and TMEM190) downregulated by hypermethylation. HUS1, GSTO2, and TMEM190 were expressed at lower levels in GC than in adjacent samples ( P < 0.05 ). Moreover, H. pylori infection decreased HUS1, GSTO2, and TMEM190 expression in vitro and in vivo. Our study identified HUS1, GSTO2, and TMEM190 as novel methylation markers for H. pylori-associated GC.

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Mass eradication of Helicobacter pylori to reduce gastric cancer incidence and mortality: a long-term cohort study on Matsu Islands

Gut ◽

10.1136/gutjnl-2020-322200 ◽

2020 ◽

pp. gutjnl-2020-322200 ◽

Cited By ~ 1

Author(s):

Tsung-Hsien Chiang ◽

Wei-Jung Chang ◽

Sam Li-Sheng Chen ◽

Amy Ming-Fang Yen ◽

Jean Ching-Yuan Fann ◽

...

Keyword(s):

Gastric Cancer ◽

Helicobacter Pylori ◽

Cancer Incidence ◽

Control Period ◽

Eradication Therapy ◽

Incidence Rates ◽

Long Term Effects ◽

Incidence And Mortality ◽

H Pylori

ObjectiveAlthough mass eradication of Helicobacter pylori has been proposed as a means to eliminate gastric cancer, its long-term effects remain unclear.DesignMass eradication of H. pylori infection was launched in 2004 and continued until 2018 for a high-risk Taiwanese population aged 30 years or older dwelling on Matsu Islands with prevalent H. pylori infection. Test positives for the 13C-urea breath test underwent eradication therapy. We evaluated the effectiveness of the mass eradication in reducing two main outcomes, incidence and mortality rates of gastric cancer, until the end of 2016 and 2018, respectively.ResultsAfter six rounds of mass screening and eradication, the coverage rate reached 85.5% (6512/7616). The referral rate for treatment was 93.5% (4286/4584). The prevalence rates of H. pylori fell from 64.2% to 15.0% with reinfection rates of less than 1% per person-year. The presence and severity of atrophic gastritis and intestinal metaplasia also decreased with time. Compared with the historical control period from 1995 to 2003, the effectiveness in reducing gastric cancer incidence and mortality during the chemoprevention period was 53% (95% CI 30% to 69%, p<0.001) and 25% (95% CI −14% to 51%, p=0.18), respectively. No significant changes were noted in the incidence rates of other digestive tract cancers or the antibiotic resistance rate of H. pylori.ConclusionPopulation-based eradication of H. pylori has significantly reduced gastric cancer incidence with no increase in the likelihood of adverse consequences. A significant reduction in mortality is likely to be achieved with a longer follow-up period.Trial registration numberNCT00155389

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Helicobacter pylori dupA and gastric acid secretion are negatively associated with gastric cancer development

Journal of Medical Microbiology ◽

10.1099/jmm.0.021816-0 ◽

2010 ◽

Vol 59 (12) ◽

pp. 1484-1489 ◽

Cited By ~ 19

Author(s):

Shinobu Imagawa ◽

Masanori Ito ◽

Masaharu Yoshihara ◽

Hidetaka Eguchi ◽

Shinji Tanaka ◽

...

Keyword(s):

Gastric Cancer ◽

Duodenal Ulcer ◽

Gastric Acid ◽

Acid Output ◽

Rank Test ◽

Peptic Ulcers ◽

Log Rank Test ◽

H Pylori

Few reports have described the cancer prevalence of peptic ulcer patients with long-term follow-up studies. We have conducted a long-term retrospective cohort study of Japanese peptic ulcer patients and evaluated the risk factors for the occurrence of gastric cancer (GCa). A total of 136 patients diagnosed with peptic ulcers from 1975 to 1983 were enrolled. These 136 cases [102 males and 34 females; 69 gastric ulcer (GU) and 67 duodenal ulcer (DU) patients at the time of enrolment; mean follow-up period of 14.4 years (range 1–30 years)] after being matched with a tumour registry database in Hiroshima prefecture were surveyed for GCa. We investigated Helicobacter pylori duodenal ulcer promoter gene A (dupA) using paraffin-embedded gastric biopsy specimens in 56 cases. Gastric acid secretion and basal acid output (BAO) in 40 cases, and maximal acid output in 68 cases, had been measured at first diagnosis of peptic ulcers. GCa was detected in 24 patients (17 with GU, 7 with DU) during the follow-up. The prevalence of GCa was significantly higher in GU patients than in DU patients (log-rank test P<0.05). dupA-positive H. pylori was detected not only in DU patients (9/20) but also in GU patients (9/36). Gastric acid output was significantly larger in quantity in patients with dupA-positive H. pylori than in those with dupA-negative H. pylori (P<0.05). The occurrence of GCa was significantly lower in patients with dupA-positive H. pylori and a high BAO level (log-rank test P<0.05). DUs, higher acid output and dupA-positive H. pylori were negatively associated with GCa.

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Evidence of origin with epigenetic change of metachronous lesions in early gastric cancer after endoscopic submucosal dissection

10.21203/rs.3.rs-675469/v1 ◽

2021 ◽

Author(s):

Yo Kubota ◽

Satoshi Tanabe ◽

Mizutomo Azuma ◽

Kazue Horio ◽

Yoshiki Fujiyama ◽

...

Keyword(s):

Gastric Cancer ◽

Dna Methylation ◽

Early Gastric Cancer ◽

Endoscopic Submucosal Dissection ◽

Operating Characteristic ◽

Cysteine Dioxygenase ◽

Epigenetic Change ◽

Submucosal Dissection ◽

H Pylori

Abstract Early gastric cancer (EGC) with metachronous lesions developing on scars after endoscopic submucosal dissection (ESD) is extremely rare and hard to treat. We evaluated whether DNA methylation of the cancer-specific methylation gene, cysteine dioxygenase type 1 (CDO1), would predict such lesions. CDO1 methylation (TaqMeth) values were compared between 11 patients with metachronous lesions developing on scars after ESD (M group) identified from 2,055 patients (0.5%) and 33 patients with EGC with no confirmed evidence of metachronous lesions at > 3 years after ESD (solitary [S] group). To assess Helicobacter pylori influence, 11 H. pylori-negative EGC patients (N group) were also analyzed. Each ESD specimen was measured at the tumor (T) and 4-points separated tumor-adjacent noncancerous mucosa (TAM). TaqMeth values for T were significantly higher than TAM (S + M) (P = 0.0019) and TAM (N) (P < 0.0001). Moreover, TAM (M) had significantly higher TaqMeth values than TAM (S) (P < 0.0001) suggesting that TAM (M) exhibited CDO1 hypermethylation similar to T (P = 0.5713). Additionally, TaqMeth values for TAM (S) were significantly higher than TAM (N) (P < 0.0001). The receiver operating characteristic for discriminating the highest TaqMeth values separated TAMs (M) from those of TAMs (S) was 0.81. CDO1 hypermethylation promisingly predicted EGC with metachronous lesions developing on scars after ESD.

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Efficacy and Long-Term Safety of H. pylori Eradication for Gastric Cancer Prevention

Cancers ◽

10.3390/cancers11050593 ◽

2019 ◽

Vol 11 (5) ◽

pp. 593 ◽

Cited By ~ 10

Author(s):

Jyh-Ming Liou ◽

Yi-Chia Lee ◽

Emad M. El-Omar ◽

Ming-Shiang Wu

Keyword(s):

Gastric Cancer ◽

Antibiotic Resistance ◽

Cohort Studies ◽

Prospective Cohort ◽

Meta Analysis ◽

Eradication Therapy ◽

Prospective Cohort Studies ◽

Gastric Cancer Prevention ◽

H Pylori

Helicobacter pylori (H. pylori) has been shown to be a causal factor of gastric cancer in cohort studies and animal models. Meta-analysis of case-control studies nested within prospective cohorts showed that H. pylori infection was associated with a 5.9-fold increased risk of non-cardia gastric cancer. Prospective cohort studies showed that gastric cancer developed in 1–4% of H. pylori-infected subjects. Gastric cancer was successfully induced in Mongolian gerbils and insulin-gastrin (INS-GAS) transgenic mice after inoculation of H. pylori. Meta-analysis of randomized control trials also showed that eradication of H. pylori may reduce the risk of gastric cancer. However, there are several concerns regarding the widespread use of antibiotics to prevent gastric cancer, including the emergence of antibiotic resistance and the perturbation of gut microbiota after H. pylori eradication. Recent studies showed that eradication of H. pylori resulted in an increase in the bacterial diversity and restoration of the relative abundance of other bacteria to levels similar to H. pylori non-infected subjects in the gastric microbiota. The administration of antibiotics may also alter the composition of intestinal microbiota. The α-diversity and β-diversity of fecal microbiota are significantly altered immediately after H. pylori eradication but are gradually restored to levels similar to those before therapy. Yet, the rate of recovery varies with regimens. The diversity was restored at week 8 after triple therapy but was not yet fully recovered at 1 year after concomitant and quadruple therapies. Some studies showed that supplementation of probiotics may reduce the dysbiosis during H. pylori eradication therapy. Although some earlier studies showed high levels of macrolide resistance after triple therapy, recent studies showed that the increased antibiotic resistance rate may be restored 2–12 months after eradication therapy. These results collectively provide evidence of the long-term safety of H. pylori eradication. Yet, more prospective cohort studies and randomized trials are warranted to assess the efficacy and long-term safety of H. pylori eradication for gastric cancer prevention.

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