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Home > Organization > Divisions and Independent Research Units > Group for Development of Molecular diagnostics and Individualized Therapy > Division of Epigenomics > Research Projects > DNA methylation accumulation and gastric cancer risk

DNA methylation accumulation and gastric cancer risk

We previously demonstrated that H. pylori infection, almost the sole gastric cancer inducer in Asian countries, induces aberrant DNA methylation in gastric epithelial cells, and that the accumulation level of aberrant DNA methylation correlates with gastric cancer risk (Maekita, 2006 [PubMed], Nakajima, 2006 [PubMed]). In addition to the stomach, accumulation of DNA methylation in normal-appearing tissues is associated with cancer risk for esophageal, colon, liver, and breast cancer (Ushijima, 2007 [PubMed], Hattori and Ushijima, 2016 [PubMed]).

We are trying to bring the findings into cancer risk diagnosis based upon the methylation level in the normal stomach. As a clinical study, we had two possibilities. The first group was gastric cancer patients who were treated for their initial gastric cancer by endoscopic submucosal dissection (people in the blue square; Fig. 1). The other group was healthy people after eradication of H. pylori (people in the red square).

The risk diagnosis strategy we are developing is applicable to other types of inflammation-associated cancers, such as colitic cancer, cervical cancers, and liver cancers.


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Fig.1 Prediction of cancer risk by accumulation of DNA methylation level in normal stomach
Chronic inflammation caused by H. pylori infection strongly induced aberrant DNA methylation in gastric tissue. Even after eradication of H. pylori, aberrant methylation still remains, and its level correlates with cancer risk. Gastric cancer patients cured by endoscopic treatment still have high risk (blue square), have a high incidence of cancer, but the hazard ratio (HR) by the methylation level will be small. Healthy people after H. pylori eradication have a low incidence (red square), but HR will be large.

 

A prospective study in gastric cancer patients treated with endoscopy

Early gastric cancer can be cured by endoscopic treatment, and preservation of the stomach gives a good quality of life. However, this group of people are known to suffer from another gastric cancer (metachronous cancer) with a yearly rate of 2.0-2.5 %. Therefore, we decided to conduct our initial multicenter prospective study in this population, in 2008.

We collected one piece of biopsy from the non-cancerous region of gastric cancer patients cured with endoscopic treatment after eradication of H. pylori, and measured DNA methylation levels of three marker genes (miR-124a-3, EMX1, and NKX6-1). The patients were followed up by annual endoscopic examination. Among the 795 patients with a 5-year follow-up, metachronous gastric cancer developed in 133 participants. Even after excluding those developed within one year of enrollment, 116 patients developed a metachronous cancer.

We stratified the patients into four groups according to the methylation levels of the marker genes. Patients with the highest methylation level of miR-124a-3 had a three times higher risk of developing a metachronous gastric cancer. The results were essentially the same using any marker genes (Asada et al.,2015 [PubMed], Maeda et al.,2017 [PubMed]).

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Fig.2 Impact of DNA methylation level on cumulative incidence of metachronous gastric cancer.
When patients were stratified by methylation levels into four groups, the group with the highest methylation level (Q4:red) had a three times higher HR compared with the group with the lowest methylation level (Q1:green).

A prospective study in healthy people after eradication of H. pylori

Eradication of H. pylori was approved by national health insurance in 2013 in Japan. In response to this movement, we started another multicenter prospective study with healthy individuals after H. pylori eradication. It is known that, even after H. pylori eradication, gastric cancer develops with a yearly rate of 0.4-0.5 %, but some people mistakenly believe that they are risk-free. Other people continue to worry about gastric cancer believing they are at high risk. Therefore, gastric cancer risk diagnosis for healthy people is necessary.

In this clinical study, we measure DNA methylation levels of two biopsy pieces in the normal stomach after H. pylori eradication, and follow the participants with annual endoscopy. After a five-year follow-up, the predictive power of DNA methylation in normal tissues for cancer risk will become clear. We already closed recruitment of participants on May 31, 2019.

We provide information of this study on the web site of UMIN.

(UMIN000016894:https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000019470)

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Fig.3 Participating institutions in the study for healthy people after H. pylori eradication