Demonstration of the usefulness of epigenetic cancer risk prediction by a multicentre prospective cohort study

Abstract

BackgroundEpigenetic alterations accumulate in normal-appearing tissues of patients with cancer, producing an epigenetic field defect. Cross-sectional studies show that the degree of the defect may be associated with risk in some types of cancer, especially cancers associated with chronic inflammation.ObjectiveTo demonstrate, by a multicentre prospective cohort study, that the risk of metachronous gastric cancer after endoscopic resection (ER) can be predicted by assessment of the epigenetic field defect using methylation levels.DesignPatients with early gastric cancer, aged 40–80 years, who planned to have, or had undergone, ER, were enrolled at least 6 months after Helicobacter pylori infection discontinued. Methylation levels of three preselected genes (miR-124a-3, EMX1 and NKX6-1) were measured by quantitative methylation-specific PCR. Patients were followed up annually by endoscopy, and the primary endpoint was defined as detection of a metachronous gastric cancer. Authentic metachronous gastric cancers were defined as cancers excluding those detected within 1 year after the enrolment.ResultsAmong 826 patients enrolled, 782 patients had at least one follow-up, with a median follow-up of 2.97 years. Authentic metachronous gastric cancers developed in 66 patients: 29, 16 and 21 patients at 1–2, 2–3 and ≥3 years after the enrolment, respectively. The highest quartile of the miR-124a-3 methylation level had a significant univariate HR (95% CI) (2.17 (1.07 to 4.41); p=0.032) and a multivariate-adjusted HR (2.30 (1.03 to 5.10); p=0.042) of developing authentic metachronous gastric cancers. Similar trends were seen for EMX1 and NKX6-1.ConclusionsAssessment of the degree of an epigenetic field defect is a promising cancer risk marker that takes account of life history.

Incidence of and risk factors for metachronous gastric cancer after endoscopic resection and successful Helicobacter pylori eradication: results of a large-scale, multicenter cohort study in Japan

“…MGC was defined as a new gastric cancer detected at least 1 year after successful H. pylori eradication and located in an area other than the site of the previous endoscopic resection; this definition was in accordance with the previous study [23].…”

“…Implementation of third-line and further eradication therapy was at the discretion of the attending physician. To confirm continuous H. pylori negative status, the urea breath test, serum anti-H. pylori antibody test, and the culture method were performed at 3 and 5 years after the patients' enrollment in the previous study [23]. If any of these follow-up examinations revealed positivity for H. pylori, additional eradication was performed.…”

“…A total of 826 patients who underwent ESD for early gastric cancer between 1999 and 2010 in one of three hospitals (National Cancer Center Hospital, Tokyo University Hospital, and Wakayama Medical University Hospital) were enrolled between 2008 and 2010 in the multicenter prospective cohort study [23]. One hundred nineteen patients who tested negative for H. pylori infection without previous eradication were excluded, as were 100 patients who had already achieved successful eradication before detection of their initial gastric cancer.…”

“…To demonstrate the usefulness of assessing the degree of epigenetic field cancerization, we recently conducted a multicenter prospective cohort study with a median follow-up of 2.97 years, and demonstrated that the methylation level of miR-124a-3 was associated with an increased risk of developing MGC [23]. The cohort established in the study has a high value because of its size, the sufficiently long period of follow-up (a median of 4.5 years), and the high patient followup rate (97.9 %; 809 of 826 patients).…”

Morphologic Characterization of Residual DNA Methylation in the Gastric Mucosa after Helicobacter Pylori Eradication

“…The multivariate analysis showed that atrophic type or intestinal metaplasia was the strong independent risk for DNA methylation after H. pylori eradication. Although DNA hypermethylation might be a risk of gastric cancer regardless of H. pylori infection status [6,[19][20][21], in our study, the most important factor of DNA hypermethylation was magnifying NBI and histologic features. This indicates that the methylation change is closely linked to the magnifying NBI and histologic features within the focal points.…”