Precision risk stratification of primary gastric cancer after eradication of H. pylori by a DNA methylation marker: a multicentre prospective study

Abstract

Background: Precision cancer risk stratification for gastric cancer is urgently needed for the growing number of healthy people after Helicobacter pylori eradication. The epimutation burden in non-malignant tissues has been associated with cancer risk in multiple cross-sectional studies.

Objective: To confirm the clinical usefulness of a DNA methylation marker for epimutation burden, and to identify a cut-off methylation level for a super-high-risk population.

Design: Healthy people after H. pylori eradication with open-type atrophy were prospectively recruited. DNA methylation levels of a marker gene, RIMS1, were measured in biopsy specimens from gastric antrum and body. The primary endpoint was the incidence rate of gastric cancer in quartiles of the methylation levels.

Results: 1624 participants had at least one endoscopic follow-up with a median follow-up of 4.05 years, and a primary gastric cancer developed in 27 participants. The highest quartile of RIMS1 methylation levels had a higher incidence rate (972.8 per 100 000 person-years) than the lowest quartile (127.1). Cox regression analysis revealed a univariate HR of 7.7 (95% CI 1.8-33.7) and an age- and sex-adjusted HR of 5.7 (95% CI 1.3-25.5). As a secondary objective, a cut-off methylation level of 25.7% (95% CI 1.7-7.7) was obtained to identify a population with a super-high risk based on the number needed to screen of 1000.

Conclusion: A DNA methylation marker can risk-stratify healthy people after H. pylori eradication even though all of them have clinically high risk. Individuals with super-high risk will need more frequent gastric cancer screening than currently recommended.

Trial registration number: UMIN-CTR000016894.

Keywords: BIOMARKERS; EPIGENETICS; GASTRIC CANCER; HELICOBACTER PYLORI; METHYLATION.

Figure 1. Participant enrolment and outcomes. (A) Schema of the study design. (B) A total of 1874 healthy people after Helicobacter pylori eradication with open-type gastric atrophy were assessed for eligibility, and 1757 were enrolled and underwent biopsy. Among them, 1624 participants were followed up by endoscopic examination at least once, and 27 people developed primary gastric cancer. The data on smoking were available for 1405 participants.

Figure 2. Distribution of RIMS1 methylation levels. (A) Distribution of maximum RIMS1 methylation levels in the 1624 participants who were followed up at least once. (B) Correlation between RIMS1 methylation levels in antrum and that in body. Its correlation coefficient was 0.516 and highly significant (p<0.001).

Figure 3. Cumulative incidences of primary gastric cancer in quartiles of the maximum RIMS1 DNA methylation levels. Estimates of cumulative incidences of primary gastric cancer in the quartiles of the maximum RIMS1 DNA methylation level. The Kaplan-Meier analysis was conducted in the 1624 patients who were followed up at least once, and the characteristics of the individual quartiles are shown in online supplemental table S1. The red solid line shows quartile 4 (Q4); black line, Q3; light grey line, Q2; and blue line, Q1. Vertical bars show the date of the last endoscopic follow-up.

Figure 4. Predicted 1-year probability of primary gastric cancer occurrence according to the maximum RIMS1 methylation level. The predicted 1-year probability of gastric cancer occurrence as a function of the maximum RIMS1 methylation level for a population of participants aged 40 years with 50.8% of women was estimated. This analysis was done in the 1624 patients who were followed up at least once. Dotted lines show 95% CI.