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

Abstract

Background: Epigenetic 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.

Objective: To 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.

Design: Patients 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.

Results: Among 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.

Conclusions: Assessment of the degree of an epigenetic field defect is a promising cancer risk marker that takes account of life history.

Keywords: GASTRIC CANCER; METHYLATION.

Figure 1

Study profile. ER, endoscopic resection.

Figure 2

The distribution of methylation levels of miR-124a-3, EMX1 and NKX6-1 among the 782 patients. miR-124a-3 and EMX1 showed bimodal distributions, whereas NKX6-1 showed a unimodal distribution.

Figure 3

Cumulative incidence of all the metachronous gastric cancers for patients in quartile (Q1–Q4) of methylation levels of miR-124a-3, EMX1, and NKX6-1. The Q4 methylation had higher incidences of a metachronous gastric cancer than the Q1 methylation with p values of 0.17, 0.08 and 0.54 for miR-124a-3, EMX1 and NKX6-1, respectively, by the log-rank test.