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

Gut. 2015 Mar;64(3):388-96. doi: 10.1136/gutjnl-2014-307094. Epub 2014 Jun 2.


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.


Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • DNA Methylation*
  • Epigenesis, Genetic*
  • Female
  • Genetic Markers / genetics
  • Homeodomain Proteins / genetics
  • Humans
  • Male
  • MicroRNAs / genetics
  • Middle Aged
  • Neoplasms, Second Primary / etiology*
  • Neoplasms, Second Primary / genetics
  • Polymerase Chain Reaction
  • Prospective Studies
  • Risk Assessment
  • Risk Factors
  • Stomach Neoplasms / etiology*
  • Stomach Neoplasms / genetics
  • Transcription Factors / genetics


  • Genetic Markers
  • Homeodomain Proteins
  • MIRN124 microRNA, human
  • MicroRNAs
  • NKX6-1 protein, human
  • Transcription Factors
  • empty spiracles homeobox proteins