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


METHODS
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.
Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.
Kiyoshi
K
Asada
Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan.
Takeshi
T
Nakajima
Epidemiology and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan.
Taichi
T
Shimazu
Department of Gastroenterology, University of Tokyo, Tokyo, Japan.
Nobutake
N
Yamamichi
Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan.
Takao
T
Maekita
Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Tokyo, Japan.
Chizu
C
Yokoi
Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan.
Ichiro
I
Oda
Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.
Takayuki
T
Ando
Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan.
Takeichi
T
Yoshida
Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.
Sohachi
S
Nanjo
Department of Gastroenterology, University of Tokyo, Tokyo, Japan.
Mitsuhiro
M
Fujishiro
Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan Department of Gastroenterology and Hepatology, Tokyo Medical University, Tokyo, Japan.
Takuji
T
Gotoda
Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan.
Masao
M
Ichinose
Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.
Toshikazu
T
Ushijima
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics; D008875:Middle Aged; D016609:Neoplasms, Second Primary / Q000209:etiology* / Q000235:genetics; D016133:Polymerase Chain Reaction; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013274:Stomach Neoplasms / Q000209:etiology* / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D000099260:Empty Spiracles Homeobox Proteins
D005819:Genetic Markers; D018398:Homeodomain Proteins; D035683:MicroRNAs; D014157:Transcription Factors; D000099260:Empty Spiracles Homeobox Proteins; C509207:MIRN124 microRNA, human; C105201:NKX6-1 protein, human
GASTRIC CANCER; METHYLATION