Aberrant methylation of microRNA-34b/c is a predictive marker of metachronous gastric cancer risk.
BACKGROUND
Metachronous gastric cancer (GC) can develop after endoscopic resection of GC and cannot be predicted based on clinical signature. Aberrant DNA methylation in noncancerous gastric mucosa is strongly implicated in gastric carcinogenesis and could be a useful biomarker of GC risk. We evaluated the clinical utility of DNA methylation as a biomarker of metachronous GC risk.


METHODS
We carried out scheduled follow-up endoscopy in 129 patients after curative endoscopic resection of GC. Biopsy specimens were collected from noncancerous mucosa in the gastric antrum and body, after which quantitative methylation analysis of miR-34b/c, SFRP1, SFRP2, SFRP5, DKK2 and DKK3 was carried out using bisulfite pyrosequencing. The utility of the methylation for predicting the risk of metachronous GC development was assessed using Kaplan-Meier and Cox proportional hazards model analyses.


RESULTS
During the follow-up period, 17 patients (13%) developed metachronous GCs. The cumulative incidence of metachronous GC was significantly higher among patients with elevated miR-34b/c, SFRP2 and DKK2 methylation in their gastric body. MiR-34b/c showed the strongest association with the risk of metachronous GC, and the cumulative incidence of metachronous GC was much higher in the high-miR-34b/c-methylation group than the low-methylation group. Multivariate analysis adjusted for age, sex, H. pylori status and pathological findings showed miR-34b/c methylation in gastric body to be an independent predictor of metachronous GC risk.


CONCLUSIONS
Our results suggest that methylation of miR-34b/c in the mucosa of the noncancerous gastric body may be a useful biomarker for predicting the risk of metachronous GC.
Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University, S1, W16, Chuo-Ku, Sapporo, 060-8543, Japan.
Ryo
R
Suzuki
Eiichiro
E
Yamamoto
Masanori
M
Nojima
Reo
R
Maruyama
Hiro-O
HO
Yamano
Kenjiro
K
Yoshikawa
Tomoaki
T
Kimura
Taku
T
Harada
Masami
M
Ashida
Takeshi
T
Niinuma
Akiko
A
Sato
Katsuhiko
K
Nosho
Hiroyuki
H
Yamamoto
Masahiro
M
Kai
Tamotsu
T
Sugai
Kohzoh
K
Imai
Hiromu
H
Suzuki
Yasuhisa
Y
Shinomura
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D005773:Gastroscopy; D020022:Genetic Predisposition to Disease; D016481:Helicobacter Infections / Q000150:complications; D016480:Helicobacter pylori / Q000302:isolation & purification; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000382:microbiology / Q000473:pathology; D011446:Prospective Studies; D012334:RNA, Neoplasm / Q000235:genetics; D018570:Risk Assessment / Q000379:methods; D013274:Stomach Neoplasms / Q000235:genetics* / Q000382:microbiology / Q000473:pathology / Q000601:surgery
D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D012334:RNA, Neoplasm