title: Aberrant methylation of RASGRF1 is associated with an epigenetic field defect and increased risk of gastric cancer.
abstract: Aberrant DNA methylation is implicated in the epigenetic field defect seen in gastric cancer. Our aim in this study was to identify predictive biomarkers by screening for DNA methylation in noncancerous background gastric mucosa from patients with gastric cancer. Using methylated-CpG island amplification coupled with CpG island microarray (MCAM) analysis, we identified 224 genes that were methylated in the noncancerous gastric mucosa of patients with gastric cancer. Among them, RASGRF1 methylation was significantly elevated in gastric mucosa from patients with either intestinal or diffuse type gastric cancer, as compared with mucosa from healthy individuals (8.3% vs. 22.4%, P < 0.001; 8.3% vs. 19.4%, P < 0.001). RASGRF1 methylation was independent of mucosal atrophy and could be used to distinguish both serum pepsinogen test-positive [sensitivity, 70.0%; specificity, 86.7%; area under the receiver operator characteristic (ROC) curve, AUC, 0.763] and -negative patients with gastric cancer (sensitivity, 72.2%; specificity, 87.0%; AUC, 0.844) from healthy individuals. Ectopic expression of RASGRF1 suppressed colony formation and Matrigel invasion by gastric cancer cells, suggesting it may be involved in gastric tumorigenesis. Collectively, our data suggest that RASGRF1 methylation is significantly involved in an epigenetic field defect in the stomach, and that it could be a useful biomarker to identify individuals at high risk for gastric cancer.
authors.affiliation: Department of Molecular Biology, Sapporo Medical University, Chuo-Ku, Sapporo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takamaru
authors.forename: Eiichiro
authors.initials: E
authors.lastname: Yamamoto
authors.forename: Hiromu
authors.initials: H
authors.lastname: Suzuki
authors.forename: Masanori
authors.initials: M
authors.lastname: Nojima
authors.forename: Reo
authors.initials: R
authors.lastname: Maruyama
authors.forename: Hiro-O
authors.initials: HO
authors.lastname: Yamano
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Yoshikawa
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Kimura
authors.forename: Taku
authors.initials: T
authors.lastname: Harada
authors.forename: Masami
authors.initials: M
authors.lastname: Ashida
authors.forename: Ryo
authors.initials: R
authors.lastname: Suzuki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kai
authors.forename: Takashi
authors.initials: T
authors.lastname: Tokino
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Sugai
authors.forename: Kohzoh
authors.initials: K
authors.lastname: Imai
authors.forename: Minoru
authors.initials: M
authors.lastname: Toyota
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Shinomura
mesh_terms: D000368:Aged; D015153:Blotting, Western; D016022:Case-Control Studies; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D018899:CpG Islands; D019175:DNA Methylation; D057890:Epigenomics; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000209:etiology* / Q000473:pathology; D020666:ras-GRF1 / Q000235:genetics*
chemical_list: C513039:RASGRF1 protein, human; D012333:RNA, Messenger; D020666:ras-GRF1