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. Cancer Prev Res; 5(10); 1203-12. Ó2012 AACR.

Relationship between LINE-1 hypomethylation and Helicobacter pylori infection in gastric mucosae

“…Similarly, methylation silencing of miRNA genes contributes to the formation of epigenetic field defects in gastric cancers [37]. Among these, methylated miR-34b/c and RASGRF1 have been identified as useful biomarkers for identifying individuals at high risk of gastric cancer [38][39][40]. However, whether H. pylori influences the methylation of miR34b/c and RASGRF1 remains unclear.…”

Epigenetics and imprinting in human disease

“…1 (Azzi et al, 2014); 2 (Cassidy et al, 2012, Mabb et al, 2011; 3 (Ankolkar et al, 2013, Docherty et al, 2010, Iglesias-Platas et al, 2013, Kamikihara et al, 2005; 4 (Lecumberri et al, 2010, Linglart et al, 2013, Turan and Bastepe, 2013; 5 (Huang et al, 2007, Jorgensen et al, 2013, Kawakami et al, 2006, Sutton and Shaffer, 2000; 6 (Dowdy et al, 2005, Trouillard et al, 2004, Van den Veyver et al, 2001; 7 (Gao et al, 2010, Tsou et al, 2003; 8 (Kobayashi et al, 1997, Lee andBartolomei, 2013); 9 (Hysi et al, 2010, Takamaru et al, 2012, Tarnowski et al, 2012, Zhu et al, 2013 methylation and biallelic expression of imprinted genes (Kaneda et al, 2004). Through the use of the de novo DNA methyltransferases DNMT3A and DNMT3B and the accessory protein DNMT3L, ICRs and DMRs are specifically methylated in the male or female germline (Bartolomei and Ferguson-Smith, 2011).…”

An eQTL analysis of the human glioblastoma multiforme genome

“…In the adjusted data set, the two probes associated with the largest numbers of SNPs. The first is RASGRF1 (a guanine exchange factor and a receptor in the sonic hedgehog Ras signal transduction pathway known for its role as a tumor suppressor checkpoint, see [62,63]), which has 11 associated eQTLs. The second is PRDM2 (a PR domain with zinc finger receptors, associated with 12 eQTLs).…”