1. ¹Department of Pathology, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
2. ²Department of Pathology, Kyung Hee University College of Medicine, Seoul, Korea
3. ³Department of Surgery, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
4. ⁴Department of Biochemistry and Molecular Biology, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA

Correspondence: Professor GH Kang, MD, Department of Pathology, Seoul National University College of Medicine and Cancer Research Institute, 28 Yongon-dong, Chongno-gu, Seoul 110-744, Korea. E-mail: ghkang@snu.ac.kr

Received 30 May 2007; Revised 31 October 2007; Accepted 1 November 2007; Published online 24 December 2007.

Abstract

Transcriptional silencing by CpG island hypermethylation is a potential mechanism for the inactivation of tumor-related genes. Virtually, all types of human cancers show CpG island hypermethylation, and gastric carcinoma (GC) is one of the tumors with a high frequency of aberrant CpG island hypermethylation. In this study, we prescreened DNA methylation of 170 CpG island loci in a training set of 8 paired GC and GC-associated non-neoplastic mucosae (GCN) using MethyLight technology and selected 27 DNA methylation markers showing higher methylation frequency or level in GC than in GCN. These markers were then analyzed in a tester set of 25 paired GC and GCN and 27 chronic gastritis (CG) from non-cancer patients to generate their DNA methylation profiles. We identified 17 novel methylation markers in GC, including SFRP4, SEZ6L, TWIST1, BCL2, KL, TERT, SCGB3A1, IGF2, GRIN2B, SFRP5, DLEC1, HOXA1, CYP1B1, SMAD9, MT1G, NR3C1, and HOXA10. Of the 27 selected CpG island loci, 23 were methylated in GC, GCN, and CG and the remainder four loci (DLEC1, CHFR, CYP1B1, and NR3C1) were only methylated in GC. We found that the number of methylated loci was significantly higher in GC than in GCN or CG and that Helicobacter pylori infection was strongly associated with aberrant CpG island hypermethylation in CG. Hypermethylation was more prevalent in Epstein–Barr virus (EBV)-positive GC than in EBV-negative GC and in diffuse-type GC than in intestinal-type GC. Through our large-scale screening of 170 CpG island loci, we found 17 new DNA methylation markers of GC, which may serve as useful markers that may identify a distinct subset of GC.