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Higher Methylation Levels in Gastric Mucosae Significantly Correlate with Higher Risk of Gastric Cancers

¹ Endoscopy Division, National Cancer Center Hospital; ² Carcinogenesis Division, National Cancer Center Research Institute; ³ Statistics and Cancer Control Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan; ⁴ Second Department of Internal Medicine, Yokohama City University, Yokohama, Japan; and ⁵ Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan

Requests for reprints: Toshikazu Ushijima, Carcinogenesis Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. Phone: 81-3-3547-5240; Fax: 81-3-5565-1753. E-mail: tushijim{at}ncc.go.jp

Background: Helicobacter pylori infection potently induces methylation of CpG islands in gastric mucosae, which is considered to decrease to a certain level after active H. pylori infection discontinues. Noncancerous gastric mucosae of H. pylori–negative cases with a gastric cancer had higher methylation levels than those of H. pylori–negative healthy individuals. Here, using cases with multiple gastric cancers, we analyzed whether the higher methylation levels correlated with the higher risk of gastric cancers.

Methods: Twenty-six healthy volunteers (HV), 30 cases with a single well-differentiated gastric cancer (S cases), and 32 cases with multiple well-differentiated gastric cancers (M cases) were recruited. H. pylori infection status was analyzed by the culture method. Methylation levels were quantified by real-time methylation-specific PCR of seven CpG islands.

Results: In H. pylori–negative individuals, significant increasing trends were present in the order of HV, S cases, and M cases for FLNc and HAND1 methylation levels (P < 0.01, Spearman's rank-order test). Furthermore, the FLNc methylation level of M cases was significantly higher than that of S cases (P < 0.01, t test). Even adjusted by the extent of gastric atrophy, the FLNc methylation level retained a significant increasing trend (P = 0.03). In contrast, methylation levels in H. pylori–positive individuals were increased to various degrees in all the three groups.

Conclusions: In H. pylori–negative individuals, methylation levels in gastric mucosae significantly increased in cases with a single gastric cancer and more in cases with multiple gastric cancers. Quantitative analysis of methylation levels is a promising risk marker for gastric cancers. (Cancer Epidemiol Biomarkers Prev 2006;15(11):2317–21)