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(American Journal of Pathology. 2006;169:1643-1651.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.060552

Methylation of Multiple Genes in Gastric Glands with Intestinal Metaplasia

A Disorder with Polyclonal Origins

Mami Mihara^*, Yukinari Yoshida^*, Tetsuya Tsukamoto, Ken-ichi Inada, Yukihiro Nakanishi, Yukiko Yagi^*, Kohzoh Imai, Takashi Sugimura^*, Masae Tatematsu and Toshikazu Ushijima^*

From the Carcinogenesis^* and Pathology Divisions, National Cancer Center Research Institute, Tokyo; Laboratory of Tumor Pathology, Aichi Cancer Center Research Institute, Nagoya; and First Department of Internal Medicine, Sapporo Medical University, School of Medicine, Sapporo, Japan

Gene silencing by methylation of promoter CpG islands is deeply involved in cancers, but its involvement in polyclonal disorders is still unclear. Here, we analyzed the presence of gene silencing in intestinal metaplasia (IM) of the stomach, a polyclonal disorder, in which multiple gastric glands aberrantly differentiate into those with intestinal characteristics. By a genome-wide screening, CpG islands in the putative promoter regions of four genes (ZIK1, ZNF141, KAL1, and FGF14) were found to be specifically methylated in glands with IM, and their expression was markedly decreased. When demethylation was induced in cell lines with their methylation by 5-aza-2'-deoxycytidine, expression of ZIK1, KAL1, and FGF14 was restored, supporting causal roles of methylation in their silencing. Analysis of ZIK1 methylation in a single gland showed that the vast majority of DNA molecules isolated from a gland with IM were methylated and that those from a gland without IM were not. ZIK1 methylation was present in glands isolated from physically distant positions within a stomach, showing that methylation occurred multifocally. These data indicate that methylation of multiple genes occurs independently in multiple glands, each of which has its own stem cell, demonstrating that involvement of aberrant gene silencing in noninherited polyclonal human disorders needs more attention.