Distinct promoter hypermethylation of p16INK4a, CDH1, and RAR‐beta in intestinal, diffuse–adherent, and diffuse–scattered type gastric carcinomas

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Abstract
Hypermethylation of CpG islands in gene promoters is associated with silencing of various tumour suppressor genes. Recent studies of colorectal and gastric carcinomas have defined a CpG island methylator phenotype (CIMP), which involves the targeting of multiple genes by promoter hypermethylation. In this study, methylation‐specific polymerase chain reaction (PCR) was performed to study methylation of CpG islands in the promoters of the p16INK4a, cadherin 1 (CDH1), and retinoic acid receptor‐beta (RAR‐beta) genes in 45 gastric carcinomas and to investigate whether CDH1 and RAR‐beta promoter hypermethylation is associated with CIMP‐positive gastric carcinoma. CpG island hypermethylation of the p16INK4a, CDH1, and RAR‐beta promoters was detected in 12 (27%), 26 (58%), and 24 (53%) of the 45 gastric carcinomas, respectively. Hypermethylation of the p16INK4a promoter was more common in intestinal type than in diffuse type gastric carcinomas (p = 0.0023; Fisher's exact test) and was inversely associated with p53 mutations (p = 0.0225; Fisher's exact test). However, CDH1 and RAR‐beta promoter hypermethylation was observed more frequently in diffuse–scattered type gastric carcinoma than in other types (intestinal and diffuse–adherent types) (p = 0.0175 and p = 0.0335, respectively; Fisher's exact test) and was not associated with p53 mutation status. Moreover, hypermethylation of the CDH1 and RAR‐beta promoters occurred concordantly (p < 0.0001; Fisher's exact test). These results suggest that at least two types of promoter methylation status are involved in the development of the intestinal (p16INK4a promoter hypermethylation) and diffuse–scattered types (CDH1 and RAR‐beta promoter hypermethylation) of gastric carcinoma. Copyright © 2002 John Wiley & Sons, Ltd.