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Distinct promoter hypermethylation of p 16 INK 4 a , CDH1 , and RAR‐beta in intestinal, diffuse–adherent, and diffuse–scattered type gastric carcinomas
Author(s) -
Oue Naohide,
Motoshita Junichi,
Yokozaki Hiroshi,
Hayashi Ken,
Tahara Eiichi,
Taniyama Kiyomi,
Matsusaki Keisuke,
Yasui Wataru
Publication year - 2002
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.1170
Subject(s) - cdh1 , cpg site , dna methylation , promoter , methylation , biology , cancer research , microbiology and biotechnology , exact test , gene , medicine , genetics , cadherin , gene expression , cell
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 p 16 INK 4 a , 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 p 16 INK 4 a , CDH1 , and RAR‐beta promoters was detected in 12 (27%), 26 (58%), and 24 (53%) of the 45 gastric carcinomas, respectively. Hypermethylation of the p 16 INK 4 a 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 p 53 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 p 53 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 ( p 16 INK 4 a promoter hypermethylation) and diffuse–scattered types ( CDH1 and RAR‐beta promoter hypermethylation) of gastric carcinoma. Copyright © 2002 John Wiley & Sons, Ltd.