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Concerted promoter hypermethylation of hMLH1 , p16 INK4A , and E‐cadherin in gastric carcinomas with microsatellite instability
Author(s) -
Kim Hyunki,
Kim Yun Hee,
Kim Sung Eun,
Kim NamGyun,
Noh Sung Hoon,
Kim Hoguen
Publication year - 2003
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.1325
Subject(s) - microsatellite instability , methylation , dna methylation , cancer research , biology , cpg site , cancer , gene , microbiology and biotechnology , microsatellite , gene expression , genetics , allele
In most sporadic gastric carcinomas, microsatellite instability (MSI) originates from inactivation of the hMLH1 gene by promoter hypermethylation. However, the methylation patterns of other genes and their consequences in high MSI (MSI‐H) gastric carcinomas are not well characterized. To address the aberrant promoter methylation profiles of MSI‐H gastric carcinomas, promoter methylation of six genes ( hMLH1 , p16 INK4A , E‐cadherin, Rb, RASSF1A , and VHL ) and CpG island methylator phenotype (CIMP) were explored in 36 MSI‐H gastric carcinomas and the results were compared with those of 43 microsatellite‐stable (MSS) gastric carcinomas. Frequent promoter hypermethylation was found in hMLH1 , p16 INK4A , and E‐cadherin and the frequency was significantly higher in MSI‐H gastric carcinomas. Promoter hypermethylation of hMLH1, E‐cadherin , and p16 INK4A was found in 89%, 78%, and 33% of MSI‐H gastric carcinomas and in 16%, 32%, and 11% of MSS carcinomas, respectively ( p = 0.01). Selective absent or decreased expression of the gene product related to the hypermethylated promoter was found for hMLH1 and p16 INK4A in MSI‐H carcinoma, whereas the expression of E‐cadherin was generally decreased both in the MSI‐H and in the MSS carcinomas. MSI‐H gastric carcinomas were also related to the high CIMP (CIMP‐H, three or more of the five loci examined showing methylation). Twenty‐two (61%) MSI‐H gastric carcinomas were CIMP‐H, compared with only seven (16%) MSS carcinomas ( p = 0.001). These findings indicate that hMLH1 is one of the frequent methylation targets in CIMP‐H gastric carcinomas and that inactivation of hMLH1 through promoter hypermethylation results in tumours following the MSI pathway. Copyright © 2003 John Wiley & Sons, Ltd.