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Concerted promoter hypermethylation of hMLH1, p16INK4A, and E-cadherin in gastric carcinomas with microsatellite instability

 Hyunki Kim  ;  Yun Hee Kim  ;  Hoguen Kim  ;  Sung Hoon Noh  ;  Nam-Gyun Kim  ;  Sung Eun Kim 
 JOURNAL OF PATHOLOGY, Vol.200(1) : 23-31, 2003 
Journal Title
Issue Date
Adaptor Proteins, Signal Transducing ; Cadherins/genetics ; Carrier Proteins ; CpG Islands/genetics* ; DNA Methylation* ; DNA, Neoplasm/genetics ; Female ; Genes, Neoplasm/genetics* ; Genes, Tumor Suppressor ; Genes, p16 ; Humans ; Immunohistochemistry/methods ; Ligases/genetics ; Male ; Microsatellite Repeats/genetics* ; Middle Aged ; MutL Protein Homolog 1 ; Neoplasm Proteins/genetics ; Nuclear Proteins ; Promoter Regions, Genetic/genetics* ; Retinoblastoma Protein/genetics ; Stomach Neoplasms/genetics* ; Tumor Suppressor Proteins* ; Ubiquitin-Protein Ligases* ; Von Hippel-Lindau Tumor Suppressor Protein
microsatellite instability ; CpG island methylator phenotype ; gastric carcinoma ; hMLH1 ; p16^INK 4A ; E-cadherin
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, p16INK4A, 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, p16INK4A, and E-cadherin and the frequency was significantly higher in MSI-H gastric carcinomas. Promoter hypermethylation of hMLH1, E-cadherin, and p16INK4A 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 p16INK4A 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.
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1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Hogeun(김호근)
Noh, Sung Hoon(노성훈) ORCID logo https://orcid.org/0000-0003-4386-6886
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