title: Concerted promoter hypermethylation of hMLH1, p16INK4A, and E-cadherin in gastric carcinomas with microsatellite instability.
abstract: 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.
authors.affiliation: Department of Pathology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Hyunki
authors.initials: H
authors.lastname: Kim
authors.forename: Yun Hee
authors.initials: YH
authors.lastname: Kim
authors.forename: Sung Eun
authors.initials: SE
authors.lastname: Kim
authors.forename: Nam-Gyun
authors.initials: NG
authors.lastname: Kim
authors.forename: Sung Hoon
authors.initials: SH
authors.lastname: Noh
authors.forename: Hoguen
authors.initials: H
authors.lastname: Kim
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D015820:Cadherins / Q000235:genetics; D002352:Carrier Proteins; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D052138:Genes, Neoplasm / Q000235:genetics*; D016147:Genes, Tumor Suppressor; D019942:Genes, p16; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008025:Ligases / Q000235:genetics; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics*; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic / Q000235:genetics*; D016160:Retinoblastoma Protein / Q000235:genetics; D013274:Stomach Neoplasms / Q000235:genetics*; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015820:Cadherins; D002352:Carrier Proteins; D004273:DNA, Neoplasm; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C411762:RASSF1 protein, human; D016160:Retinoblastoma Protein; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000070957:MutL Protein Homolog 1; D008025:Ligases; C497446:VHL protein, human