title: Concurrent hypermethylation of gene promoters is associated with a MSI-H phenotype and diploidy in gastric carcinomas.
abstract: Changes in the pattern of DNA methylation are among the most common alterations observed in human cancers, such as gastric carcinomas. We analysed in a series of 51 sporadic gastric carcinomas the methylation status of the promoter regions of the hMLH1, CDH1, MGMT and COX2 genes. We aimed to determine the frequency of CpG island hypermethylation and to find out whether the occurrence of concurrent hypermethylation is related to the clinicopathological features of the gastric carcinomas. Using methylation-sensitive restriction analysis/polymerase chain reaction (PCR) and methylation-specific PCR (MSP) strategies, we searched for the presence of hypermethylation on the promoter region of the 4 selected genes. All showed hypermethylation of their promoter regions with frequencies of 37, 51, 61 and 29% for hMLH1, CDH1, MGMT and COX2, respectively. Concurrent hypermethylation was more frequently observed in MSI-H (P=0.0005) and diploid (P=0.029) tumours. Hypermethylation of hMLH1 was associated with MSI-H tumours (P=0.0001), whereas hypermethylation of MGMT was associated with MSI-H (p=0.021) and diploid tumours (p=0.012). Our results indicate that concurrent hypermethylation is a common event in gastric cancer, suggesting that global methylation changes play an important role in the development of sporadic gastric carcinoma. Moreover, inactivation of different gene promoters by hypermethylation is significantly associated with microsatellite instability (MSI-H) and diploidy: hMLH1 determines MSI-H and MGMT the diploid status of gastric carcinomas.
authors.affiliation: IPATIMUP-Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal.
authors.forename: B
authors.initials: B
authors.lastname: Carvalho
authors.forename: M
authors.initials: M
authors.lastname: Pinto
authors.forename: L
authors.initials: L
authors.lastname: Cirnes
authors.forename: C
authors.initials: C
authors.lastname: Oliveira
authors.forename: J C
authors.initials: JC
authors.lastname: Machado
authors.forename: G
authors.initials: G
authors.lastname: Suriano
authors.forename: R
authors.initials: R
authors.lastname: Hamelin
authors.forename: F
authors.initials: F
authors.lastname: Carneiro
authors.forename: R
authors.initials: R
authors.lastname: Seruca
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D015820:Cadherins / Q000235:genetics; D002352:Carrier Proteins; D018899:CpG Islands / Q000235:genetics; D051546:Cyclooxygenase 2; D019175:DNA Methylation; D004171:Diploidy; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000235:genetics; D008297:Male; D008565:Membrane Proteins; D018895:Microsatellite Repeats / Q000235:genetics*; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics; D010641:Phenotype; D016133:Polymerase Chain Reaction / Q000379:methods; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D013274:Stomach Neoplasms / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D002352:Carrier Proteins; D007527:Isoenzymes; C501486:MLH1 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000070957:MutL Protein Homolog 1