Methylation of the hMLH1 promoter but no hMLH1 mutations in sporadic gastric carcinomas with high‐level microsatellite instability

• Published in: International journal of cancer Vol. 87; no. 2; pp. 200 - 203
• Main Authors: Bevilacqua, Roberta A.U., Simpson, Andrew J.G.
• Format: Journal Article
• Language: English
• Published: New York John Wiley & Sons, Inc 15.07.2000; Wiley-Liss
• Subjects: Adaptor Proteins, Signal Transducing; Adult; Aged; Aged, 80 and over; Alleles; Biological and medical sciences; Carrier Proteins; DNA Methylation; DNA-Binding Proteins; Female; Gastric Mucosa - metabolism; Gastroenterology. Liver. Pancreas. Abdomen; Gene Silencing; Germ-Line Mutation; Humans; Male; Medical sciences; Microsatellite Repeats; Middle Aged; Mutation; MutL Protein Homolog 1; MutS Homolog 2 Protein; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - genetics; Nuclear Proteins; Polymorphism, Genetic; Polymorphism, Single-Stranded Conformational; Promoter Regions, Genetic; Proto-Oncogene Proteins - biosynthesis; Proto-Oncogene Proteins - genetics; Stomach Neoplasms - genetics; Stomach Neoplasms - metabolism; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Trinucleotide Repeat Expansion; Tumor Cells, Cultured; Tumors; Human; Stomach; Carcinoma; Sporadic; Transcription promoter; Malignant tumor; Base mismatching; Gene; Microsatellite DNA; DNA; Digestive diseases; Genetics; Instability; Repair; Gastric disease
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/1097-0215(20000715)87:2<200::AID-IJC7>3.0.CO;2-I

Microsatellite instability (MSI) in tumors from patients with hereditary non‐polyposis colorectal cancer (HNPCC) is caused by germline mutations in mismatch repair (MMR) genes, principally hMSH2 and hMLH1. In contrast, somatic mutations in MMR genes are relatively rare in sporadic MSI+ colon cancers. Rather, the majority of mutation‐negative, MSI+ cases involve hypermethylation of the hMLH1 promoter and subsequent lack of expression of hMLH1. The details of the mechanisms of this epigenetic gene silencing remain to be elucidated. In some colon cancer cell lines, hMLH1 promoter methylation is accompanied by mutation of 1 of the 2 alleles, whereas in other cell lines and tumors, such combinations have not been reported. To contribute to the characterization of MSI in gastric cancer and to directly investigate whether hMLH1 promoter methylation is accompanied by gene mutation in these cancers, we have analyzed 42 gastric tumors and corresponding normal tissue for MSI, hypermethylation of the hMLH1 promoter, and mutations in hMLH1 as well as hMSH2. We found that 10 (23.8%) of 42 cases of sporadic gastric cancer were MSI+ and that 8 had at least 2 of 12 altered microsatellite loci. All samples with at least 2 altered loci exhibited methylation of the hMLH1 promoter region, but none had detectable mutations in hMLH1 or hMSH2. Our results confirm the importance of methylation of the hMLH1 promoter region in MSI+ gastric tumors and suggest that methylation takes place in the absence of hMLH1 mutations in these tumors. Int. J. Cancer 87:200–203, 2000. © 2000 Wiley‐Liss, Inc.