BRAF/K-ras mutation, microsatellite instability, and promoter hypermethylation of hMLH1/MGMT in human gastric carcinomas

• DOI: 10.1007/s10120-004-0300-9
• Publication Date: 2004-12-22T18:25:49Z
• Authors: Ming Wu; Shuho Semba; Naohide Oue; Nobunao Ikehara; Wataru Yasui; Hiroshi Yokozaki
• Keywords: Proto-Oncogene Proteins B-raf; DNA Repair; Base Pair Mismatch; Carcinoma; DNA Mutational Analysis; Nuclear Proteins; DNA Methylation; Neoplasm Proteins; 3. Good health; O(6)-Methylguanine-DNA Methyltransferase; 03 medical and health sciences; Genes, ras; 0302 clinical medicine; Stomach Neoplasms; Disease Progression; Tumor Cells, Cultured; Humans; Carrier Proteins; MutL Protein Homolog 1; Promoter Regions, Genetic; Adaptor Proteins, Signal Transducing; Microsatellite Repeats

The BRAF and K-ras genes are the most frequently mutated oncogenes in various human malignancies. We examined BRAF and K-ras mutations in human gastric cancer, and investigated their relationship with microsatellite instability (MSI) and the hypermethylation of promoter regions in hMLH1 and O6-methylguanine DNA methyltransferase (MGMT).Sixteen gastric cancer cell lines and 62 gastric cancer tissue samples were screened for BRAF and K-ras mutations by direct sequencing. We also performed a microsatellite assay and investigated methylation status in the promoter regions of hMLH1 and MGMT.mutation was not found in any of the cancer cell lines examined. One (1.6%) cancer tissue sample showed a point mutation in the BRAF gene (GTG --> GAG; V599E). K-ras mutation (GGT --> GAT, G12D) was detected in five (31%) gastric cancer cell lines and in 1 (1.6%) gastric cancer tissue sample. In the gastric cancer tissue samples examined, MSI was detected in 23 (37%) samples. Hypermethylated promoter regions in hMLH1 and MGMT, respectively, were detected in 6 (10%) and 13 (21%) gastric cancer tissue samples. Microsatellite stable (MSS) tumors showed frequent lymphatic invasion (P = 0.050).Although BRAF mutation has been reported in a variety of other human cancers, it is a rare event in the carcinogenesis and progression/development of gastric cancer.