Aberrant methylation in gastric cancer associated with the CpG island methylator phenotype

• Published in: Cancer research (Chicago, Ill.) Vol. 59; no. 21; pp. 5438 - 5442
• Main Authors: TOYOTA, M, AHUJA, N, SUZUKI, H, ITOH, F, OHE-TOYOTA, M, IMAI, K, BAYLIN, S. B, ISSA, J.-P. J
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.11.1999
• Subjects: Adaptor Proteins, Signal Transducing; Alleles; Biological and medical sciences; Carrier Proteins; CpG Islands - genetics; Cyclin-Dependent Kinase Inhibitor p16 - genetics; Cyclin-Dependent Kinase Inhibitor p16 - metabolism; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Regulation, Neoplastic; Humans; Medical sciences; Methylation; Models, Genetic; Mucous Membrane - metabolism; MutL Protein Homolog 1; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Nuclear Proteins; Phenotype; Polymerase Chain Reaction; Stomach Neoplasms - genetics; Stomach Neoplasms - metabolism; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumors; Human; Stomach; Pathogenesis; Tumoral tissue; Malignant tumor; Inactivation; Carcinogenesis; CDKN2 gene; Phenotype; Digestive diseases; Methylation; Gastric disease; Tumor suppressor gene
• ISSN: 0008-5472; 1538-7445

Aberrant methylation of 5' CpG islands is thought to play an important role in the inactivation of tumor suppressor genes in cancer. In colorectal cancer, a group of tumors is characterized by a hypermethylator phenotype termed CpG island methylator phenotype (CIMP), which includes methylation of such genes as p16 and hMLH1. To study whether CIMP is present in gastric cancer, the methylation status of five newly cloned CpG islands was examined in 56 gastric cancers using bisulfite-PCR. Simultaneous methylation of three loci or more was observed in 23 (41%) of 56 cancers, which suggests that these tumors have the hypermethylator phenotype CIMP. There was a significant concordance between CIMP and the methylation of known genes including p16, and hMLH1; methylation of p16 was detected in 16 (70%) of 23 CIMP+ tumors, 1 (8%) of 12 CIMP intermediate tumors, and 1 (5%) of 21 CIMP- tumors (P<0.0001). Methylation of the hMLH1 gene was detected in three of five tumors that showed microsatellite instability, and all three of the cases were CIMP+. The CIMP phenotype is an early event in gastric cancer, being present in the normal tissue adjacent to cancer in 5 of 56 cases. These results suggest that CIMP may be one of the major pathways that contribute to tumorigenesis in gastric cancers.