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

Aberrant methylation of 5' CpG islands is thought to play an important role in the inactivation of tumor suppressor genes in cancer. In colorectal can cer, a group of tumors is characterized by a hypermethylator phenotype term ed CpG island methylator phenotype (CIMP), which includes methylation of su ch genes as p16 and hMLH1, To study whether CIMP is present in gastric canc er, 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 th ese 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 defected in three of five tumors that showed microsatellite instability, and all three of the cases were CI MP+. 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 sug gest that CIMP may be one of the major pathways that contribute to tumorige nesis in gastric cancers.