DNA methylation profiles of differentiated-type gastric carcinomas with distinct mucin phenotypes

Gastric carcinomas (GC) are classified into four phenotypes according to mucin expression. Previous studies revealed the association of distinct genetic profiles in GC with mucin phenotypic expression; however, the roles of epigenetic changes, such as DNA methylation, are poorly understood. We examined whether the phenotypic expression of GC was associated with DNA methylation of hMLH1, MGMT, p16^INK4a, RAR-beta or CDH1. Expression of HGM, M-GGMC-1, MUC2, and CD10 was analyzed immunohistochemically in 33 advanced GC with differentiated histology. HGM was expressed in 14 (42.4%) cases, M-GGMC-1 in five (15.2%) cases, MUC2 in 15 (45.5%) cases and CD10 in 18 (54.5%) cases. DNA methylation was detected in five (15.2%) cases for hMLH1, 11 (33.3%) cases for MGMT, 13 (39.4%) cases for p16^INK4a, 17 (51.5%) cases for RAR-beta and 14 (42.4%) cases for CDH1 by bisulfite-polymerase chain reaction and methylation-specific polymerase chain reaction. DNA methylation of hMLH1 occurred more frequently in MUC2-negative GC than in MUC2-positive GC (P = 0.0488, Fisher's exact test). In contrast, MGMT was more frequently methylated in MUC2-positive GC than in MUC2-negative GC (P = 0.0078, Fisher's exact test). There was no correlation between gastric or intestinal-markers and methylation of the p16^INK4a, RAR-beta and CDH1 genes. These results indicate that DNA methylation of specific genes, such as hMLH1 and MGMT, may be involved partly in the distinct phenotypic expression of GC.