Molecular analysis of gastric differentiated-type intramucosal and submucosal cancers.

Identification of the molecular characteristics of intramucosal (IMCs) and submucosal cancers (SMCs) is essential to our understanding of early gastric carcinogenesis. However, little is known regarding the differences between the 2 lesions. One hundred and forty-eight patients with primary early gastric cancer [IMC, 106; SMC, 42] were characterized for expression of cell cycle-related proteins and loss of heterozygosity (LOH). We also examined microsatellite instability (MSI) and methylation status. For LOH and methylation studies, we used a panel of 17 microsatellite markers (3p, 4p, 5q, 9p. 13q, 17p, 18q and 22q) and promoter regions of 9 genes (MLH-1, RUNX3, p16, HPP1, RASSF2A, SFRP1, DKK-1, ZFP64 and SALL4) that are frequently altered or methylated in gastric cancers. Overexpression of p53 and cyclin D1 was observed in SMC. In addition, low expression of p27 was more frequent in SMC than in IMC. Frequencies of 4p, 9p, 13q and 22q were significantly higher in SMC than in IMC. The SALL4 gene was frequently methylated in SMC compared with IMC. However, other gene methylations were common in both IMC and SMC. The frequency of LOH-high status/methylation-low status was significantly higher in SMC than in IMC. However, LOH-low status/methylation-high status in SMC was more frequently found in IMC. Our data confirm that methylation of cancer-related genes plays a major role in the development of IMCs. Importantly, the results also show that gastric submucosal progression is characterized by the accumulation of specific genetic alterations. In addition, changes of cell cycle-related proteins are associated with cancer progression.