Distal colorectal cancers with microsatellite instability (MSI) display distinct gene expression profiles that are different from proximal MSI cancers

Promoter methylation of the mismatch repair gene plays a key role in sporadic microsatellite instability (MST) colorectal cancers. However, promoter methylation often occurs in proximal colon cancers, and molecular phenotypes underlying MST cancers in distal colon have not been fully clarified. Our goal was to clarify the difference between MST and microsatellite stability (MSS) cancers and, furthermore, to determine distinct characteristics of proximal and distal MST cancers. By DNA microarray analysis of 84 cancers (33 MST and 51 MSS), we identified discriminating genes (177 probe sets), which predicted MST status with a high accuracy rate (97.6%). These genes were related to phenotypic characteristics of MST cancers. Next, we identified 24 probe sets that were differentially expressed in proximal and distal MST cancers. These genes included promoter methylation-mediated genes, whose expression was significantly down-regulated in proximal MST cancers. Among discriminating genes between MST and MSS, nine methylation-mediated genes showed down-regulation in MST cancers. Of these, 7 (77.8%) showed down-regulation in proximal MST cancers. Furthermore, methylation-specific PCR confirmed that frequency of hMLH1 promoter methylation was significantly higher in proximal MST cancers (P = 0.0317). These results suggested that there is a difference between proximal and distal MST cancers in methylation-mediated influence on gene silencing. In conclusion, using DNA microarray, we could distinguish MST and MSS cancers. We also showed distinct characteristics of proximal and distal MST cancers. The inactivation form of hMLH, per se, differed between proximal and distal MST cancers. These results suggested that distal MST cancers constitute a distinct subgroup of sporadic MST cancers.