Abstract

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

Highlights

  • Microsatellite instability (MSI) cancers have unique characteristics compared with microsatellite stability (MSS) cancers, such asNote: Supplementary data for this article are available at Cancer Research Online.I2006 American Association for Cancer Research. doi:10.1158/0008-5472.CAN-06-1163 proximal anatomic location and severe inflammatory cell infiltration [1, 2]

  • Using DNA microarray, we identified gene expression signatures that could distinguish MSI from MSS cancers

  • We showed that gene expression profiles differ significantly in proximal and distal MSI cancers

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Summary

Introduction

Microsatellite instability (MSI) cancers have unique characteristics compared with microsatellite stability (MSS) cancers, such asNote: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).I2006 American Association for Cancer Research. doi:10.1158/0008-5472.CAN-06-1163 proximal anatomic location and severe inflammatory cell infiltration [1, 2]. Microsatellite instability (MSI) cancers have unique characteristics compared with microsatellite stability (MSS) cancers, such as. In the carcinogenesis of MSI cancers, mononucleotide repeat is considered to be the target site, whereas the chromosomal instability pathway underlies MSS cancers [4]. Most of the promoter methylation of the genes is known to occur in proximal colon cancers [5]. This accounts for why many sporadic MSI cancers show proximal predominance. Some sporadic MSI cancers are located in the distal colon and the molecular phenotypes underlying distal MSI cancers have not been fully clarified

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