Distal Colorectal Cancers with Microsatellite Instability (MSI) Display Distinct Gene Expression Profiles that Are Different from Proximal MSI Cancers

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.

Familial colorectal cancer type X: genetic profiles and phenotypic features

“…70 MMR-proficient and MMR-deficient tumors show distinct profiles with 65-2070 significantly deregulated genes, including genes involved in growth factor receptors, transcription, cell cycle function, DNA repair, chromatin structure, drug metabolism, and chemoresistance. [70][71][72][73][74][75][76] Gene expression data from FCCTX tumors suggest similarity to sporadic MMR-proficient colorectal cancers with upregulation of genes involved in peptidyl-amino acid modification, enzyme-linked receptor protein signaling, growth regulation, DNA repair pathways, vascular smooth muscle contraction, and G protein-coupled receptor signaling. 25,77 The limited data available regarding signaling pathways in FCCTX tumors indicate involvement of G proteincoupled signaling and candidate genes involved in proliferation and migration, for example, CDH26, SRC, and ASIP (located in chromosome 20q).…”

Is rectal cancer prone to metastasize to lymph nodes than colon cancer?

“…The second point is about the significance of tumor location in the colon. Previous studies [3,4] , including ours [5] , have shown that patients with distal colon cancers exhibpatients with distal colon cancers exhibdistal colon cancers exhibited significantly better survival than those with proximal ed significantly better survival than those with proximal significantly better survival than those with proximal those with proximal proximal cancers, suggesting that it might be better to analyze proximal colon and distal colon separately.…”

Replication error deficient and proficient colorectal cancer gene expression differences caused by 3′UTR polyT sequence deletions

“…More recently, Jorissen et al (22) published a list of 829 probesets consistently differentially expressed across three independent datasets using primary tissue samples total of 82 RER− cases and 93 RER+ cases, which included the samples analyzed by Watanabe et al (21)(22)(23). Jorissen et al also gave a list of 192 probesets consistently differentially expressed across four independent datasets that included data from 10 RER+ and 10 RER− cell lines (2).…”