The methylator phenotype in microsatellite stable colorectal cancers is characterized by a distinct gene expression profile

The CpG island methylator phenotype (CIMP) in colorectal tumors can be recognized by an increased frequency of aberrant methylation in a specific set of genomic loci. Because of the strong association of CIMP with high microsatellite instability (MSI-H), the identification of CIMP+ tumors within microsatellite stable (MSS) colorectal cancers may not be straightforward. To overcome this potential limitation, we have built an improved 7-loci set of methylation markers that includes CACNA1G, IGF2, RUNX3, HTR6, RIZ1, MINT31 and MAP1B. This new set of CIMP markers revealed a bimodal distribution of methylation frequencies in a group of 95 MSS colorectal cancers, which allowed a clearer separation between CIMP classes. Correlation of MSS CIMP+ tumors with bio-pathological traits revealed significant associations with location to the proximal colon, mucinous histology, BRAF mutation and chromosomal stability. A potential trend toward an adverse prognosis of CIMP+ cases was associated with the high frequency of BRAF mutations present within this cohort of tumors. Microarray analysis revealed that CIMP+ tumors are characterized by a unique expression profile, a result that confirms that CIMP+ tumors represent a truly distinct molecular class within MSS colorectal cancers.