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

Abstract

The CpG island methylator phenotype (CIMP) in colorectal tumours 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+ tumours within microsatellite stable (MSS) colorectal cancers may not be straightforward. To overcome this potential limitation, we have built an improved seven-locus 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+ tumours with bio-pathological traits revealed significant associations with location to the proximal colon, mucinous histology, BRAF mutation, and chromosomal stability. A potential trend towards an adverse prognosis of CIMP+ cases was associated with the high frequency of BRAF mutations present within this cohort of tumours. Microarray analysis revealed that CIMP+ tumours are characterized by a unique expression profile, a result that confirms that CIMP+ tumours represent a truly distinct molecular class within MSS colorectal cancers.

The Role of the CpG Island Methylator Phenotype in Colorectal Cancer Prognosis Depends on Microsatellite Instability Screening Status

“…Although this subgroup was small, the result was consistent in both patient groups and was largely independent of potential confounding factors. Some studies, however, have reported contradictive findings (20,24,27,31).…”

“…A poor prognosis in CIMP-high CRC patients might result from other factors closely related to CIMP, such as the BRAF V600E mutation, rather than to an effect of the phenotype itself (20,22,26,27). MSI is another prime candidate, given its tight association with CIMP, but MSI is predictive of a better prognosis (28).…”

“…MSI is another prime candidate, given its tight association with CIMP, but MSI is predictive of a better prognosis (28). In addition, a shorter survival in patients with multiple promoter hypermethylation has frequently been attributed to the microsatellite stable (MSS) subgroup (6,19,20,22,26,29,30), although other studies have not found this association (27,31). The interpretation of studies investigating CIMP in CRC survival is also complicated by the different methods and gene panels used to assess CIMP status, but taking these issues into consideration does not explain the lack of consistency in findings.…”

Expression of MUC2, MUC5AC, MUC5B, and MUC6 mucins in colorectal cancers and their association with the CpG island methylator phenotype

“…[3][4][5] CIMP colorectal cancers are associated with clinicopathological features such as proximal location, poor grade, presence of tumor-infiltrating lymphocytes, and mucinous differentiation, as well as frequently demonstrating molecular somatic events including the BRAF p.V600E mutation and high levels of microsatellite instability, but with much lower levels of TP53 mutation than their chromosomal unstable colorectal carcinoma counterparts. [6][7][8][9][10][11][12] Mucins are high-molecular weight proteins characterized by the presence of large amino acid tandem repeat sequences that show allelic size variation. Secreted or gel-forming mucins comprise five known types: MUC2, MUC5AC, MUC5B, MUC6, and MUC19.…”

Chromosomally and microsatellite stable colorectal carcinomas without the CpG island methylator phenotype in a molecular classification

“…Thus, based on CIN, these tumours would appear to be related most closely to the 'standard type sporadic CRC' (group 4). In fact, as CIN was observed frequently in groups 2 and 3, it could be argued that CIMP would be relevant for CRC carcinogenesis only if the MLH1 gene promoter is affected, although global expression analyses have shown unique gene expression patterns for CIMP-high tumours without MSI-H (20).…”