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

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.

Ferracin M ，Gafà R ，Miotto E ，Veronese A ，Pultrone C ，Sabbioni S ，Lanza G ，Negrini M ... -  《JOURNAL OF PATHOLOGY》

Fatty acid synthase overexpression in colorectal cancer is associated with microsatellite instability, independent of CpG island methylator phenotype.

Ogino S ，Kawasaki T ，Ogawa A ，Kirkner GJ ，Loda M ，Fuchs CS ... -  《HUMAN PATHOLOGY》

The CpG island methylator phenotype and chromosomal instability are inversely correlated in sporadic colorectal cancer.

Goel A ，Nagasaka T ，Arnold CN ，Inoue T ，Hamilton C ，Niedzwiecki D ，Compton C ，Mayer RJ ，Goldberg R ，Bertagnolli MM ，Boland CR ... -  《GASTROENTEROLOGY》

The role of the CpG island methylator phenotype in colorectal cancer prognosis depends on microsatellite instability screening status.

Dahlin AM ，Palmqvist R ，Henriksson ML ，Jacobsson M ，Eklöf V ，Rutegård J ，Oberg A ，Van Guelpen BR ... -  《-》

Comprehensive analysis of CpG island methylator phenotype (CIMP)-high, -low, and -negative colorectal cancers based on protein marker expression and molecular features.

CpG island methylator phenotype (CIMP) is being investigated for its role in the molecular and prognostic classification of colorectal cancer patients but is also emerging as a factor with the potential to influence clinical decision-making. We report a comprehensive analysis of clinico-pathological and molecular features (KRAS, BRAF and microsatellite instability, MSI) as well as of selected tumour- and host-related protein markers characterizing CIMP-high (CIMP-H), -low, and -negative colorectal cancers. Immunohistochemical analysis for 48 protein markers and molecular analysis of CIMP (CIMP-H: ≥ 4/5 methylated genes), MSI (MSI-H: ≥ 2 instable genes), KRAS, and BRAF were performed on 337 colorectal cancers. Simple and multiple regression analysis and receiver operating characteristic (ROC) curve analysis were performed. CIMP-H was found in 24 cases (7.1%) and linked (p < 0.0001) to more proximal tumour location, BRAF mutation, MSI-H, MGMT methylation (p = 0.022), advanced pT classification (p = 0.03), mucinous histology (p = 0.069), and less frequent KRAS mutation (p = 0.067) compared to CIMP-low or -negative cases. Of the 48 protein markers, decreased levels of RKIP (p = 0.0056), EphB2 (p = 0.0045), CK20 (p = 0.002), and Cdx2 (p < 0.0001) and increased numbers of CD8+ intra-epithelial lymphocytes (p < 0.0001) were related to CIMP-H, independently of MSI status. In addition to the expected clinico-pathological and molecular associations, CIMP-H colorectal cancers are characterized by a loss of protein markers associated with differentiation, and metastasis suppression, and have increased CD8+ T-lymphocytes regardless of MSI status. In particular, Cdx2 loss seems to strongly predict CIMP-H in both microsatellite-stable (MSS) and MSI-H colorectal cancers. Cdx2 is proposed as a surrogate marker for CIMP-H.

Zlobec I ，Bihl M ，Foerster A ，Rufle A ，Lugli A ... -  《-》