Loss of CDX2 expression is associated with aggressive clinical behavior and can be used as a prognostic marker in CRCs.

CpG island methylator phenotype (CIMP) is a recently described subset of colorectal cancers (CRC) with widespread methylation of multiple promoter CpG islands. But the prognostic implication of CIMP in CRC has not been clarified. Thus, the aim of the present study was to differentiate the unique characteristics of CIMP from those of microsatellite instability (MSI)-high CRC, especially with regard to prognosis. CIMP, MSI, and mutations of KRAS codons 12 and 13 and of BRAF codon 600 were evaluated in 134 sporadic CRC. Patient survival and other clinicopathological variables were correlated with CIMP or genetic changes. High CIMP, high MSI, and mutations in KRAS or BRAF were detected in 31.3%, 14.2%, 33.6%, and 4.5% of overall CRC, respectively. High CIMP was closely associated with MSI and BRAF mutation but not with KRAS mutation. CIMP-high, microsatellite-stable (MSS) CRC were significantly associated with proximal location and nodal metastasis and had close but non-significant associations with liver metastasis. A worse clinical outcome was found for CIMP-high, MSS CRC with KRAS/BRAF mutation but not for those lacking KRAS/BRAF mutation. The findings support the contention that CIMP-high CRC have distinct clinicopathological and epidemiological features and suggest that the alleged poor clinical outcome of CIMP-high CRC patients is closely associated with the presence of KRAS/BRAF mutation.

Background. The prognostic significance of microsatellite instability (MSI) in colorectal cancers (CRCs) has been addressed in many studies since the initial description of better survival rates in MSI-positive (MSI?) tumors than in MSI-negative (MSI-) tumors. Recent studies have demonstrated that a higher degree of hypomethylation of long interspersed nuclear element-1 (L1) is related to poor prognosis of CRCs and that a wide variation of L1 methylation levels exist within MSI? CRCs. Our aim was to identify whether L1 and Alu methylation status could predict clinical outcomes within MSI? CRCs. Methods. We analyzed 207 MSI? CRCs for their methylation levels in L1 and Alu repetitive DNA elements using pyrosequencing and correlated them with clinicopathological information including survival data. Results. Univariate survival analysis showed that low Alu methylation status (\18.60 %) and low L1 methylation status (\53.00 %) were significantly associated with shorter overall survival time (log-rank test, P = 0.009 and P \ 0.001, respectively). Multivariate analysis using nine parameters (Alu methylation status, L1 methylation status, patient's age, disease stage [tumor, node, metastasis staging system], differentiation, Crohn-like lymphoid reaction, KRAS/BRAF mutation status, CpG island methylator phenotype [CIMP] status, and peritumoral lymphocytic infiltration), which were significantly prognostic in MSI? CRCs, revealed that low L1 methylation status was an independent prognostic factor of MSI? CRCs (P = 0.009), whereas low Alu methylation status was not.Conclusions. Clinical outcomes of MSI? CRCs depend on L1 methylation status, suggesting that lower L1 methylation status serves as a significant prognostic parameter of adverse prognosis in MSI? CRCs.