Molecular and prognostic heterogeneity of microsatellite-unstable colorectal cancer

Colorectal cancers (CRCs) with a high level of microsatellite instability (MSI-H) are clinicopathologically distinct tumors characterized by predominance in females, proximal colonic localization, poor differentiation, mucinous histology, tumor-infiltrating lymphocytes, a Crohn’s-like lymphoid reaction and a favorable prognosis. In terms of their molecular features, MSI-H CRCs are heterogeneous tumors associated with various genetic and epigenetic alterations, including DNA mismatch repair deficiency, target microsatellite mutations, BRAF mutations, a CpG island methylator phenotype-high (CIMP-H) status, and a low level of genomic hypomethylation. The molecular heterogeneity of MSI-H CRCs also depends on ethnic differences; for example, in Eastern Asian countries, relatively low frequencies of CIMP-H and BRAF mutations have been observed in MSI-H CRCs compared to Western countries. Although the prognostic features of MSI-H CRCs include a favorable survival of patients and low benefit of adjuvant chemotherapy, there may be prognostic differences based on the molecular heterogeneity of MSI-H CRCs. Here, we have reviewed and discussed the molecular and prognostic features of MSI-H CRCs, as well as several putative prognostic or predictive molecular markers, including HSP110 expression, beta2-microglobulin mutations, myosin 1a expression, CDX2/CK20 expression, SMAD4 expression, CIMP status and LINE-1 methylation levels.

Loss of CDX2 expression is associated with poor prognosis in colorectal cancer patients

AIM:To investigate the clinicopathologic characteristics and prognostic implications associated with loss of CDX2 expression in colorectal cancers(CRCs).METHODS:We immunohistochemically evaluated CDX2 expression in 713 CRCs and paired our findings to clinicopathologic and molecular characteristics of each individual.Endpoints included cytokeratin 7 and CK20 expression,microsatellite instability,Cp G island methylator phenotype,and KRAS and BRAF mutation statuses.Univariate and multivariate survival analysis was performed to reveal the prognostic value of CDX2 downregulation.RESULTS:CDX2 expression was lost in 42(5.9%) patients.Moreover,loss of CDX2 expression was associated with proximal location,infiltrative growth,advanced T,N,M and overall stage.On microscopic examination,loss of CDX2 expression was associated with poor differentiation,increased number of tumor-infiltrating lymphocytes,luminal serration and mucin production.Loss of CDX2 expression was also associated with increased CK7 expression,decreased CK20 expression,Cp G island methylator phenotype,microsatellite instability and BRAF mutation.In a univariate survival analysis,patients with loss of CDX2 expression showed worse overall survival(P < 0.001) and progression-free survival(P < 0.001).In a multivariate survival analysis,loss of CDX2 expression was an independent poor prognostic factor of overall survival [hazard ratio(HR) = 1.72,95%CI:1.04-2.85,P = 0.034] and progression-free survival(HR = 1.94,95%CI:1.22-3.07,P = 0.005).CONCLUSION:Loss of CDX2 expression is associated with aggressive clinical behavior and can be used as a prognostic marker in CRCs.

Annexin A10 expression in colorectal cancers with emphasis on the serrated neoplasia pathway

AIM: To validate the utility of Annexin A10 as a surrogate marker of the serrated neoplasia pathway in invasive colorectal cancers(CRCs).METHODS: A total of 1133 primary CRC patients who underwent surgical resection at Seoul National University Hospital between January 2004 and December 2007 were enrolled.Expression of Annexin A10 was evaluated by immunohistochemistry using tissue microarray and paired to our findings on clinicopathologic and molecular characteristics of each individual.Cp G island methylator phenotype was determined by Methy Light assay and microsatellite instability was determined by high performance liquid chromatography.KRAS and BRAF mutation status was evaluated by direct sequencing and allele-specific PCR.Univariate and stage-specific survival analyses were performed to reveal the prognostic value of Annexin A10 expression.RESULTS: Annexin A10 expression was observed in 66(5.8%) of the 1133 patients.Annexin A10 expression was more commonly found in females and was associated with proximal location,ulcerative gross type,advanced T category,N category and TNM stage.CRCs with Annexin A10 expression showed an absence of luminal necrosis,luminal serration and mucin production.CRCs with Annexin A10 expression were associated with Cp G island methylator phenotype,microsatellite instability and BRAF mutation.In survival analysis,Annexin A10 expression was associated with poor overall survival and progression-free survival,especially in stage Ⅳ CRCs.CONCLUSION: Annexin A10 expression is associated with poor clinical behavior and can be used a supportive surrogate marker of the serrated neoplasia pathway in invasive CRCs.