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

Walsh MD, Clendenning M, Williamson E, Pearson SA, Walters RJ, Nagler B, Packenas D, Win AK, Hopper JL, Jenkins MA, Haydon AM, Rosty C, English DR, Giles GG, McGuckin MA, Young JP, Buchanan DD (2013) Expression of MUC2, MUC5AC, MUC5B, and MUC6 mucins in colorectal cancers and their association with the CpG island methylator phenotype. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 26:1642-1656

Mucinous differentiation is associated with both CpG island methylator phenotype and microsatellite instability in colorectal cancer. The mucinous phenotype derives from abundant expression of the colonic goblet cell mucin, MUC2, and de novo expression of gastric foveolar mucin, MUC5AC. We, therefore, investigated the protein expression levels of MUC2 and MUC5AC, as well as MUC5B and MUC6, in molecular subtypes of colorectal cancer. Seven-hundred and twenty-two incident colorectal carcinomas occurring in 702 participants of the Melbourne Collaborative Cohort Study were characterized for methylator status, MLH1 methylation, somatic BRAF and KRAS mutations, microsatellite-instability status, MLH1, MSH2, MSH6, and PMS2 mismatch repair, and p53 protein expression, and their histopathology was reviewed. Protein expression levels of MUC2, MUC5AC, MUC5B, MUC6, and the putative mucin regulator CDX2 were compared with molecular and clinicopathological features of colorectal cancers using odds ratios and corresponding 95% confidence intervals. MUC2 overexpression (>25% positive tumor cells) was observed in 33% colorectal cancers, MUC5B expression in 53%, and de novo MUC5AC and MUC6 expression in 50% and 39%, respectively. Co-expression of two or more of the mucins was commonly observed. Expression of MUC2, MUC5AC and MUC6 was strongly associated with features associated with tumorigenesis via the serrated neoplasia pathway, including methylator positivity, somatic BRAF p.V600E mutation, and mismatch repair deficiency, as well as proximal location, poor differentiation, lymphocytic response, and increased T stage (all P<0.001). overexpression="" was="" observed="" in="" tumors="" with="" and="" without="" mucinous="" differentiation.="" there="" were="" inverse="" associations="" between="" expression="" of="" all="" four="" mucins="" and="" p53="" overexpression.="" cdx2="" expression="" was="" inversely="" associated="" with="" muc2,="" muc5ac="" and="" muc6="" expression.="" our="" results="" suggest="" that,="" in="" methylator-positive="" tumors,="" mucin="" genes="" on="" chromosome="" 11p15.5="" region="" undergo="" increased="" expression="" via="" mechanisms="" other="" than="" direct="" regulation="" by="" cdx2.modern="" pathology="" advance="" online="" publication,="" 28="" june="" 2013;="">