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.