<i>MUC5</i><scp><i>AC</i></scp> hypomethylation is a predictor of microsatellite instability independently of clinical factors associated with colorectal cancer

<jats:p>Colorectal cancers (CRC) with microsatellite instability (MSI) display unique clinicopathologic features including a mucinous pattern with frequent expression of the secreted mucins MUC2 and MUC5AC. The mechanisms responsible for this altered pattern of expression remain largely unknown. We quantified DNA methylation of mucin genes (<jats:italic>MUC2</jats:italic>, <jats:italic>MUC5AC</jats:italic>, <jats:italic>MUC4</jats:italic>) in colonic cancers and examined the association with clinicopathological characteristics and molecular (MSI, <jats:italic>KRAS</jats:italic>, <jats:italic>BRAF,</jats:italic> and <jats:italic>TP53</jats:italic> mutations) features. A control cohort was used for validation. We detected frequent hypomethylation of <jats:italic>MUC2</jats:italic> and <jats:italic>MUC5AC</jats:italic> in CRC. <jats:italic>MUC2</jats:italic> and <jats:italic>MUC5AC</jats:italic> hypomethylation was associated with MUC2 and MUC5AC protein expression (<jats:italic>p</jats:italic> = 0.004 and <jats:italic>p</jats:italic> < 0.001, respectively), poor differentiation (<jats:italic>p</jats:italic> = 0.001 and <jats:italic>p</jats:italic> = 0.007, respectively) and MSI status (<jats:italic>p</jats:italic> < 0.01 and <jats:italic>p</jats:italic> < 0.001, respectively). Interestingly, <jats:italic>MUC5AC</jats:italic> hypomethylation was specific to MSI cancers. Moreover, it was significantly associated with <jats:italic>BRAF</jats:italic> mutation and CpG island methylator phenotype (<jats:italic>p</jats:italic> < 0.001 and <jats:italic>p</jats:italic> < 0.001, respectively). All these results were confirmed in the control cohort. In the multivariate analysis, <jats:italic>MUC5AC</jats:italic> hypomethylation was a highly predictive biomarker for MSI cancers. <jats:italic>MUC5AC</jats:italic> demethylation appears to be a hallmark of MSI in CRC. Determination of <jats:italic>MUC5AC</jats:italic> methylation status may be useful for understanding and predicting the natural history of CRC.</jats:p>