Upregulated MUC2 Is an Unfavorable Prognostic Indicator for Rectal Cancer Patients Undergoing Preoperative CCRT

Abstract

For locally advanced rectal cancer patients, introducing neoadjuvant concurrent chemoradiotherapy (CCRT) before radical resection allows tumor downstaging and increases the rate of anus retention. Since accurate staging before surgery and sensitivity prediction to CCRT remain challenging, a more precise genetic biomarker is urgently needed to enhance the management of such situations. The epithelial mucous barrier can protect the gut lumen, but aberrant mucin synthesis may defend against drug penetration. In this study, we focused on genes related to maintenance of gastrointestinal epithelium (GO: 0030277) and identified mucin 2 (MUC2) as the most significantly upregulated gene correlated with CCRT resistance through a public rectal cancer transcriptome dataset (GSE35452). We retrieved 172 records of rectal cancer patients undergoing CCRT accompanied by radical resection from our biobank. We also assessed the expression level of MUC2 using immunohistochemistry. The results showed that upregulated MUC2 immunoexpression was considerably correlated with the pre-CCRT and post-CCRT positive nodal status (p = 0.001 and p < 0.001), advanced pre-CCRT and post-CCRT tumor status (p = 0.022 and p < 0.001), vascular invasion (p = 0.015), and no or little response to CCRT (p = 0.006). Upregulated MUC2 immunoexpression was adversely prognostic for all three endpoints, disease-specific survival (DSS), local recurrence-free survival (LRFS), and metastasis-free survival (MeFS) (all p < 0.0001), at the univariate level. Moreover, upregulated MUC2 immunoexpression was an independent prognostic factor for worse DSS (p < 0.001), LRFS (p = 0.008), and MeFS (p = 0.003) at the multivariate level. Collectively, these results imply that upregulated MUC2 expression is characterized by a more advanced clinical course and treatment resistance in rectal cancer patients undergoing CCRT, revealing the potential prognostic utility of MUC2 expression.

Keywords: MUC2; chemoradiotherapy; mucous barrier; rectal cancer; treatment resistance.

Figure 1

Expression profiling of genes associated with maintenance of gastrointestinal epithelium (GO: 0030277) in relation to the response to CCRT. We identified MUC2 as the most significantly upregulated gene connected with maintenance of gastrointestinal epithelium among CCRT non-responders.

Figure 2

Immunohistochemical detection of MUC2. Representative images of rectal adenocarcinoma exhibiting high MUC2 immunoexpression among CCRT non-responders. (A) CCRT responder; (B) CCRT non-responder (signet-ring cell carcinoma); (C) CCRT non-responder (adenocarcinoma with ordinary glandular morphology).

Figure 3

Survival analysis. Kaplan-Meier plots were generated and showed that high MUC2 immunoexpression was considerably connected with inferior (A) disease-specific survival; (B) local recurrence-free survival; and (C) metastasis-free survival.