Prognostic and therapeutic value of a 23-gene risk score tailored to the molecular characteristics of mucinous colorectal cancer.

BACKGROUND

Mucinous adenocarcinoma (MuC), a colorectal cancer (CRC) subtype, exhibits distinct molecular features and poorer response to chemoradiotherapy than non-mucinous adenocarcinoma (NMuC). Conventional treatments often fail to address CRC heterogeneity, particularly in stage II disease. Therefore, improved biomarkers for risk stratification and personalised treatment are needed.

METHODS

We analysed gene expression and mutation data from 259 CRC samples to identify characteristics of MuC. A 23-gene risk score (MuC-RS) was developed and validated across four independent cohorts (n = 1157). Statistical analyses, including generalised linear model likelihood ratio tests, Kaplan-Meier curves, log-rank tests, and Cox regression models, evaluated the prognostic utility of the MuC-RS.

RESULTS

MuC showed significant upregulation of fibroblast-associated genes, pathways related to epithelial-mesenchymal transition, and mucin glycosylation. The MuC-RS effectively stratified patients into high-risk (MuC-H) and low-risk (MuC-L) groups, with multivariate analysis confirming its prognostic value (HR = 1.72, 95% CI = 1.31-2.25, P < 0.001). Stage II MuC-L patients had poorer outcomes after conventional chemotherapy, but responded better to immune checkpoint inhibitors (ICIs), linked to higher tumour mutation burden and immune activation.

CONCLUSIONS

The MuC-RS effectively predicts recurrence and guides personalised treatment in CRC, particularly benefiting stage II MuC patients through improved risk stratification and treatment selection.