Clinicopathological and prognostic significance of mucin signatures in lower gastrointestinal cancer–a systematic review and meta-analysis

Aberrant mucin expression is implicated in lower gastrointestinal tract (GIT) cancers, yet its clinicopathological relevance remains poorly understood. To identify distinct mucin signatures in association with (pre)tumour subtypes, anatomical location, and clinical outcomes, we conducted a systematic review and meta-analysis of MEDLINE articles published between January 2001 and September 2025. Studies were included if they assessed mucin expression in lower GIT (pre)malignant lesions. Fifty-eight studies were eligible. MUC2 and MUC5AC expression was upregulated in serrated polyps and mucinous- and microsatellite instability (MSI)-associated proximal adenocarcinomas, whereas a downregulation of MUC2 was noted in advanced adenomas and non-mucinous distal tumours. Discrepancies in survival in relation to high-level or low-level MUC2 further suggested that this glycoprotein cooperates with other mucins during carcinogenesis. Notably, abundant MUC1 expression was seen in adenomas with high-grade dysplasia and together with high-level MUC13 correlated with (non-)mucinous CRC types and poor prognosis. Similar mucin signatures were also found in small intestinal adenocarcinoma, yet MUC2 was downregulated and increased MUC5AC rather associated with a worse survival, emphasizing the role of tumour location in influencing tumour behaviour. In conclusion, aberrant mucin signatures reflect distinct molecular pathways in (pre)malignant GIT lesions and highlight their potential utility as biomarkers and therapeutic targets. Schematic representation of the main findings regarding altered mucin signalling in several precancerous lesions (adenomatous (i.e., conventional pathway 1) and serrated polyps (i.e. pathway 2)) and small intestinal (SIA) and colorectal (CRC) adenocarcinomas and its clinicopathological significance (outcome, anatomical location (proximal/distal), molecular subtypes (MSI, (non)-mucinous).