# Interplay Between p53 and Wnt/β-Catenin Signaling in Colorectal Cancer: Associations with Mismatch Repair Status, Tumor Microenvironment, and Clinicopathological Outcomes

## TL;DR

This study explores how p53 and Wnt/β-catenin signaling interact in colorectal cancer, linking these pathways to tumor behavior and patient outcomes.

## Contribution

The study reveals how p53 dysfunction alters Wnt/β-catenin signaling and identifies a composite score that improves prognostic assessment in colorectal cancer.

## Key findings

- Tumors with abnormal p53 show increased nuclear β-catenin and aggressive features like tumor budding.
- A composite score combining p53 and Wnt/β-catenin markers improves survival prediction beyond tumor stage.
- Low nuclear β-catenin predicts recurrence and worse survival in mismatch repair-proficient tumors.

## Abstract

Colorectal cancer is biologically diverse, and treatment decisions are largely guided by tumor stage. In this study, we examined how abnormalities in p53, a key tumor suppressor protein frequently altered in cancer, are associated with alterations in the Wnt/β-catenin signaling pathway, including its activating ligand Wnt3, which regulates cell growth and invasion. β-catenin normally functions as a cell adhesion molecule at the cell membrane, but when Wnt signaling becomes dysregulated, it moves to the nucleus, where it activates genes that promote tumor progression. We also assessed how these alterations relate to DNA repair status and invasive-front features such as tumor budding and poorly differentiated clusters. Tumors with abnormal p53 expression showed increased nuclear β-catenin accumulation and more active invasive fronts, with higher tumor budding and poorly differentiated cluster formation, despite similar levels of Wnt3 expression. In contrast, tumors with intact p53 were more often associated with defects in DNA repair mechanisms. Although the pathological stage remained the strongest determinant of survival, combining key tumor markers with standard clinical assessment provided additional prognostic information and may help identify patients at higher risk of recurrence.

The interplay between TP53 alterations and Wnt/β-catenin signaling in colorectal cancer (CRC) remains unclear regarding mismatch repair (MMR) status, tumor budding (TB), poorly differentiated cluster (PDC), and prognosis. We analyzed 146 resected CRC cases, quantifying p53, Wnt3, and β-CTN indices and assessing MMR by PMS2 and MSH6 immunohistochemistry. p53 overexpression was associated with younger patients, left-sided tumors, nodal metastasis, and advanced stage, whereas wild-type tumors showed more mucinous differentiation. Deficient MMR was enriched among wild-type p53 cases. Principal component analysis identified distinct axes defined by p53, Wnt3, and β-CTN. Despite comparable Wnt3 levels, nuclear β-CTN accumulation was enhanced in tumors with aberrant (overexpression or null) p53 tumors, with increased TB and PDC indices. Low nuclear β-CTN independently predicted recurrence in stage I–III disease and worse overall survival in proficient MMR tumors (HR 3.07 and 2.52; p = 0.03 for both). A composite score integrating p53 binary status (aberrant vs. wild) with Wnt3 and whole β-CTN indices predicted survival beyond stage; each 1-point increase conferred a 2.56- and 1.77-fold higher risk of cancer-specific and overall mortality (p = 0.004 and 0.04). These findings suggest that p53 dysfunction is associated with alterations in Wnt/β-CTN signaling and that integrating signaling markers with staging may improve prognostic assessment in colorectal cancer.