ARID1A immunohistochemical expression is associated with metachronous colorectal polyp risk: Evidence from integrated genomic and transcriptomic analyses

Current post-polypectomy surveillance strategies rely on morphological features and fail to capture the biological heterogeneity that underlies early colorectal neoplasia. While the SWI/SNF subunit ARID1A is frequently altered in colorectal cancer, its clinical utility and biological role during the pre-malignant stage remain unclear. We evaluated ARID1A protein expression via immunohistochemistry (IHC) in colorectal polyp tissue microarrays (TMAs, n=1184). To define the underlying biology, we integrated somatic mutation profiling, bulk RNA sequencing and multiplex immunofluorescence for immune context (CD3, CD8, FOXP3, and CD68). High ARID1A expression was independently associated with a significantly increased risk of metachronous lesions (p<0.001), consistently stratifying patients otherwise classified as low risk by conventional criteria (e.g., single polyps). Somatic ARID1A mutations correlated with reduced protein expression (p<0.001), supporting a genetic basis for these divergent phenotypes. Transcriptomic profiling revealed that high-ARID1A polyps were driven by Myc- target pathways, high cell proliferation, transcriptional activation and a pronounced regenerative stem-cell signature, alongside increased FOXP3+ regulatory T-cell infiltration. Conversely, ARID1A-low lesions were characterised by transcriptional repression, cell- differentiation pathways, and increased CD8+ T-cell infiltration. Tissue ARID1A expression captures the underlying pathogenic heterogeneity in pre-malignant colorectal disease, linking distinct genomic, transcriptomic and immune profiles directly to clinical behaviour. Assessing ARID1A status provides a powerful, biologically informed framework for improving post-polypectomy risk stratification beyond conventional clinicopathological criteria.