ARID1A protein expression enhances risk stratification in colorectal polyp surveillance

Background: Polyps detected during bowel cancer screening indicate an increased risk of developing metachronous colorectal lesions. Current British Society of Gastroenterology (BSG 2020) surveillance guidelines use polyp size, number, histology, and dysplasia grade to assess this risk but do not include molecular markers limiting accurate risk stratification. To address this gap, we investigated ARID1A expression as a potential predictive biomarker for metachronous colorectal lesions. Methods: A total of n=1184 archival colorectal polyp samples assembled into tissue microarrays (TMAs) were stained for ARID1A protein expression using immunohistochemistry (IHC) and epithelial ARID1A histoscores were assessed using Qupath. Data were divided into training (n=819) and test (n=365) datasets. Molecular profiling included somatic mutation sequencing (n=623) and bulk RNA Temp-O-seq comparing low vs high ARID1A expression (n=117 for each group). Pathway analyses incorporated Hallmark gene sets using GSEA and ssGSEA as well as Reactome pathway enrichment and Dorothea transcription factor activity scoring. Results: High ARID1A expression was identified as a predictor of metachronous disease independent of number of polyps, location of index polyp, dysplasia grade and sex (training HR=1.372, p=0.014; test HR=1.893, p=0.003). ARID1A predictive value was particularly strongest in patients with 1-4 polyps and in left-sided lesion and the rectum. ARID1A was among the most frequently mutated genes in precancerous polyps. ARID1A protein expression was decreased in presence of ARID1A and KMT2D mutations (p<0.001 and p=0.021, respectively). The most common type of base alteration in ARID1A mutations was C>T (47.96%) followed by G>A (16.33%). Truncation mutations accounted for 48% of ARID1A gene mutations and significantly correlated with reduced protein expression (p<0.001). Transcriptomic analysis showed a significant enrichment of proliferative Myc-targets_V2 pathway in ARID1A-high polyps, whereas inflammatory and differentiation pathways were enriched in ARID1A-low polyps. Transcription factor activity suggested a shift toward regenerative stem-cell signatures in ARID1A-high lesions, whereas ARID1A-low lesions showed TFs linked to suppression of transcription. Conclusion: ARID1A expression is a promising molecular biomarker that improves prediction of metachronous colorectal lesions beyond current guideline criteria, particularly among patients currently classified as low risk. The associated biological programs highlight increased proliferation and activation of regenerative stem-cell pathways in ARID1A-high polyp, supporting ARID1A's potential utility in personalised surveillance strategies.