ARID1A expression and genomic alterations as predictive biomarkers for metachronous colorectal polyp risk stratification

BackgroundCurrent British bowel cancer surveillance guidelines (BSG2020) rely on polyp size, number, histology and dysplasia grade to predict metachronous polyp risk. However, these criteria fail to accurately distinguish true high-and low-risk patients, resulting in either unnecessary surveillance or misclassification of patients at true risk of metachronous lesions. No molecular biomarkers have yet been integrated into risk stratification, limiting the potential for personalised surveillance strategies. We investigated ARID1A expression and copy number alterations (CNAs) in KMT2C, SMG1 and TRAF7 as predictive markers for colorectal metachronous lesions. MethodsA total of n=1184 archival colorectal polyp tissue microarrays (TMAs) were analysed for ARID1A expression using immunohistochemistry (IHC). Genomic and transcriptomic characterisation of a subset of patients (n=623) was performed using somatic mutation profiling, CNAs and bulk RNA sequencing. ResultsARID1A was identified as an independent predictor of metachronous disease. ARID1A protein expression correlated with ARID1A and KMT2D mutations. Patients with ARID1A mutations exhibited fewer CNAs than non-mutants. Among CNAs, KMT2C, SMG1 and TRAF7 were the most frequently altered genes and were predictive of metachronous polyp formation. Combining ARID1A expression with KMT2C, SMG1 and TRAF7 CNAs refined risk stratification within BSG2020-defined risk groups. Several pathways, including cell cycle regulation and DNA repair, differed between ARID1A-CNA risk groups. Conclusion: ARID1A expression, in combination with KMT2C, SMG1 and TRAF7 CNAs, presents a novel biomarker tool to enhance metachronous polyp risk stratification alongside the BSG2020 criteria, potentially improving personalisation of surveillance.