Classical driver mutations are not associated with metachronous lesion risk in patients undergoing post-polypectomy surveillance following removal of conventional adenomas in a bowel screening setting

Classical driver mutations in adenomas do not predict the risk of metachronous lesions after polypectomy, indicating that mutation profiling alone is insufficient for effective surveillance.

Summary and findings

This study examined the association between mutational status in index adenomas and the risk of metachronous lesions in patients aged 50–74 who underwent polypectomy. A total of 895 adenomas from 723 patients were analyzed, focusing on mutations in KRAS and TP53. The findings indicated that classical driver mutations do not predict metachronous lesion risk post-polypectomy.

Abstract

<h4>Introduction</h4> Patients undergoing polypectomy at colonoscopy remain at risk of metachronous neoplasia despite surveillance guided by histopathological features. Mutational profiling of adenomas, including canonical driver mutations in APC, KRAS , and TP53 , may offer additional predictive value. This study aimed to determine whether mutational status in index adenomas was associated with metachronous lesion risk. <h4>Methods</h4> The INCISE cohort included patients aged 50–74 who underwent polypectomy within the Scottish Bowel Screening Programme and subsequent surveillance colonoscopy within 6 years. Targeted next-generation sequencing was performed on formalin-fixed paraffin- embedded polyps. Driver mutation frequency, tumour mutational burden (TMB), and variant allele frequency (VAF) were analysed and correlated with histopathological features and metachronous outcomes using appropriate statistical models. <h4>Results</h4> A total of 895 adenomas from 723 patients were analysed. In conventional adenomas, as the number of high-risk histopathological features (size ≥10mm, villous architecture, and high- grade dysplasia) increased there was a stepwise increase in the proportion of samples with a mutation in KRAS from 13% to 51% (padj<0.001) and TP53 from 8% to 35% (padj<0.001). However, neither mutation frequency (p=0.901), nor median tumour mutation burden (TMB) (2.27 vs 2.15 mut/Mb, p=0.242), in index adenomas was associated with the development of metachronous lesions. <h4>Conclusions</h4> While classical driver mutations reflect histopathological progression within adenomas, they do not predict metachronous lesion risk post-polypectomy. Targeted mutation profiling alone is insufficient for surveillance risk stratification, highlighting the need for integrated molecular approaches in this setting.

Limitations

• Not reported in abstract.

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