Abstract Background Introduction: Inflammatory bowel disease (IBD) confers an increased lifetime risk of colorectal cancer (CRC), and IBD patients are enrolled into bowel surveillance programs which aim to identify and remove cancer precursors (i.e. dysplasia). Endoscopic resection of dysplastic lesions has become central to the management of dysplasia in IBD, providing an organ-preserving alternative to colectomy1. Risk stratification traditionally relies on histopathology, with en bloc and complete (R0) resection conferring a more favourable risk profile. However, it is well-established that histologically nondysplastic IBD mucosa can harbour potentially carcinogenic genomic alterations (“field cancerisation”)2,3, therefore we hypothesise that a resection margin that appears “histologically clear” of dysplastic cells may not be “genomically clear” of cells with precancerous alterations. Methods We analysed a cohort of 26 ulcerative colitis patients, 4 of whom progressed to advanced neoplasia (high-grade dysplasia or CRC) within 3 years (“progressors”), and 22 who did not progress (“non-progressors”). From each patient we microdissected histologically clear resection margins and dysplastic lesions, then extracted DNA from each region and performed low coverage whole genome sequencing (lcWGS). We generated genome-wide copy number alterations (CNA). Results Dysplastic lesions in progressors exhibited higher percentage genome altered (PGA) than those in the non-progressors (median 38.5% vs 4.7%, p = 0.005), in line with a previous study from our group that showed CNA burden in LGD is strongly prognostic4. Remarkably, when we considered only the histologically nondysplastic resection margins PGA was markedly higher in progressors (45.8% vs 1.9%, p = 0.006). We performed Cox regression analysis and showed that the presence of margin CNAs was associated with a 20-fold higher risk of progression (HR 20.3, p = 0.005) than those that had low PGA in the margins. Conclusion Our work demonstrates that histologically inconspicuous IBD resection margins can harbour significant precancerous genomic change. By performing genomic analysis of these margins, we could identify residual field cancerization and use this to refine prognostication after endoscopic resection. Incorporating molecular clearance into post-resection risk models could identify patients at particularly low risk of recurrence, supporting personalised surveillance intervals and reducing unnecessary procedures. References: Moran, G.W. et al. British Society of Gastroenterology guidelines on inflammatory bowel disease in adults: 2025. Gut 74, s1–s101 (2025) Baker, A.M. et al. Evolutionary history of human colitis-associated colorectal cancer. Gut 68, 985–995 (2019). Leedam, S.J. et al. Clonality, Founder Mutations, and Field Cancerization in Human Ulcerative Colitis-Associated Neoplasia. Gastroenterology 136, (2009). Al Bakir, I. et al. Low-coverage whole genome sequencing of low-grade dysplasia strongly predicts advanced neoplasia risk in ulcerative colitis. Gut 74, 740–751 (2025). Conflict of interest: Fisher, Jennifer: Nil Bräutigam, Konstantin: n/a Grant, Heather: Nil Sakr, Chirine: Nil Mossner, Max: Nil Baker, Anne-Marie: Nil Graham, Trevor: Nil Hart, Ailsa: Grant: Takeda Personal Fees: Abbvie, Amgen, Arena, AZ, Falk, Celltrion, Eli Lilly, Ferring, Genentech/ Roche, GSK, Pfizer, Takeda, Napp, Pharmacosmos, Janssen (J&J), Bristol-Myers Squibb, Gilead, Galapagos, Alfasigma
Fisher et al. (Thu,) studied this question.