Genomic alterations in histologically clear low grade dysplasia resection margins forecast advanced neoplasia in ulcerative colitis
- 1Institute of Cancer Research
Abstract
BackgroundEndoscopic resection is used for the management of dysplasia in ulcerative colitis (UC), but a subset of patients develop subsequent advanced neoplasia (AN), i.e., high-grade dysplasia and/or colorectal cancer, despite apparently complete resection with histologically clear margins. Current risk stratification relies predominantly on histopathological and procedural features, which does not capture underlying genomic field cancerization of morphologically normal mucosa.
ObjectiveTo determine whether genomic alterations within histologically non-dysplastic resection margins are associated with subsequent neoplastic progression following endoscopic resection of UC-associated dysplasia.
DesignWe analysed a retrospective cohort of 51 UC patients, who underwent endoscopic resection of dysplastic lesions at a tertiary referral centre, with a median follow-up of 1947 days. 11 of these had local progression. We performed low-coverage whole genome sequencing (lcWGS) of 56 dysplastic lesions and 91 adjacent histologically non-dysplastic margins. Somatic copy number alteration (CNA) burden and phylogenetic analysis were correlated with progression to AN.
ResultsHistologically non-dysplastic margins from lesions that subsequently progressed to AN demonstrated significantly higher CNA burden compared with non-progressors. In multivariate analysis high margin CNA burden was independently associated with local progression, whereas histologically clear resection margins and en bloc excisions were not.
ConclusionHistological clearance does not necessarily indicate clearance of the cancerised field in UC-associated dysplasia. Genomic detection of field cancerisation within histologically non-dysplastic resection margins identifies patients at increased risk of subsequent neoplasia and provides a potential biomarker for biologically informed post-resection surveillance.
What is already known on this topicO_LIEndoscopic resection is increasingly used for colitis-associated dysplasia, but some patients subsequently develop advanced neoplasia despite histologically complete resections with clear margins. C_LIO_LICurrent risk stratification post-resection relies on histopathological and procedural features, which likely do not capture the cancerised field. C_LI
What this study addsO_LIHistomorphologically non-dysplastic margins can harbour genomic alterations that are shared with the dysplastic lesion, indicating a cancerised field. C_LIO_LIA high burden of copy number alterations in resection margins independently predicts subsequent progression to advanced neoplasia, beyond conventional measures of resection completeness. C_LI
How this study might affect research, practice or policyO_LIBeyond histopathology, genomic assessment of resection margins is low-cost, fast and reproducible and may enable biologically informed risk stratification following endoscopic resection of colitis-associated dysplasia. C_LI
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BibTeX
@misc{fisher2026genomic,
title = {{Genomic alterations in histologically clear low grade dysplasia resection margins forecast advanced neoplasia in ulcerative colitis}},
author = {J. Fisher and K. Brautigam and H. E. Grant and M. Mossner and C. Sakr and I. Al Bakir and B. Saunders and N. Suzuki and A. Wilson and A.-M. Baker and A. L. Hart and T. A. Graham},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.10.26362759},
url = {https://www.medrxiv.org/content/10.64898/2026.09.10.26362759v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Genomic alterations in histologically clear low grade dysplasia resection margins forecast advanced neoplasia in ulcerative colitis
AU - J. Fisher
AU - K. Brautigam
AU - H. E. Grant
AU - M. Mossner
AU - C. Sakr
AU - I. Al Bakir
AU - B. Saunders
AU - N. Suzuki
AU - A. Wilson
AU - A.-M. Baker
AU - A. L. Hart
AU - T. A. Graham
PY - 2026
DA - 2026/09/10
PB - medRxiv
DO - 10.64898/2026.09.10.26362759
UR - https://www.medrxiv.org/content/10.64898/2026.09.10.26362759v1
AB - BackgroundEndoscopic resection is used for the management of dysplasia in ulcerative colitis (UC), but a subset of patients develop subsequent advanced neoplasia (AN), i.e., high-grade dysplasia and/or colorectal cancer, despite apparently complete resection with histologically clear margins. Current risk stratification relies predominantly on histopathological and procedural features, which does not capture underlying genomic field cancerization of morphologically normal mucosa. ObjectiveTo determine whether genomic alterations within histologically non-dysplastic resection margins are associated with subsequent neoplastic progression following endoscopic resection of UC-associated dysplasia. DesignWe analysed a retrospective cohort of 51 UC patients, who underwent endoscopic resection of dysplastic lesions at a tertiary referral centre, with a median follow-up of 1947 days. 11 of these had local progression. We performed low-coverage whole genome sequencing (lcWGS) of 56 dysplastic lesions and 91 adjacent histologically non-dysplastic margins. Somatic copy number alteration (CNA) burden and phylogenetic analysis were correlated with progression to AN. ResultsHistologically non-dysplastic margins from lesions that subsequently progressed to AN demonstrated significantly higher CNA burden compared with non-progressors. In multivariate analysis high margin CNA burden was independently associated with local progression, whereas histologically clear resection margins and en bloc excisions were not. ConclusionHistological clearance does not necessarily indicate clearance of the cancerised field in UC-associated dysplasia. Genomic detection of field cancerisation within histologically non-dysplastic resection margins identifies patients at increased risk of subsequent neoplasia and provides a potential biomarker for biologically informed post-resection surveillance. What is already known on this topicO_LIEndoscopic resection is increasingly used for colitis-associated dysplasia, but some patients subsequently develop advanced neoplasia despite histologically complete resections with clear margins. C_LIO_LICurrent risk stratification post-resection relies on histopathological and procedural features, which likely do not capture the cancerised field. C_LI What this study addsO_LIHistomorphologically non-dysplastic margins can harbour genomic alterations that are shared with the dysplastic lesion, indicating a cancerised field. C_LIO_LIA high burden of copy number alterations in resection margins independently predicts subsequent progression to advanced neoplasia, beyond conventional measures of resection completeness. C_LI How this study might affect research, practice or policyO_LIBeyond histopathology, genomic assessment of resection margins is low-cost, fast and reproducible and may enable biologically informed risk stratification following endoscopic resection of colitis-associated dysplasia. C_LI
ER -