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Lookup NU author(s): Dr Rebecca Hall, Dr Richard GallonORCiD, Christine HayesORCiD, Rachel Phelps, Donna Job, Ruth Wake, Mary Ferrier, Dr Rachel O'DonnellORCiD, Bhavan Rai, Dr Richard Martin, Dr Ciaron McAnulty, Dr Mauro Francisco Santibanez Koref, Professor Rakesh Heer, Dr Michael JacksonORCiD, Professor Sir John BurnORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Background: Urothelial carcinoma is the third most common cancer in Lynch syndrome but there is no approved screening method. Lynch syndrome cancers are characterised by high levels of microsatellite instability (MSI/MSI-H). Here, we assess the feasibility of urine MSI analysis for non-invasive urothelial carcinoma screening.Methods: We analysed urine cell-free DNA samples from two cohorts using an amplicon-sequencing MSI assay: (1) Sequential cases of upper tract urothelial carcinoma (UTUC) provided paired tumour/pre-operative urine samples for MSI analysis and mismatch repair protein immunohistochemistry (MMR IHC) and those with an MMR deficient (MMRd) tumour were offered constitutional Lynch syndrome testing (2) Eligible individuals with a diagnosis of MSH2-Lynch syndrome (aged 30-75 years, without recent cancer diagnosis) were offered urine MSI analysis via a clinic appointment or postal urine sample collection. All cases were followed up for at least 12 months.Findings: Three of 50 cases of UTUC (6.00%) were MSI-H, MMRd by IHC and detectable by MSI-H or borderline-MSI-H urine signals. All occurred in individuals with new Lynch syndrome diagnoses. Urines and tumours from the remaining 47 patients were microsatellite stable (MSS) and tumours were MMR proficient by IHC. Urine MSI analysis achieved 100% sensitivity and specificity for symptomatic UTUC (95% CI 29.2%-100% and 92.4%-100% respectively). 81 of 142 eligible individuals with a diagnosis of MSH2-Lynch syndrome participated (57.0%) with one later excluded following urothelial carcinoma diagnosis between enrolment and sample collection. MSI-H urines were identified in 5/80 (6.25%), with urothelial carcinoma subsequently diagnosed in 4/5. None of the 75 participants with an MSS urine had a urothelial carcinoma diagnosis during follow up. Urine MSI analysis achieved 100% sensitivity, 98.7% specificity, 80% positive predictive value, and 100% negative predictive value for asymptomatic Lynch syndrome urothelial carcinoma (95% CIs: 39.8-100%, 92.9-99.9%, 28.4-99.5% and 95.2-100% respectively).Interpretation: Urine MSI testing using a low-cost assay which is suitable for routine surveillance can detect asymptomatic Lynch syndrome urothelial carcinoma, facilitating early diagnosis. Further studies are needed to define accuracy and patient outcomes.
Author(s): Hall R, Gallon R, Hayes C, Herrero-Belmonte P, Phelps R, Job D, Wake R, Ferrier M, Turner H, O'Donnell R, Nambiar A, Rai B, Martin R, McAnulty C, Santibanez-Koref M, Heer R, Jackson MS, Burn J
Publication type: Article
Publication status: Published
Journal: eBioMedicine
Year: 2025
Volume: 121
Print publication date: 01/11/2025
Online publication date: 25/10/2025
Acceptance date: 29/09/2025
Date deposited: 18/11/2025
ISSN (electronic): 2352-3964
Publisher: Elsevier Ltd
URL: https://doi.org/10.1016/j.ebiom.2025.105969
DOI: 10.1016/j.ebiom.2025.105969
Data Access Statement: MSI-Plus assay FASTQ files are freely available from the European Nucleotide Archive using study identifier PRJEB85932 (https://www.ebi.ac.uk/ena/browser/view/PRJEB85932)
PubMed id: 41138669
Notes: This study explores the use of urine MSI analysis-based screening for urothelial carcinoma in the high-risk Lynch syndrome population. Urine MSI analysis of 80 individuals with a diagnosis of MSH2-Lynch syndrome recruited from Northeast England identified four asymptomatic urothelial carcinomas, including two low-grade, early stage (Ta) upper tract urothelial carcinomas which were treatable endoscopically. In comparison to previous work exploring urinalysis or urine cytology-based screening, urine MSI analysis demonstrated high sensitivity and specificity after a minimum 12 months follow up of each participant. Implications of all the available evidence Urine MSI analysis may provide a much-needed screening test for urothelial cancer in Lynch syndrome. Further study of larger and longitudinal cohorts is required to assess the impact of screening on morbidity and mortality. Additionally, assessments of patient acceptability and cost-effectiveness will be needed. The low cost and high-throughput MSI assay used here is already in routine clinical use for colorectal cancer testing, which will facilitate clinical adoption.
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