Detection of urothelial carcinoma in Lynch syndrome using microsatellite instability analysis of urine cell-free DNA

作者：R. E. Hall, Richard Gallon, Christine Hayes, Patricia Herrero-Belmonte, Rachel Phelps, Donna Job, Ruth Wake, Mary Ferrier, Helen Turner, Rachel O’Donnell, Arjun Nambiar, Bhavan Rai, Richard J. Martin, Ciaron McAnulty, Mauro Santibanez‐Koref, Rakesh Heer, Michael S. Jackson, John Burn · 发表于：EBioMedicine · 年份：2025 · DOI：10.1016/j.ebiom.2025.105969 · 被引用次数：4 · 研究领域：Genetic factors in colorectal cancer、Multiple and Secondary Primary Cancers、Colorectal Cancer Screening and Detection

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 par...