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Lynch syndrome-associated urothelial carcinoma: clinical and molecular findings from a single-institution cohort.

A Rametta·M Barella·A Scardino·F Barbetta·E Tamborini·F Perrone·A Busico·L Agnelli·S Rota·E Gusmaroli·M Stellato·A Nuzzo·V Guadalupi·M Claps·M T Ricci·G Procopio·G Pruneri·M Milione·P Giannatempo·M Vitellaro
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Abstract

Lynch syndrome-associated urothelial carcinoma (LS-UC) is a rare and undercharacterized clinical entity. While FGFR3 alterations are well described in sporadic urothelial carcinoma, their prevalence and clinical implications in LS-UC remain unclear. We aimed to provide a comprehensive clinical and molecular characterization of LS-UC. We conducted a retrospective single-center study including patients with Lynch syndrome (LS) and histologically confirmed urothelial carcinoma (UC). Clinical, pathological, treatment, and follow-up data were collected. Targeted next-generation sequencing was performed on available tumor samples to assess genomic alterations, with particular attention to FGFR3 mutations. A total of 27 patients with LS-UC were identified, with a predominance of upper urinary tract involvement (70%). Most tumors were diagnosed at an early stage and initially managed with local treatment. During a median follow-up of 92 months, 48% of patients experienced recurrence, with a median time to recurrence of 37 months. Recurrences were predominantly local and were mainly managed with additional surgical or intravesical treatments. No deaths were attributable to UC at last follow-up. Molecular analysis was feasible in 9 cases. FGFR3 mutations were detected in 67% of evaluable samples, with the recurrent p.Arg248Cys hotspot identified in 55% of cases. Additional alterations involved TP53, SWI/SNF complex genes, and PIK3CA, which co-occurred with FGFR3 p.Arg248Cys. No gene fusions were identified. This study expands the limited molecular and clinical evidence on Lynch syndrome-associated urothelial carcinoma. Beyond confirming the recurrent role of FGFR3 (notably p.Arg248Cys), our comprehensive multigene profiling enriches the current genomic knowledge for this rare population. Multi-center collaborative efforts remain essential to aggregate larger datasets and ultimately guide personalized patient management.

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HumansReceptor, Fibroblast Growth Factor, Type 3Colorectal Neoplasms, Hereditary NonpolyposisFemaleMaleRetrospective StudiesAgedMiddle AgedMutationNeoplasm Recurrence, LocalAged, 80 and overHigh-Throughput Nucleotide SequencingAdultUrologic NeoplasmsCarcinoma, Transitional CellFGFR3Hereditary cancerLynch syndromeMolecular profilingUTUCUpper tract urothelial carcinomaUrothelial CarcinomaJournal Article

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A Rametta, M Barella, A Scardino, F Barbetta, E Tamborini, F Perrone, A Busico, L Agnelli, S Rota, E Gusmaroli, M Stellato, A Nuzzo, V Guadalupi, M Claps, M T Ricci, G Procopio, G Pruneri, M Milione, P Giannatempo, M Vitellaro. 2026-09-02. Lynch syndrome-associated urothelial carcinoma: clinical and molecular findings from a single-institution cohort.. https://doi.org/10.1007/s10689-026-00599-4

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