Abstract Introduction: Lynch syndrome (LS) is a hereditary cancer syndrome caused by germline variants in DNA mismatch repair (MMR) genes (MSH2, MLH1, MSH6 and PMS2), with up to 25% lifetime risk for urothelial cancer (UC). LS-UCs are commonly located in the upper urothelial tract, where tumors are difficult to detect early. No evidence-based screening strategy exists. We and others have shown that UC can be sensitively detected using urine tumor DNA (utDNA) mutation analysis. Methods: LS-URO is an international, prospective, multicenter study enrolling LS carriers aged 50-75 years from the Finnish LS Registry and the BC Cancer Hereditary Cancer Program. Participants receive an at-home 100-mL urine collection kit (with preservative) for mail return. Urine cell pellet DNA is analyzed using the UroScout 25-gene deep targeted sequencing assay, which includes common UC drivers (e.g., FGFR3, ARID1A, KMT2D) and MMR genes. Samples with ≥2 somatic mutations are reviewed by a molecular tumor board, with utDNA-positive cases examined by cystoscopy, urine cytology and imaging, as well as repeat urine sequencing. Results: Between May 2023 and October 2025, 213 participants were recruited, and 160 returned urine samples. Mean participant satisfaction with the urine collection procedure was 4.46/5. utDNA analysis is complete for 135 participants (76 Finland, 59 Canada). Nine (6.7%) participants were utDNA-positive with a median cancer fraction of 9% (range 4-17%) and median of four somatic mutations detected per sample (range 3-18). In 8/9 (89%) utDNA-positive participants, a somatic MMR second hit beyond the germline defect was detected. A total of 28 follow-up urine samples from five initially utDNA-positive participants revealed consistent detection of original mutations, with new mutations emerging in four. Eight out of nine (89%) positive participants harbored an FGFR3 hotspot mutation (of which 88% R248C), whereas only one out of nine (11%) carried a TERT promoter mutation, consistent with our published observation that such mutations are rare in LS-UC. Two asymptomatic UC cases have been confirmed (one at initial examination, one 28 months after the first utDNA-positive screening sample during protocol-scheduled follow-up CT imaging). Four positive cases are pending initial urologic investigation, and the remainder are under continued surveillance through additional sampling and clinical follow-up. Conclusions: utDNA-based screening in LS is feasible, well accepted, and enables early, non-invasive cancer detection. Interim results demonstrate high compliance and promising diagnostic yield, pending long-term clinical follow-up. These findings support large-scale implementation of urine biopsy-based screening, to be further evaluated in the randomized PREDI-LYNCH trial. Citation Format: Jussi Nikkola, Lauri Ryyppö, Juuso Vuorinen, Jack V. Bacon, John Pham, Sara Singh, Lauren Deneault, Chuyi Zheng, Hanna Selin, Päivi Martikainen, Cecily Q. Bernales, Melissa Koudjanian, Kirsi Pylvänäinen, Matti Nykter, Thea Veitonmäki, Jukka-Pekka Mecklin, Alexander Wyatt, Kasmintan Schrader, Toni Seppälä, Peter C. Black, Gillian Vandekerkhove, Matti Annala. Feasibility and interim results from the prospective international LS-URO study: Urine tumor DNA-based screening for urothelial cancer in Lynch syndrome carriers abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5107.
Nikkola et al. (Fri,) studied this question.