Abstract 6594: Constrained hypermutation and absence of TERT promoter mutations in Lynch syndrome-associated urothelial cancer

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Abstract Lynch syndrome (LS) is a hereditary cancer syndrome characterized by a defective DNA mismatch repair (MMR) system and a high frequency of different cancers, including urothelial cancers (UC) of the upper urinary tract and bladder. We studied the somatic landscape of LS-associated UCs (LS-UC) by analysing 41 tumor samples and 3 urine DNA samples collected from 34 LS-UC patients. We demonstrate that mutations of the telomerase reverse transcriptase (TERT) promoter are present in 83% of sporadic UC and are scarcely present (5%) in LS-UC (p < 0.00001). As a substitute, all LS-UC patients possessed a 5-methylcytosine deamination (CG>TG) and microsatellite instability driven mutation landscape with highly frequent ARID1A (82%), FGFR3 (80%), and KMT2D (78%) mutations. We suggest that the scarcity of TERT promoter mutations in LS-UC is due to an inability to create the required GABP binding motif (5’-GGAA) through CG>TG mutation or microsatellite instability. Our data indicates that LS-UC is a distinct disease entity characterized by unique genomic features. Citation Format: Jussi Nikkola, Lauri Ryyppö, Juuso Vuorinen, Lauri Moilanen, Maarit Ahtiainen, Kirsi Pylvänäinen, Hanna Selin, Tuomo Virtanen, Matti Nykter, Thea Veitonmäki, Jukka-Pekka Mecklin, Toni T. Seppälä, Matti Annala. Constrained hypermutation and absence of TERT promoter mutations in Lynch syndrome-associated urothelial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6594.

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