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

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

doi:10.1016/j.celrep.2025.116388

Cancer BiologyCell ReportsOct 1, 2025

Peer-reviewed journal article

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

Jussi Nikkola iD, Lauri Ryyppö, Juuso Vuorinen, Lauri Moilanen iD, Maarit Ahtiainen iD, Kirsi Pylvänäinen iD, Hanna Selin, Tuomo Virtanen iD, Matti Nykter iD, Thea Veitonmäki, Jukka‐Pekka Mecklin iD, Toni T. Seppälä iD, Matti Annala iD

PDF DOI Preprint

Post to X

Threads on X Post to Bluesky Threads on Bluesky

Abstract

Lynch syndrome (LS) is a hereditary condition characterized by defective DNA mismatch repair (MMR) and high incidence of several cancers, including urothelial cancers (UC) of the upper urinary tract and bladder. We set out to study the somatic landscape of LS-associated urothelial cancer (LS-UC) by analyzing 41 surgical tumor samples and 3 urine DNA samples from 34 LS-UC patients. We show that telomerase reverse transcriptase (TERT) promoter mutations found in 83% of sporadic UC are almost completely absent (5%) in LS-UC (p TG) and microsatellite instability driven mutation landscape characterized by highly frequent ARID1A (82%), FGFR3 (80%), and KMT2D (78%) mutations, as well as preferential usage of CG>TG mutation hotspots. We propose that the scarcity of TERT promoter mutations in LS-UC is due to inability to create the necessary GABP binding motif (5-GGAA) through CG>TG mutation or microsatellite instability. Our data shows that LS-UC represents a disease entity with unique genomic characteristics.