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

Abstract

Lynch syndrome (LS) is a hereditary condition characterized by defective DNA mismatch repair and a high incidence of several cancers. In this study, we investigate the somatic landscape of LS-associated urothelial cancer (LS-UC) by analyzing 41 tumor and 3 urine samples from 34 patients with LS-UC. We show that telomerase reverse transcriptase (TERT) promoter mutations found in 83% of sporadic UC are almost absent (5%) in LS-UC. Instead, LS-UC carries a 5-methylcytosine-deamination- (CG>TG) and microsatellite-instability-driven mutation landscape characterized by frequent ARID1A (82%), FGFR3 (80%), and KMT2D (81%) mutations. We propose that the scarcity of TERT promoter mutations in LS-UC is due to the inability to create the GA-binding protein (GABP) binding motif 5′-GGAA through CG>TG mutations or microsatellite instability. Our data demonstrate that LS-UC represents a disease entity with unique genomic characteristics relevant for diagnosis and screening, and represents the largest analysis to date of the LS-UC mutation landscape.