Cross_species_analysis_of_the_genomic_landscape_of_canine__feline__bovine_and_human_bladder_urothelial_carcinoma_reveals_a_novel_mutational_signature_associated_with_bracken_fern_consumption

Urothelial carcinoma (UC) of the urinary bladder that has invaded the muscle (MIBC) is a highly aggressive tumour that is associated with a poor prognosis due to a propensity for recurrence and metastasis. Companion animals (specifically pet dogs and cats) develop invasive UC with histological and clinical similarities to MIBC in humans and cattle that graze on bracken fern, containing the carcinogen ptaquiloside, also develop UC, thus these species may represent relevant animal models of spontaneous and carcinogen-induced UC. Whole-exome sequencing of tumour/normal pairs of domestic canine (n=87), feline (n=23) and bovine (n=8) invasive UC compared to human MIBC showed a convergence of driver genes (ARID1A and KDM6A in dogs, and TP53, FAT1 and NRAS in cats), evidence of mismatch repair deficiency, and focally amplified and deleted genes. The bovine UC showed a high mutational load, and DNA mutational signature analysis identified two novel single base substitution signatures, as well as unique indel and doublet substitution spectra. Importantly, we were able to recapitulate these mutational signatures by treating a human urinary bladder UC cell line with either bracken fern extracts or purified ptaquiloside. Thus, we have shown that canine and feline urinary bladder invasive UC represent relevant models of spontaneous MIBC in humans, and bracken fern-grazing cattle represent a potential model of carcinogen-induced MIBC. Furthermore, we have characterised the mutational signature of bracken fern and ptaquiloside exposure, which is linked to cancer in humans.