Cross-species oncogenomics offers insight into human muscle-invasive bladder cancer

Abstract

Background In humans, muscle-invasive bladder cancer (MIBC) is highly aggressive and associated with a poor prognosis. With a high mutation load and large number of altered genes, strategies to delineate key driver events are necessary. Dogs and cats develop urothelial carcinoma (UC) with histological and clinical similarities to human MIBC. Cattle that graze on bracken fern also develop UC, associated with exposure to the carcinogen ptaquiloside. These species may represent relevant animal models of spontaneous and carcinogen-induced UC that can provide insight into human MIBC. Results Whole-exome sequencing of domestic canine (n = 87) and feline (n = 23) UC, and comparative analysis with human MIBC reveals a lower mutation rate in animal cases and the absence of APOBEC mutational signatures. A convergence of driver genes (ARID1A, KDM6A, TP53, FAT1, and NRAS) is discovered, along with common focally amplified and deleted genes involved in regulation of the cell cycle and chromatin remodelling. We identify mismatch repair deficiency in a subset of canine and feline UCs with biallelic inactivation of MSH2. Bovine UC (n = 8) is distinctly different; we identify novel mutational signatures which are recapitulated in vitro in human urinary bladder UC cells treated with bracken fern extracts or purified ptaquiloside. Conclusion Canine and feline urinary bladder UC represent relevant models of MIBC in humans, and cross-species analysis can identify evolutionarily conserved driver genes. We characterize mutational signatures in bovine UC associated with bracken fern and ptaquiloside exposure, a human-linked cancer exposure. Our work demonstrates the relevance of cross-species comparative analysis in understanding both human and animal UC.

Review of Molecular Technologies for Investigating Canine Cancer

“…In addition to cfDNA in the blood, cfDNA in the urine of dogs has also been used for genomic characterisation. For example, NGS of FFPE tissue samples has demonstrated the presence of the somatic BRAF p.V595E mutation in a significant proportion of canine urinary bladder urothelial carcinomas (UC) [ 24 ], while a study using NGS identified the presence of the tumour genotype ( BRAF p.V595E) in 9/9 of the matched urine sediment samples from dogs with urinary bladder UC [ 25 ]. Similarly, using PCR and Sanger sequencing (a technique detailed in Section 3.4 ), the results of BRAF p.V595E analysis in dogs with or without urinary bladder UC were identical between the FFPE tissue, cytological smear and urine sample [ 26 ].…”

“…Other studies have used WES analysis to interrogate the genetics of canine tumours. For example, several groups have performed WES analyses of canine urinary bladder urothelial carcinomas (UCs) and identified BRAF as the most recurrently mutated gene, in particular, the hotpot V595E mutation, which was found in the majority of samples [ 24 , 82 ]. WES analysis of trio samples of canine primary OSA versus OSA metastasis versus normal tissue from the same dog ( n = 10) showed that 4/10 (40%) metastases showed the acquisition of a likely pathogenic driver mutation that was not present in the primary tumour [ 80 ].…”