Canine urothelial carcinoma: genomically aberrant and comparatively relevant

Abstract

Urothelial carcinoma (UC), also referred to as transitional cell carcinoma (TCC), is the most common bladder malignancy in both human and canine populations. In human UC, numerous studies have demonstrated the prevalence of chromosomal imbalances. Although the histopathology of the disease is similar in both species, studies evaluating the genomic profile of canine UC are lacking, limiting the discovery of key comparative molecular markers associated with driving UC pathogenesis. In the present study, we evaluated 31 primary canine UC biopsies by oligonucleotide array comparative genomic hybridization (oaCGH). Results highlighted the presence of three highly recurrent numerical aberrations: gain of dog chromosome (CFA) 13 and 36 and loss of CFA 19. Regional gains of CFA 13 and 36 were present in 97% and 84% of cases, respectively, and losses on CFA 19 were present in 77% of cases. Fluorescence in situ hybridization (FISH), using targeted bacterial artificial chromosome (BAC) clones and custom Agilent SureFISH probes, was performed to detect and quantify these regions in paraffin-embedded biopsy sections and urine-derived urothelial cells. The data indicate that these three aberrations are potentially diagnostic of UC. Comparison of our canine oaCGH data with that of 285 human cases identified a series of shared copy number aberrations. Using an informatics approach to interrogate the frequency of copy number aberrations across both species, we identified those that had the highest joint probability of association with UC. The most significant joint region contained the gene PABPC1, which should be considered further for its role in UC progression. In addition, cross-species filtering of genome-wide copy number data highlighted several genes as high-profile candidates for further analysis, including CDKN2A, S100A8/9, and LRP1B. We propose that these common aberrations are indicative of an evolutionarily conserved mechanism of pathogenesis and harbor genes key to urothelial neoplasia, warranting investigation for diagnostic, prognostic, and therapeutic applications.

Cross‐species analysis of the canine and human bladder cancer transcriptome and exome

“…More generally, out of ten genes that have been previously identified as being recurrently mutated in canine bladder cancer via an exome sequencing study, we detected mutations in three genes, MITF , ROS1 , and BRAF , corresponding to an overlap between the two studies (ours and Duval et al) that is ∼31‐fold greater than would be expected by chance, on average ( P < .001, Fisher's Exact Test). Additionally, we detected a mutation in RYR2 , whose human ortholog has been previously identified as a candidate driver gene for bladder cancer and in LRP1B , which has been implicated as a possible driver gene in a cross‐species analysis of genomic alterations in invasive bladder cancer . Finally, we investigated the gene functional annotations for genes that were mutated in canine bladder cancer, to identify annotation categories that are enriched.…”

Comparative oncology: what dogs and other species can teach us about humans with cancer

“…R. Soc. B 370: 20140231 and discovered both large chromosomal and focal regions of alterations shared between the species even among a large amount of background genomic instability [18]. Given the strong environmental risk for UC in humans and the prominent genetic risk in dogs, the study of shared genomic events leading to UC tumorigenesis will prove important for both prevention and treatment across species.…”

Genome-wide assessment of recurrent genomic imbalances in canine leukemia identifies evolutionarily conserved regions for subtype differentiation

“…Identification of CNAs using oligonucleotide array comparative genomic hybridization Oligonucleotide array comparative genomic hybridization (oaCGH) was performed using a 180,000 feature CGH microarray (Agilent Technologies, Santa Clara, CA) as previously described (Thomas et al , 2014Shapiro et al 2015). The array contains repeatmasked 60mer oligonucleotides spaced approximately every 13 kb across the dog genome (CanFam version 2.0, Lindblad-Toh et al 2005).…”

“…To compliment traditional small animal models, we propose that the domestic dog offers a suitable large animal model for evaluating spontaneously occurring leukemias, exhibiting similar morphology and clinical characteristics to human leukemias. Evaluation of recurrent genetic changes using cross-species comparison between dogs and humans has identified orthologous regions of importance in brain tumors (Thomas et al 2009), colorectal cancer (Tang et al 2010), non-Hodgkin lymphoma , osteosarcoma (Angstadt et al 2012), hemangiosarcoma (Thomas et al 2014), melanoma (Poorman et al 2015), and urothelial carcinoma (Shapiro et al 2015). Each of these studies has led to the identification of genomic regions harboring candidate genes associated with pathogenesis and therapeutic potential.…”