Abstract

Spontaneously occurring malignancies in domestic animals and wildlife species are valuable models for understanding human health in the environment. Frequently, these diseases reflect both histological and clinical aspects of corresponding human diseases, and in the case of domestic animals, patients often share a similar environment and diet. In the present study, we demonstrate the use of domestic dog (Canis familiaris) and the California sea lion (CSL) (Zalophus californianus) as comparative models for urogenital carcinoma. Invasive urothelial carcinomas (UC) are aggressive and highly metastatic cancers in dogs and people. Metastatic urogenital carcinomas (UGCs) are evident in 26% of dead adult stranded California sea lions (CSL) rescued by the Marine Mammal Center in Sausalito, California.¹ Many factors have been associated with UGCs, but a definitive causal or mechanistic link remains to be determined.² Previously, we have shown that there is a high degree of synteny in the canine and human genomes. Using multicolor whole chromosome painting and chromosome specific sets of canine genome integrated canine bacterial artificial chromosome (BAC) clones, we developed a comparative cytogenetic map of the dog and CSL genomes. This map served to define the major conserved syntenic regions in the CSL and dog. Subsequently, we performed whole genome sequencing of a single CSL genome to generate a species-specific DNA sequence. Considering the amount of synteny within the canine and CSL genomes, we used DNA obtained from healthy CSL tissue to probe 1,000,000 60-mer oligonucleotides developed from the canine genome sequences to identify those suited for evaluation of CSL DNA samples (∼50%). Using a computational approach we further reduced the number of oligonucleotide probes to include only those with the highest sequence homology, while maintaining an even distribution across both the canine and CSL genomes. This resulted in a set of ∼55,000 probes, with an average interval of 40 kb across both the canine and CSL genomes. We used this custom oaCGH platform to evaluate 16 urogenital tumors from California sea lions and 34 cases of canine bladder and prostatic UC. Preliminary results suggest that UGC in CSL has a genomic signature that more closely resembles canine prostatic carcinoma (n=14) than bladder carcinoma (n=20). Due to the shared synteny between these species, we propose that identifying common aberrations between species is a vital approach to understanding disease pathogenesis, and provides a unique opportunity to identify diagnostic and therapeutic targets relevant to humans, domestic animals, and wildlife species.

Acknowledgments

The authors wish to thank all members of the Sea Lion Cancer Consortium, the staff and volunteers at The Marine Mammal Center and the Wellcome Sanger Trust Institute. We would like to thank the National Marine Fisheries Services for assistance in the study of sea lion cancer. The authors thank the NC State Cancer Genomics Fund and the Morris Animal Foundation (D10ZO-003) for financial support of this project, and Dr. Rachael Thomas for technical assistance.

*Presenting author
+Student presenter

Literature Cited

1.  Browning HM, Acevedo-Whitehouse K, Gulland FM, Hall AJ, Finlayson J, Dagleish MP, Billington KJ, Colegrove K, Hammond JA. 2014. Evidence for a genetic basis of urogenital carcinoma in the wild California sea lion. In: Proc Biol Sci. 281:20140240. http://doi.org/10.1098/rspb.2014.0240

2.  Browning HM, Gulland FM, Hammond JA, Colegrove KM, Hall A. 2015. Common cancer in a wild animal: the California sea lion (Zalophus californianus) as an emerging model for carcinogenesis. Philos Trans R Soc Lond B Biol Sci. 370: 20140228. http://doi.org/10.1098/rstb.2014.0228