Abstract 4746: Mapping genes for invasive urinary bladder cancer in the dog
Authors: Erika M. Kwon, Deborah W. Knapp, Patty Bonney, Elizabeth A. McNiel, Heidi G. Parker, Elaine A. Ostrander
Journal: Cancer Research (2010)

Abstract Transitional Cell Carcinoma (TCC) is the most common cancer of the urinary bladder in pet dogs. In approximately 50% of dogs diagnosed with TCC the disease will spread to other organs in the body such as the lungs or liver. Drugs used to treat TCC are only partially effective and as a result most affected dogs ultimately die from the cancer. While it can be found in most breeds, there are a small number for which the risk is greatly increased five to twenty-fold, indicating an inherited component to the disease. In order to identify genetic mutations that increase susceptibility to TCC of the bladder, we have conducted a genome-wide association study (GWAS) using more than 100 Scottish terriers (ST), West Highland White terriers (WHWT), and Shetland Sheepdogs (SSD) with biopsy confirmed TCC. Controls included over 100 dogs of the same three breeds that were nine years or older, and that had not been diagnosed with any form of cancer. All germline DNA samples were run on the Affymetrix v2 canine SNP chip. Data were analyzed to test for an association between markers and disease. Following correction for population structure and relatedness among individuals of the same breed we identified one primary susceptibility locus (locus1) within the Scottish terrier population (p = 5 × 10-13) and a second locus (locus2) in West Highland White terriers and Shetland Sheepdogs (p = 3 × 10-7). The association at locus1 is increased with the addition of WHWT but not SSD. Fine mapping of locus1 with a dense set of 250 SNPs spanning a 4.5 Mb region revealed a strong association across a group of genes involved in multiple cancer pathways, including some commonly deleted in human bladder cancer tumors. Haplotype analysis across this region identified two primary haplotype blocks with significant associations. Locus2 was associated with the TCC in the WHWT and SSD, when ST were excluded. Preliminary data suggests evidence of a reduced heterozygosity in both cases and controls at locus2 in the ST and we hypothesize that STs are nearing fixation at locus2, thus explaining the twenty-fold increased risk associated with this breed. We are currently further fine mapping both regions by resequencing and genotyping additional 750 SNPs and probes to assess copy number variation using a custom Goldengate assay. The identification of causal mutations will lead to a better understanding of the genetic causes of bladder cancer. In addition, since TCC of the bladder in dogs shares a similar histopathologic appearance and biological behavior with human invasive TCC of the bladder, identification of genetic risk factors for TCC will allow selection of molecular targets for early detection and treatment in both humans and dogs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4746.