We have successfully identified two loci associated with the development of TCC in the three most highly affected dog breeds in the United States. The first locus, which appears to be most highly associated with the disease in STs, has been reduced through fine mapping to two regions comprised of approximately four genes, all of which are fine candidates for enhanced tumor development and progression. We are currently sequencing the genes and searching for the causative mutations. The second locus, which was identified in WHWTs and SSD, may contain a mutation that is fixed or carried at a very high frequency in STs, explaining their increased risk of developing the disease. Studies from human bladder cancer suggest that these two loci may be interacting to create a more aggressive form of bladder cancer in dogs carrying both.