1577: Identifying the Genes Conferring Risk for Transitional Cell Carcinoma

Grant Status: Closed

Grant Amount: $45,000
Dr. Elaine A Ostrander, PhD, National Human Genome Research Institute
January 1, 2012 - June 30, 2014
Sponsor(s): German Shepherd Dog Club of America, Norwegian Elkhound Association of America, Inc., Siberian Husky Club of America
Breed(s): Shetland Sheepdog, West Highland White Terrier, Scottish Terrier
Research Program Area: Oncology

Project Summary

Cancer is the most common cause of disease related death in the dog, affecting one in four dogs. Transitional cell carcinoma (TCC) of the bladder is the most common tumor of the urinary bladder affecting as many as 30,000 dogs each year. The tumors are invasive and highly aggressive and most often result in death of the affected dog. Current treatments for cancers in dogs rely heavily on discoveries made in human medicine. In the case of TCC of the bladder, standard human treatments such as surgical removal of the tumor or complete removal of the bladder are often not feasible in dogs and current chemotherapeutics are only marginally effective. In order to improve the prognoses for dogs with TCC, new treatments must be tailored specifically for canine patients. In order to accomplish this it is important to know what specific genetic alterations are causing the disease so that they may be targeted directly. In addition, this information can be used to improve diagnostics and develop new methods for early detection and prevention. Susceptibility to TCC is strongly influenced by genetics in breeds where the disease incidence is significantly higher than average. The Scottish terrier (ST), West Highland White Terrier (WHWT), and Shetland Sheepdog (SSD) are three such breeds with risks ranging from five to 20 times greater than the average mixed breed dog. The long-term goal of our study is to identify the genetic risk factors for TCC in these highly predisposed breeds. We have completed whole-genome association studies (GWAS) on more than 300 dogs from these three breeds and have found three regions of the genome that play significant roles in disease development. The first region was identified in the ST and WHWT, the second in the SSD and the third region, also identified in SSD, was only recently revealed during an expansion of the GWAS study including the addition of more dogs. We are currently determining if genes in that region also affect ST and WHWT and are beginning the process of narrowing the region and finding mutations. It is likely that additional loci will be identified as we continue to add greater numbers of dogs to the analysis. The first associated locus, found in ST and WHWT, has been narrowed, through successive rounds of sequencing and genotyping, to include only one gene sequence and three regulatory regions that may contribute to disease susceptibility. Multiple mutations have been identified within a single regulator and are currently being assessed for disease related function. The second locus contains multiple genes involved in cell-cell junctions that are suspected to contribute to disease progression and severity. We have sequenced >95% of this region using traditional and innovative methods. Haplotype analysis has identified the most likely risk associated region of 375 Kb, which is divided into 25 haplotypes of 1-33 Kb each. These haplotypes are largely in regions that do not encode proteins making it necessary for us to determine which parts of the genome are involved in gene regulation. We have completed whole genome chromatin immunoprecipitation followed by next-generation sequencing to find the genetic sequences of regulatory regions such as gene promoters, enhancers, and suppressors. This allows us to identify the variants within our associated regions that might be altering activity of genes. We can then proceed with functional assays to confirm a role in cancer risk or progression. At the same time, we have produced genome-wide transcript sequence data from four bladder tumors and two normal bladder tissues to identify both novel genes and variations of genes caused by inherited mutations. These data also allow us to find mutations that are created within the tumors, as the cancer develops, leading to tumor growth and progression. Targeting these tumor-specific mutations will allow for the development of improved therapeutics for dogs diagnosed with TCC of the bladder. By combi

Publication(s)

- Both ends of the leash: the human link to good dogs with bad genes (2012) Ostrander EA. New England Journal of Medicine, 367(7):636-46. - Subcutaneous 5-azacitidine treatment of naturally occurring canine urothelial carcinoma: A novel epigenetic appr

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