November, 2008 Update: To date, we have validated 93 female Rottweilers that have reached exceptional longevity (i.e. at least 13 years old) and we are comparing them to 103 female Rottweilers that died with usual longevity (i.e. 9 years-old). We are working hard to construct a coherent story about what factors contribute to exceptional longevity. Now, to move closer to that goal, we are seeking to gather more information on the parents of these 196 female Rotties. This valuable information will inform us just how strongly exceptional longevity is influenced by parents versus non-genetic, lifestyle factors such as diet.

May, 2008 Update: Data thus far has validated that there is a segregation of distinct phenotypes and grades of tumors; and supports the notion that there are breed-specific differences in the age of lymphoma onset. We have identified preliminary regions in two chromosomes where gene expression signatures follow the same pattern of segregation for the gains and losses of DNA we identified previously. We predict that the results from this work will allow us to define how heritable factors influence the phenotypes and biological behavior of these tumors, setting the groundwork to develop better strategies for diagnosis, control, and treatment.

It has been apparent for some time that certain dog breeds are prone to develop certain types of cancer. Specifically, studies completed between the late 1960s and the early 1980s defined relative risk of lymphoma for different dog breeds. Yet, there has been little progress since then to define factors that account for this risk. As part of ongoing programs supported by the AKC CHF in our laboratories, we showed recently that the breed-specific risk of lymphoma extends beyond the simple disease condition to a predisposition for specific forms of lymphoma. More importantly, we showed there are recurrent chromosomal abnormalities that segregate with specific forms of lymphoma and that are more common in Golden Retrievers than in other breeds, suggesting breed-specific profiles of genetic abnormalities will be found in canine lymphoma. To continue this work, we plan to use contemporary "array-based" technologies to identify genes that map to these regions and how they contribute to the disease. We anticipate that the results from this work will allow us to predict how heritable factors influence the occurrence of abnormalities in these genes, and will set the groundwork to identify specific genes associated with breed-dependent cancer risk.

Osteosarcoma (OSA), or bone cancer, affects 8,000 - 10,000 dogs in the United States annually. Large and giant breeds are at a much higher risk for this disease, suggesting that inherited risk factors are involved. Roughly 10 - 15 percent of Rottweilers, a mastiff-type breed and 15 - 20 percent of Greyhounds, a long-limbed hound-type breed, get the disease. Recently, we have identified several regions of the canine genome that are associated with an increased risk for OSA in Rottweilers. A similar study is underway for Greyhounds and is expected to identify additional regions of importance. The purpose of this study is to identify the actual genes and mutations causing the increased risk for bone cancer in Rottweilers and Greyhounds. We will then determine the frequency of mutations in these genes in OSA in other breeds as well as in other tumors. This work should allow the development of specific genetic tests for carriers of OSA and suggest further studies leading to improved treatments for bone cancer.

The research conducted in this study will provide the basis for future research that may, ultimately, lead to scientists being able to provide a better assessment of individuals¿ risks for cancer (or for cancer in progeny), as well as determine whether a given dog is a good candidate for a given therapy. This project has helped to broaden the understanding of why tumors happen, so that the abnormalities can be targeted and better therapies devised. Researchers developed and tested gene therapy for melanoma. In a clinical trial involving five dogs with facial or oral melanoma, they found that the gene therapy, in which tumors were injected with modified genes, was both free of adverse effects and effective.

Canine Hip Dysplasia is the number one genetic health problem in dogs, with a significant frequency in over 100 breeds. The mode of inheritance may be polygenic (due to more than one gene) which has discouraged some studies of the genetic cause. However, with the proper approach, a polygenic disease can also be solved, and a DNA test or tests can be offered to help get rid of the disease. We propose a comprehensive approach studying 12 breeds and 11 additional candidate genes (beyond 2 already ruled out). Using multiple breeds increases the chance a given candidate gene will score a "hit." When a hit occurs, we will develop a DNA test to detect affected and carriers. In those breeds where the candidate gene search fails, we will do a genome-wide scan to establish linkage, which may allow us to offer a linked marker test, but in the longer run, will lead to gene discovery through homologous mapping. In the end, we expect to have a DNA test for hip dysplasia in most breeds.

Hemangiosarcoma (HAS) is a common cancer in dogs that originates from cells lining the blood vessels. HAS can affect any dog, but is seen more often in German Shepherds, Skye Terriers, and Golden Retrievers. This suggests that this disease has a heritable component. Tumors arise when cells respond inappropriately to growth factors, allowing them to divide continuously in an uncontrolled fashion. Tumor suppressor genes contain or eliminate these rapidly dividing cells, but mutations in these genes can disable their ability to function correctly. Our laboratory is examining the idea that the loss of function of one of these tumor suppressor genes, PTEN, leads to the increased production of tumor growth factors. In our studies, we will examine the frequency of the mutations in the PTEN gene from dogs with HAS, and the relationship of these mutations to increased production of a specific tumor growth factor, VEGF. The results of our research could lead to tests for screening dogs for mutations in PTEN, and information could have an immediate and long-lasting impact on canine health when used judiciously for breeding decisions. We will also test the ability of a novel therapeutic approach to restore normal function within these cells as a treatment for HAS. Such work may lead the way for the further development of novel therapies for the treatment of canine hemangiosarcoma.

Subvalvular aortic stenosis (SAS) is a congenital heart disease characterized by a fibrous ridge located below the aortic valve. Affected dogs are at risk of developing heart valve infections, congestive heart failure or sudden death. This trend has been reported with increasing frequency in the Rottweiler. The defect has been shown to be inherited in the Newfoundland breed, however the inherited nature of the disease in other breeds of dogs, including the Rottweiler, is unknown. The objectives of this study are to define the clinical presentation of SAS in the Rottweiler, compile pedigrees with reference to defined clinical cardiovascular status and evaluate for specific modes of inheritance, and accumulate a databank of clinical information, pedigrees and DNA from Rottweilers affected with SAS and all surviving family members. This study will help define both the clinical attributes and inherited nature of the disease. Information obtained in this study will provide the background for developing both screening and treatment programs and provide the initial materials for molecular studies to be performed in the future. Final Report: Read findings/results; read more on SAS