Heritable & Sporadic Genetic Lesions in Canine Lymphoma & Osteosarcoma
Lymphoma (cancer of lymph glands) and osteosarcoma (bone cancer) are two common cancers of dogs with remarkable breed predisposition. Lymphoma accounts for approximately 20 percent of all canine tumors, and more than 80 percent of cancers originating from blood cells. Osteosarcoma is the most common bone tumor in dogs, accounting for 85 percent of skeletal cancers. All cancers have a genetic basis, and in effect, these conditions represent various diseases, each sharing one or few genetic abnormalities that contribute to overall risk and treatment response. However, a means does not exist to identify individuals at risk, or tumors that are likely to respond to conventional therapy. We have identified individual genes and larger regions within the genome that appear to be important in canine cancer. For this project, we propose to confirm the frequency and significance of these genetic anomalies in lymphoma and osteosarcoma of Golden Retrievers, Rottweilers, Irish Setters, and Bernese Mountain Dogs. This work will begin to determine which of these anomalies may be heritable and which may be sporadic, and pave the way to apply this knowledge for clinical benefits by providing potential targets for treatment, and tools to define individual risk to develop these types of cancer or produce cancer-prone progeny.
Summary of results:
This project was designed to study how heritable factors contribute to the origin and progression of canine lymphoma and osteosarcoma. Thanks to funds from this project, we have compiled a unique resource that is unlikely to be duplicated. Specifically, we have obtained samples from more than 100 dogs with lymphoma (predominantly Golden Retrievers) and more than 60 dogs with osteosarcoma (predominantly Rottweilers), as well as blood samples from unaffected relatives for each dog in the study. In addition, we have developed a series of tools and reagents that will accelerate progress on multiple aspects of canine cancer and canine genetics research.
Briefly, our results show that there not only are there differences in breed susceptibility to lymphoma, but also that different breeds tend to get different subtypes of this cancer. Moreover, disease risk and the frequency with which each subtype of lymphoma occurs are similar among closely related breeds. Genetic abnormalities found in each subtype of lymphoma are distinct, but perhaps a more exciting result is that while some abnormalities define these lymphoma subtypes, others occur more frequently in a given subtype for a specific breed. This begins to illuminate a path that will allow us to identify heritable factors that contribute to the origin and progression of lymphoma in all dogs, as well as in specific breeds. Therefore, in our ongoing work we seek to define precise genes that are responsible for disease susceptibility (risk) as well as those that determine disease progression and response to therapy.
With respect to osteosarcoma, our data suggest that the disease is very complex, genetically speaking. There are a large number of genetic abnormalities found in these tumors, which probably reflect the natural history of the disease and the fact that it is diagnosed at a relatively advanced stage. Yet, identification of recurrent abnormalities will allow us to “simplify” the disease by focusing only on those that are relevant to risk, prognosis (behavior of the tumor), and predictive value (response to therapy). This in turn, will let us uncover general factors to classify clinically relevant subtypes of the disease, as well as heritable factors that increase the risk of dogs from certain breeds to develop this disease.
Ultimately, our long-term goals are to identify such genes or factors for both lymphoma and osteosarcoma, enabling us to determine if they provide reasonable targets for treatment, as well as whether they lend themselves to manipulation to reduce disease risk through judicious breeding. Once defined, the methods applied here adapted to identify risk-associated genes for complex diseases (such as these and other cancers) in many different dog breeds.
The Molecular Cytogenetics of Canine Lymphosarcoma; Correlating Chromosomal Changes with Clinical Disease
Cancer kills. Twenty years ago, the diagnosis of lymphosarcoma (a tumor of the lymph glands) in humans was almost invariably fatal. However, with the development of improved means to sub-classify this neoplasm and the tailoring of therapies that are subtype-specific, more and more forms of lymphosarcoma are treatable.
One of the most important means of sub-classification of human tumors is based on the identification of chromosome abnormalities. In the dog, lymphosarcoma comprises one in five malignancies; however, the extent and identity of chromosome aberrations is still unknown. This is largely because the chromosomes of dogs were extremely difficult to identify with confidence.
Recently, we have developed a set of canine chromosome-specific reagents that allow us to identify conclusively every dog chromosome. We propose to use these reagents to identify the chromosome aberrations associated with dog lymphosarcoma and to investigate the correlation between these aberrations and the clinical disease. Such an approach offers a means to potentially sub-divide this diverse disease in dogs, thereby offering new information of diagnosis, prognosis and therapy. Identification of specific chromosome aberrations will also help to investigate the correlation between the genetic etiologies in dogs with those in humans.
Mapping Genes Associated with Osteosarcoma in Large Dog Breeds
Eight thousand to 10,000 cases of a malignant bone tumor called osteosarcoma are reported in dogs in the United States annually, representing a significant health concern. In the majority of cases, spread of the tumor through the body and death follows within a few years.
Osteosarcomas affect all dogs, but the disease frequency is considerably higher in large and giant breeds, including the long-limbed hounds (Irish Wolfhound, Great Dane, Greyhound, Scottish Deerhound, Rhodesian Ridgeback, Great Pyrenees and Borzoi) and mastiff-type breeds (Rottweiler, Labrador Retriever, Flat-Coated Retriever, Golden Retriever, Mastiff, Bullmastiff, Saint Bernard, Irish Setter, and Newfoundland). It is clear the genetics plays an important role.
We propose to identify the genetic risk factors for osteosarcoma in two breeds: Greyhound and Rottweiler. While certain characteristics of these two breeds make them ideal to study, we expect that the genes identified in these breeds may also be associated with osteosarcoma in related breeds. This study should lead to the development of genetic tests for osteosarcoma that could be used to eliminate carriers from breeding populations, eventually reducing the frequency of this devastating cancer. Ultimately, it could also lead to improvements in treatment of osteosarcoma.
Both Ridgebacks diagnosed with osteosarcoma and healthy older dogs are needed for this study. Click here to learn more.
Growth Signaling Pathways in the Pathogenesis and Treatment of Canine Cancer
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.