0002254B: Heritable and Sporadic Genetic Lesions in Canine Lymphoma and Osteosarcoma

Grant Status: Closed

Grant Amount: $184,165
Matthew Breen, PhD; North Carolina State University
September 30, 2002 - September 30, 2005

Sponsor(s): American Boxer Charitable Foundation, Nestle Purina PetCare Company

Breed(s): -All Dogs
Research Program Area: Oncology
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Abstract

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 > 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 more genetic abnormalities that contribute to overall risk and treatment response. However, a method does not exist to identify individuals at risk, or whether a dog that develops a tumor is likely to respond to conventional therapy. We have identified individual genes and larger regions within the genome that appear to be important in some canine cancers. 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.

Publication(s)

Dickerson, E. B., Thomas, R., Fosmire, S. P., Lamerato-Kozicki, A. R., Bianco, S. R., Wojcieszyn, J. W., … Modiano, J. F. (2005). Mutations of Phosphatase and Tensin Homolog Deleted from Chromosome 10 in Canine Hemangiosarcoma. Veterinary Pathology, 42(5), 618–632. https://doi.org/10.1354/vp.42-5-618
 
Fosmire, S. P., Thomas, R., Jubala, C. M., Wojcieszyn, J. W., Valli, V. E. O., Getzy, D. M., … Modiano, J. F. (2007). Inactivation of the p16 Cyclin-Dependent Kinase Inhibitor in High-Grade Canine Non-Hodgkin’s T-Cell Lymphoma. Veterinary Pathology, 44(4), 467–478. https://doi.org/10.1354/vp.44-4-467
 
Frantz, A. M., Sarver, A. L., Ito, D., Phang, T. L., Karimpour-Fard, A., Scott, M. C., … Modiano, J. F. (2013). Molecular Profiling Reveals Prognostically Significant Subtypes of Canine Lymphoma. Veterinary Pathology, 50(4), 693–703. https://doi.org/10.1177/0300985812465325
 
Jubala, C. M., Wojcieszyn, J. W., Valli, V. E. O., Getzy, D. M., Fosmire, S. P., Coffey, D., … Modiano, J. F. (2005). CD20 Expression in Normal Canine B Cells and in Canine non-Hodgkin Lymphoma. Veterinary Pathology, 42(4), 468–476. https://doi.org/10.1354/vp.42-4-468
 
Karlsson, E. K., Sigurdsson, S., Ivansson, E., Thomas, R., Elvers, I., Wright, J., … Lindblad-Toh, K. (2013). Genome-wide analyses implicate 33 loci in heritable dog osteosarcoma, including regulatory variants near CDKN2A/B. Genome Biology, 14(12), R132. https://doi.org/10.1186/gb-2013-14-12-r132
 
Modiano, J. F., Breen, M., Burnett, R. C., Parker, H. G., Inusah, S., Thomas, R., … Avery, A. C. (2005). Distinct B-Cell and T-Cell Lymphoproliferative Disease Prevalence among Dog Breeds Indicates Heritable Risk. Cancer Research, 65(13), 5654–5661. https://doi.org/10.1158/0008-5472.CAN-04-4613
 
Sarver, A. L., Thayanithy, V., Scott, M. C., Cleton-Jansen, A.-M., Hogendoorn, P. C., Modiano, J. F., & Subramanian, S. (2013). MicroRNAs at the human 14q32 locus have prognostic significance in osteosarcoma. Orphanet Journal of Rare Diseases, 8(1), 7. https://doi.org/10.1186/1750-1172-8-7
 
Scott, M. C., Sarver, A. L., Gavin, K. J., Thayanithy, V., Getzy, D. M., Newman, R. A., … Modiano, J. F. (2011). Molecular subtypes of osteosarcoma identified by reducing tumor heterogeneity through an interspecies comparative approach. Bone, 49(3), 356–367. https://doi.org/10.1016/j.bone.2011.05.008
 
Tamburini, B. A., Phang, T. L., Fosmire, S. P., Scott, M. C., Trapp, S. C., Duckett, M. M., … Modiano, J. F. (2010). Gene expression profiling identifies inflammation and angiogenesis as distinguishing features of canine hemangiosarcoma. BMC Cancer, 10(1). https://doi.org/10.1186/1471-2407-10-619
 
Thayanithy, V., Park, C., Sarver, A. L., Kartha, R. V., Korpela, D. M., Graef, A. J., … Subramanian, S. (2012). Combinatorial Treatment of DNA and Chromatin-Modifying Drugs Cause Cell Death in Human and Canine Osteosarcoma Cell Lines. PLoS ONE, 7(9), e43720. https://doi.org/10.1371/journal.pone.0043720
 
Thayanithy, V., Sarver, A. L., Kartha, R. V., Li, L., Angstadt, A. Y., Breen, M., … Subramanian, S. (2012). Perturbation of 14q32 miRNAs-cMYC gene network in osteosarcoma. Bone, 50(1), 171–181. https://doi.org/10.1016/j.bone.2011.10.012
 
Thomas, R., Wang, H. J., Tsai, P.-C., Langford, C. F., Fosmire, S. P., Jubala, C. M., … Breen, M. (2009). Influence of genetic background on tumor karyotypes: evidence for breed-associated cytogenetic aberrations in canine appendicular osteosarcoma. Chromosome Research, 17(3), 365–377. https://doi.org/10.1007/s10577-009-9028-z

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