00615A-T: Heritable and Sporadic Genetic Lesions in Canine Lymphoma
Grant Status: Closed
Project Summary
We are aware that these progress reports are made available to representatives from breed clubs or agencies that have contributed financially to support the project. We respectfully remind readers that data included in this progress report may be preliminary and require further confirmation. We request that all contents of this report be maintained in strict confidence until there is public disclosure (publication). The investigators are generally willing to provide updates on the research for newsletters or other outlets that will describe our findings without compromising the integrity of the data. It has been apparent for some time that certain dog breeds are prone to develop certain types of cancer. To date, there has been little progress to define factors that account for this risk. 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 (with that form of the disease) than in other breeds, suggesting breed-specific profiles of genetic abnormalities exist in canine lymphoma. To continue this work, we have used contemporary "array-based" technologies to identify genes that map to these regions and how they contribute to the disease. The results from these analysis are in many ways comforting, as they show differences that are proportional to what would be expected based on the known biology of lymphoma. In other words, tumors differ more based on phenotype (B-cell vs. T-cell) than they do based on histologic grade. Also, T-cell malignancies harbor more differences among them than B-cell malignancies. The data show that breedspecific changes extend to age of onset for lymphoma, providing additional support for the central hypothesis, and 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. Nevertheless, gene expression differences are subtle, and in the case of breed and gender, they are few in number. This is a remarkable result, since these small differences may define genes and pathways that are heavily involved in risk and progression of the disease in specific breeds. We predict that the results from this work will allow us to define how heritable factors influence the phenotype and biological behavior of these tumors, setting the groundwork to develop better strategies for diagnosis, control, and treatment.
Publication(s)
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
Ito, D., Endicott, M. M., Jubala, C. M., Helm, K. M., Burnett, R. C., Husbands, B. D., … Modiano, J. F. (2011). A Tumor-Related Lymphoid Progenitor Population Supports Hierarchical Tumor Organization in Canine B-Cell Lymphoma: Canine B-Cell Lymphoma. Journal of Veterinary Internal Medicine, 25(4), 890–896. https://doi.org/10.1111/j.1939-1676.2011.0756.x
Ito, Daisuke, Frantz, A. M., Williams, C., Thomas, R., Burnett, R. C., Avery, A. C., … Modiano, J. F. (2012). CD40 ligand is necessary and sufficient to support primary diffuse large B-cell lymphoma cells in culture: a tool for in vitro preclinical studies with primary B-cell malignancies. Leukemia & Lymphoma, 53(7), 1390–1398. https://doi.org/10.3109/10428194.2011.654337
Ito, Daisuke, O’Brien, T. D., & Modiano, J. F. (2010). Exclusion of cytoplasmic fragments in flow cytometric analysis of lymph node samples from dogs with lymphoma using membrane-permeable violet laser-excitable DNA-binding fluorescent dye (DyeCycle Violet). Veterinary Clinical Pathology, 39(4), 494–498. https://doi.org/10.1111/j.1939-165X.2010.00252.x
Tonomura, N., Elvers, I., Thomas, R., Megquier, K., Turner-Maier, J., Howald, C., … Lindblad-Toh, K. (2015). Genome-wide Association Study Identifies Shared Risk Loci Common to Two Malignancies in Golden Retrievers. PLOS Genetics. https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1004922
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