01889-G: Innovations in Prevention, Diagnosis, and Treatment of Cancer - Goldens Lead the Way
Grant Status: Closed
Lymphoma and hemangiosarcoma are major health problems in Golden Retrievers, causing both suffering and premature death. Through ongoing collaboration, Drs. Jaime Modiano, Matthew Breen, and Kerstin Lindblad-Toh have identified several regions of the genome that contain genetic heritable risk factors for lymphoma and hemangiosarcoma in Golden Retrievers. They have tumor-specific mutations that occur recurrently in both cancers, some of which are linked to duration of remission when treated with standard of care. Their results indicate that a few heritable genetic risk factors account for as much as 50% of the risk for these cancers. These findings offer the potential to develop tests and strategies for DNA tests that can predict risk for individual dogs, as well as to manage risk across the population as a whole. Indeed, both the inherited risk factors and tumor mutations point to pathways that have been implicated in the pathogenesis of lymphoma and hemangiosarcoma, and thus should inform the development of targeted therapies. In the current study, Drs. Modiano, Breen, and Lindblad-Toh will find the precise mutations for the heritable genetic risk factors and to validate markers (mutations) used to determine risk at the heritable loci in a larger independent population of Golden Retrievers from the United States and from Europe in order to develop robust risk prediction tools and an accompanying DNA test. Further, they will identify and characterize tumor mutations and study their relationship to the heritable risk factors, tumor pathogenetic mechanisms, and disease outcome.
Borgatti, A., Koopmeiners, J. S., Sarver, A. L., Winter, A. L., Stuebner, K., Todhunter, D., … Vallera, D. A. (2017). Safe and Effective Sarcoma Therapy through Bispecific Targeting of EGFR and uPAR. Molecular Cancer Therapeutics, 16(5), 956–965. https://doi.org/10.1158/1535-7163.MCT-16-0637
Elvers, I., Turner-Maier, J., Swofford, R., Koltookian, M., Johnson, J., Stewart, C., … Alföldi, J. (2015). Exome sequencing of lymphomas from three dog breeds reveals somatic mutation patterns reflecting genetic background. Genome Research, 25(11), 1634–1645. https://doi.org/10.1101/gr.194449.115
Gorden, B. H., Kim, J.-H., Sarver, A. L., Frantz, A. M., Breen, M., Lindblad-Toh, K., … Dickerson, E. B. (2014). Identification of Three Molecular and Functional Subtypes in Canine Hemangiosarcoma through Gene Expression Profiling and Progenitor Cell Characterization. The American Journal of Pathology, 184(4), 985–995. https://doi.org/10.1016/j.ajpath.2013.12.025
Seelig, D. M., Ito, D., Forster, C. L., Yoon, U. A., Breen, M., Burns, L. J., … Linden, M. A. (2017). Constitutive activation of alternative nuclear factor kappa B pathway in canine diffuse large B-cell lymphoma contributes to tumor cell survival and is a target of new adjuvant therapies. Leukemia & Lymphoma, 58(7), 1702–1710. https://doi.org/10.1080/10428194.2016.1260122
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, 11(2), e1004922. https://doi.org/10.1371/journal.pgen.1004922
Help Future Generations of Dogs
Participate in canine health research by providing samples or by enrolling in a clinical trial. Samples are needed from healthy dogs and dogs affected by specific diseases.