01843: Further Investigation of the Genes Controlling Canine Leukemia to Properly Diagnose and Control the Disease

Grant Status: Closed

Grant Amount: $131,265
Matthew Breen, PhD; North Carolina State University
January 1, 2013 - December 31, 2014

Sponsor(s): American German Shepherd Dog Charitable Foundation, Inc., Cairn Terrier Club of America, Inc., English Cocker Spaniel Club of America, English Setter Association of America, Inc., Golden Retriever Foundation, Mastiff Club of America, Poodle Club of America Foundation, Rottweiler Health Foundation

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

Leukemia represents a range of cancers, most often classified according to the type of blood cell affected and the clinical progression. Leukemia may be chronic, progressing slowly for many years with minimal symptoms, or acute, with sudden onset and rapid progression of symptoms, often resulting in euthanasia. The true incidence of leukemia in dogs is unknown, but there is consensus that many cases remain undiagnosed. Identification of characteristic genome alterations in many human blood cancers has identified changes that are associated with different cancer subtypes. Several of the subtypes have been shown to have better response to therapy and thus correlate with prolonged survival. In previous studies we have shown that canine leukemia presents with characteristic chromosome changes shared with those present in the human counterparts. In humans such aberrations have been linked to therapeutic response and this prognostic association is used to drive clinical management.

In this multicenter study we obtained a large number of canine leukemia samples have assessed these by high resolution, genome-wide analysis of DNA copy number. We identified several regions of the canine genome that serve as predictors of subtype. Using robust informatics we developed an algorithm that allows us to use copy number to separate key subtypes using a peripheral blood sample. These data are now being evaluated for the potential to aid leukemia diagnosis. Defining the gene involved also provide opportunities to suggest new targets that may be considered for the development of improved therapies for dogs diagnosed with leukemia.

We use comparative genomics to compare our canine leukemia data with comparable data from large numbers of human leukemia patients. Using this complex process we identified numerous chromosome changes that are shared between canine and human patient data. Many of the changes we identified are:
•    able to reduce the size of key regions of the human genome and thus provide opportunities to accelerate discovery of those genes most key to both species,
•    associated with prognosis in human patients.

By defining the genes with shared copy number changes in both dog and human, and especially identifying those changes that are associated with outcome in humans, we will now pursue a new study to assess the prognostic significance of these genes in canine patients.

The major outcome of this important CHF funded study is that we are moving closer towards developing a means to able to accurately diagnose canine leukemia and also to suggest possible treatments that may improve outcome, as in human patients.

Publication(s)

Culver, S., Ito, D., Borst, L., Bell, J. S., Modiano, J. F., & Breen, M. (2013). Molecular characterization of canine BCR-ABL-positive chronic myelomonocytic leukemia before and after chemotherapy. Veterinary Clinical Pathology, 42(3), 314–322. https://doi.org/10.1111/vcp.12055

Roode, S. C., Rotroff, D., Avery, A. C., Suter, S. E., Bienzle, D., Schiffman, J. D., … Breen, M. (2015). Genome-wide assessment of recurrent genomic imbalances in canine leukemia identifies evolutionarily conserved regions for subtype differentiation. Chromosome Research, 23(4), 681–708. https://doi.org/10.1007/s10577-015-9475-7

Roode, S. C., Rotroff, D., Richards, K. L., Moore, P., Motsinger-Reif, A., Okamura, Y., … Breen, M. (2016). Comprehensive genomic characterization of five canine lymphoid tumor cell lines. BMC Veterinary Research, 12(1). https://doi.org/10.1186/s12917-016-0836-z

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