1843: Further Investigation of the Genes Controlling Canine Leukemia to Properly Diagnose and Control the Disease

Grant Status: Closed

Grant Amount: $131,265
Dr. 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

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)

- 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, 207. http://doi.org/10.1186/s12917-016-0836-z

- Sarah C. Roode, Daniel Rotroff, Anne C. Avery, Steven E. Suter, Dorothee Bienzle, Joshua D. Schiffman, Alison Motsinger-Reif, and Matthew Breen. (2015). Genome-wide assessment of recurrent genomic imbalances in canine leukemia identifies evolutionarily conserved regions subtype differentiation. Chromosome Research (on-line June 3rd 2015)  
*This was the major publication derived from this study, which uses all the data to comprehensively report on the findings and discuss their significance.

- Sarah Culver, Daisuke Ito, Luke Borst, Jerold Bell, Jamie Modiano and Matthew Breen (2013). Molecular characterization of canine BCR-ABL-positivie chronic myelomonocytic leukemia before and after chemotherapy. Vet Clin Path 42(30): 314–322

- Mayrim L. Perez*, Sarah Culver*, Jennifer Owen, Mark Dunbar, Kelvin Kow, Matthew Breen and Rowan J. Milner (2013). Partial cytogenetic response with toceranib and prednisone treatment in a young dog with chronic monocytic leukemia. Anticancer drugs 24(10):1098- 1103. *shared 1st author

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