01557: Narrowing the Search for the Genetic Basis of Histiocytic Malignancies

Grant Status: Closed

Grant Amount: $125,000
Matthew Breen, PhD; North Carolina State University
July 1, 2012 - June 30, 2014

Sponsor(s): American German Shepherd Dog Charitable Foundation, Inc., Berner Lovers, Flat-Coated Retriever Foundation, Golden Retriever Foundation, Rottweiler Health Foundation

Breed(s): Bernese Mountain Dog, Rottweiler, Flat-Coated Retriever, Labrador Retriever, Golden Retriever
Research Program Area: Oncology
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Abstract

In a previous study (CHF-760) Dr. Breen demonstrated that canine histiocytic malignancies (HMs) present with a high degree of DNA copy number alterations. His research group identified several aberrant regions of the genome that are highly recurrent between cases, suggesting that such regions are associated causally with the malignant process. Understanding the biology of genes within such regions is key to developing ways to halt the cancer and prolong life in patients whom otherwise have a poor prognosis. They now have an approach to identify DNA copy number changes that allows them to zoom in on regions of the genome with ~75-fold greater resolution than was possible even just one year ago. Using this technology they will refine the genome regions of interest and identify additional, smaller aberrations. Within these regions they will identify a series of candidate genes for functional analysis. They have developed an assay for use with archival canine tumor samples that allows them to rapidly determine the level of activity of multiple genes with higher sensitivity than was possible previously. Once they have identified the key genes of interest, they will use this assay to screen HM cases for the extent of gene deregulation, as well as identify DNA copy number changes that are shared with human HMs. Combining these approaches, they will narrow down the search for genes playing a key role in HMs and thus move a step closer to developing targeted therapies for canine patients diagnosed with this devastating cancer.

Publication(s)

Hédan, B., Rault, M., Abadie, J., Ulvé, R., Botherel, N., Devauchelle, P., Copie‐Bergman, C., Cadieu, E., Parrens, M., Alten, J., Zalcman, E. L., Cario, G., Damaj, G., Mokhtari, K., Loarer, F. L., Coulomb‐Lhermine, A., Derrien, T., Hitte, C., Bachelot, L., … André, C. (2020). PTPN11 mutations in canine and human disseminated histiocytic sarcoma. International Journal of Cancer. https://doi.org/10.1002/ijc.32991

Kennedy, K., Thomas, R., Durrant, J., Jiang, T., Motsinger-Reif, A., & Breen, M. (2019). Genome-wide DNA copy number analysis and targeted transcriptional analysis of canine histiocytic malignancies identifies diagnostic signatures and highlights disruption of spindle assembly complex. Chromosome Research. https://doi.org/10.1007/s10577-019-09606-0

Kennedy, K., Thomas, R., & Breen, M. (2016). Canine Histiocytic Malignancies—Challenges and Opportunities. Veterinary Sciences, 3(1), 2. https://doi.org/10.3390/vetsci3010002

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