@article{kennedy_thomas_durrant_jiang_motsinger-reif_breen_2019, title={Genome-wide DNA copy number analysis and targeted transcriptional analysis of canine histiocytic malignancies identifies diagnostic signatures and highlights disruption of spindle assembly complex}, volume={27}, ISSN={["1573-6849"]}, DOI={10.1007/s10577-019-09606-0}, abstractNote={Canine histiocytic malignancies (HM) are rare across the general dog population, but overrepresented in certain breeds, such as Bernese mountain dog and flat-coated retriever. Accurate diagnosis relies on immunohistochemical staining to rule out histologically similar cancers with different prognoses and treatment strategies (e.g., lymphoma and hemangiosarcoma). HM are generally treatment refractory with overall survival of less than 6 months. A lack of understanding regarding the mechanisms of disease development and progression hinders development of novel therapeutics. While the study of human tumors can benefit veterinary medicine, the rarity of the suggested orthologous disease (dendritic cell sarcoma) precludes this. This study aims to improve the understanding of underlying disease mechanisms using genome-wide DNA copy number and gene expression analysis of spontaneous HM across several dog breeds. Extensive DNA copy number disruption was evident, with losses of segments of chromosomes 16 and 31 detected in 93% and 72% of tumors, respectively. Droplet digital PCR (ddPCR) evaluation of these regions in numerous cancer specimens effectively discriminated HM from other common round cell tumors, including lymphoma and hemangiosarcoma, resulting in a novel, rapid diagnostic aid for veterinary medicine. Transcriptional analysis demonstrated disruption of the spindle assembly complex, which is linked to genomic instability and reduced therapeutic impact in humans. A key signature detected was up-regulation of Matrix Metalloproteinase 9 (MMP9), supported by an immunohistochemistry-based assessment of MMP9 protein levels. Since MMP9 has been linked with rapid metastasis and tumor aggression in humans, the data in this study offer a possible mechanism of aggression in HM.}, number={3}, journal={CHROMOSOME RESEARCH}, author={Kennedy, Katherine and Thomas, Rachael and Durrant, Jessica and Jiang, Tao and Motsinger-Reif, Alison and Breen, Matthew}, year={2019}, month={Sep}, pages={179–202} }
 @article{thomas_demeter_kennedy_borst_singh_valli_le boedec_breen_2017, title={Integrated immunohistochemical and DNA copy number profiling analysis provides insight into the molecular pathogenesis of canine follicular lymphoma}, volume={15}, ISSN={["1476-5829"]}, DOI={10.1111/vco.12227}, abstractNote={Abstract}, number={3}, journal={VETERINARY AND COMPARATIVE ONCOLOGY}, author={Thomas, R. and Demeter, Z. and Kennedy, K. A. and Borst, L. and Singh, K. and Valli, V. E. and Le Boedec, K. and Breen, M.}, year={2017}, month={Sep}, pages={852–867} }
 @article{mochizuki_kennedy_shapiro_breen_2015, title={BRAF Mutations in Canine Cancers}, volume={10}, ISSN={["1932-6203"]}, url={http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=ORCID&SrcApp=OrcidOrg&DestLinkType=FullRecord&DestApp=WOS_CPL&KeyUT=WOS:000355955300139&KeyUID=WOS:000355955300139}, DOI={10.1371/journal.pone.0129534}, abstractNote={Activating mutations of the BRAF gene lead to constitutive activation of the MAPK pathway. Although many human cancers carry the mutated BRAF gene, this mutation has not yet been characterized in canine cancers. As human and canine cancers share molecular abnormalities, we hypothesized that BRAF gene mutations also exist in canine cancers. To test this hypothesis, we sequenced the exon 15 of BRAF, mutation hot spot of the gene, in 667 canine primary tumors and 38 control tissues. Sequencing analysis revealed that a single nucleotide T to A transversion at nucleotide 1349 occurred in 64 primary tumors (9.6%), with particularly high frequency in prostatic carcinoma (20/25, 80%) and urothelial carcinoma (30/45, 67%). This mutation results in the amino acid substitution of glutamic acid for valine at codon 450 (V450E) of canine BRAF, corresponding to the most common BRAF mutation in human cancer, V600E. The evolutional conservation of the BRAF V600E mutation highlights the importance of MAPK pathway activation in neoplasia and may offer opportunity for molecular diagnostics and targeted therapeutics for dogs bearing BRAF-mutated cancers.}, number={6}, journal={PLOS ONE}, author={Mochizuki, Hiroyuki and Kennedy, Katherine and Shapiro, Susan G. and Breen, Matthew}, year={2015}, month={Jun} }