Genome-wide assessment of recurrent genomic imbalances in canine leukemia identifies evolutionarily conserved regions for subtype differentiation

Abstract

Leukemia in dogs is a heterogeneous disease with survival ranging from days to years, depending on the subtype. Strides have been made in both human and canine leukemia to improve classification and understanding of pathogenesis through immunophenotyping, yet classification and choosing appropriate therapy remains challenging. In this study, we assessed 123 cases of canine leukemia (28 ALLs, 24 AMLs, 25 B-CLLs, and 46 T-CLLs) using high-resolution oligonucleotide array comparative genomic hybridization (oaCGH) to detect DNA copy number alterations (CNAs). For the first time, such data were used to identify recurrent CNAs and inclusive genes that may be potential drivers of subtype-specific pathogenesis. We performed predictive modeling to identify CNAs that could reliably differentiate acute subtypes (ALL vs. AML) and chronic subtypes (B-CLL vs. T-CLL) and used this model to differentiate cases with up to 83.3 and 95.8 % precision, respectively, based on CNAs at only one to three genomic regions. In addition, CGH datasets for canine and human leukemia were compared to reveal evolutionarily conserved copy number changes between species, including the shared gain of HSA 21q in ALL and ∼25 Mb of shared gain of HSA 12 and loss of HSA 13q14 in CLL. These findings support the use of canine leukemia as a relevant in vivo model for human leukemia and justify the need to further explore the conserved genomic regions of interest for their clinical impact.

Canine Nervous System Lymphoma Subtypes Display Characteristic Neuroanatomical Patterns

“…26 None of these markers have been identified yet in canine DLBCL. 9,10,16,22,23 Molecular studies in domestic animals may thus be of diagnostic value in addition to identifying the mechanisms of invasion and homing of neoplastic cells.…”

The Genetic and Molecular Basis for Canine Models of Human Leukemia and Lymphoma

“…In the author's opinion, canine acute lymphoid leukemias are almost always T cell in origin. Several pieces of evidence support this conclusion: (1) The tissue equivalent (lymphoblastic B cell lymphoma) is almost never diagnosed by histopathology, whereas lymphoblastic T cell lymphoma, while not common, has been identified in several studies (5, 10), (2) When examining copy number variation in canine ALL, recurrent losses in the T cell receptor α/δ, and T cell receptor β region were observed, consistent with T cell receptor rearrangements, but similar losses were not identified in immunoglobulin heavy or light chain regions (22), (3) Evidence for B cell lineage in reports describing B-cell ALL have relied entirely on the expression of CD79a which does not have high lineage fidelity (23,24). Despite these observations, further proof of this hypothesis will require additional immunophenotypic and gene expression studies.…”

Integrated immunohistochemical and DNA copy number profiling analysis provides insight into the molecular pathogenesis of canine follicular lymphoma

“…We have shown previously that spontaneous haematologic malignancies of dogs exhibit genomic alterations that are evolutionarily conserved with those of their human counterparts, despite their highly contrasting genome organization . Notable among these are the BCR‐ABL chromosome rearrangement of chronic myelogenous leukaemia, and the MYC‐IGH translocation of Burkitt lymphoma .…”