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

Avery, Anne C.

doi:10.3389/fonc.2020.00023

Cited by 35 publications

(43 citation statements)

References 89 publications

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“…The DLBCL probably is the most investigated tumor in veterinary medicine been relevant as spontaneous model for human DLBCL 4 . There are genetic abnormalities and mutations shared between canine and human lymphomas including PTCL activation of the PI3 kinase pathways, loss of PTEN and the tumor suppressor CDKN2, constitutive activation of the NF-kB pathway, and presence of double expressing MYC/BCL2 lymphomas 6 . The second most common subtype is PTCL-NOS (Peripheral T-cell lymphoma not otherwise specified) that is relatively uncommon in humans.…”

Section: Introductionmentioning

confidence: 99%

Liquid biopsy based on small extracellular vesicles predicts chemotherapy response of canine multicentric lymphomas

Garnica

Lesbon

Ávila

et al. 2020

Sci Rep

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Lymphoma is the most common type of canine hematological malignancy where the multicentric (cMCL) form accounts for 75% of all cases. The standard treatment is the CHOP chemotherapy protocols that include cyclophosphamide, doxorubicin, vincristine and prednisone, where the majority of dogs achieve complete/partial response; however, it is very important to predict non-responsive cases to improve treatment and to develop new targeted therapies. Here we evaluate a liquid biopsy approach based on serum Small Extracellular Vesicles enriched for exosomes (SEVs) to predict cMCL chemotherapy response. Nineteen dogs at the end of the 19-week chemotherapy protocol (8 Complete Response and 11 Progressive Disease) were evaluated for serum SEVs size, concentration and screened for 95 oncomirs. PD patients had higher SEVs concentration at the diagnosis than CR patients (P = 0.034). The ROC curve was significant for SEVs concentration to predict the response to CHOP (AUC = 0.8011, P = 0.0287). A potential molecular signature based on oncomirs from SEVs (caf-miR-205, caf-miR-222, caf-mir-20a and caf-miR-93) is proposed. To the best of our knowledge, this is the first study demonstrating the potential of a liquid biopsy based on SEVs and their miRNAs content to predict the outcome of chemotherapy for canine multicentric lymphomas.

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Section: Introductionmentioning

confidence: 99%

Liquid biopsy based on small extracellular vesicles predicts chemotherapy response of canine multicentric lymphomas

Garnica

Lesbon

Ávila

et al. 2020

Sci Rep

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“…The CFA5 region colocalizes with previously-identified associations for two common hematological malignancies in golden retrievers: hemangiosarcoma (29 Mb) and B-cell lymphoma (34 Mb; Fig 4A ) [ 19 ]. Although distinct cancers, histiocytic sarcoma, B-cell lymphoma, and hemangiosarcoma all arise from cells in the hematopoietic stem cell pathway: dendritic cells and macrophages, B lymphocytes, and hematopoietic precursor cells, respectively [ 4 , 8 , 20 , 21 ]. FCRs and golden retrievers are closely related breeds, sharing an immediate common ancestor among the retriever phylogenetic clade [ 16 ].…”

Section: Resultsmentioning

confidence: 99%

Multi-omics approach identifies germline regulatory variants associated with hematopoietic malignancies in retriever dog breeds

et al. 2021

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Histiocytic sarcoma is an aggressive hematopoietic malignancy of mature tissue histiocytes with a poorly understood etiology in humans. A histologically and clinically similar counterpart affects flat-coated retrievers (FCRs) at unusually high frequency, with 20% developing the lethal disease. The similar clinical presentation combined with the closed population structure of dogs, leading to high genetic homogeneity, makes dogs an excellent model for genetic studies of cancer susceptibility. To determine the genetic risk factors underlying histiocytic sarcoma in FCRs, we conducted multiple genome-wide association studies (GWASs), identifying two loci that confer significant risk on canine chromosomes (CFA) 5 (Pwald = 4.83x10-9) and 19 (Pwald = 2.25x10-7). We subsequently undertook a multi-omics approach that has been largely unexplored in the canine model to interrogate these regions, generating whole genome, transcriptome, and chromatin immunoprecipitation sequencing. These data highlight the PI3K pathway gene PIK3R6 on CFA5, and proximal candidate regulatory variants that are strongly associated with histiocytic sarcoma and predicted to impact transcription factor binding. The CFA5 association colocalizes with susceptibility loci for two hematopoietic malignancies, hemangiosarcoma and B-cell lymphoma, in the closely related golden retriever breed, revealing the risk contribution this single locus makes to multiple hematological cancers. By comparison, the CFA19 locus is unique to the FCR and harbors risk alleles associated with upregulation of TNFAIP6, which itself affects cell migration and metastasis. Together, these loci explain ~35% of disease risk, an exceptionally high value that demonstrates the advantages of domestic dogs for complex trait mapping and genetic studies of cancer susceptibility.

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“…Thus, when CFA19 data are included, we observe greatly improved separation of cases and controls relative to analysis with CFA5 genotypes alone. (4,8,20,21). FCRs and golden retrievers are closely related breeds, sharing an immediate common ancestor among the retriever phylogenetic clade (16).…”

Section: Cfa5 and Cfa19 Confer Risk For Histiocytic Sarcomamentioning

confidence: 99%

Multi-omics approach identifies germline regulatory variants associated with hematopoietic malignancies in retriever dog breeds

Evans

Parker

Rutteman

et al. 2021

Preprint

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Histiocytic sarcoma is an aggressive hematopoietic malignancy of mature tissue histiocytes with a poorly understood etiology in humans. A histologically and clinically similar counterpart affects flat-coated retrievers (FCRs) at unusually high frequency, with 20% developing the lethal disease. The similar clinical presentation combined with the closed population structure of dogs, leading to high genetic homogeneity, makes dogs an excellent model for genetic studies of cancer susceptibility. To determine the genetic risk factors underlying histiocytic sarcoma in FCRs, we conducted multiple genome-wide association studies (GWASs), identifying two loci that confer significant risk on canine chromosomes (CFA) 5 (Pwald=4.83x10-9) and 19 (Pwald=2.25x10-7). We subsequently undertook a multi-omics approach that has been largely unexplored in the canine model to interrogate these regions, generating whole genome, transcriptome, and chromatin immunoprecipitation sequencing. These data highlight the PI3K pathway gene PIK3R6 on CFA5, and proximal candidate regulatory variants that are strongly associated with histiocytic sarcoma and predicted to impact transcription factor binding. The CFA5 association colocalizes with susceptibility loci for two hematopoietic malignancies, hemangiosarcoma and B-cell lymphoma, in the closely related golden retriever breed, revealing the risk contribution this single locus makes to multiple hematological cancers. By comparison, the CFA19 locus is unique to the FCR and harbors risk alleles associated with upregulation of TNFAIP6, which itself affects cell migration and metastasis. Together, these loci explain ~35% of disease risk, an exceptionally high value that demonstrates the advantages of domestic dogs for complex trait mapping and genetic studies of cancer susceptibility.

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

Cited by 35 publications

References 89 publications

Liquid biopsy based on small extracellular vesicles predicts chemotherapy response of canine multicentric lymphomas

Liquid biopsy based on small extracellular vesicles predicts chemotherapy response of canine multicentric lymphomas

Multi-omics approach identifies germline regulatory variants associated with hematopoietic malignancies in retriever dog breeds

Multi-omics approach identifies germline regulatory variants associated with hematopoietic malignancies in retriever dog breeds

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