Gene Expression Profiles of Sporadic Canine Hemangiosarcoma Are Uniquely Associated with Breed
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{"title"=>"Gene expression profiles of sporadic canine hemangiosarcoma are uniquely associated with breed", "type"=>"journal", "authors"=>[{"first_name"=>"Beth A.", "last_name"=>"Tamburini", "scopus_author_id"=>"8898276500"}, {"first_name"=>"Susan", "last_name"=>"Trapp", "scopus_author_id"=>"57198343041"}, {"first_name"=>"Tzu Lip", "last_name"=>"Phang", "scopus_author_id"=>"55603014000"}, {"first_name"=>"Jill T.", "last_name"=>"Schappa", "scopus_author_id"=>"26639777900"}, {"first_name"=>"Lawrence E.", "last_name"=>"Hunter", "scopus_author_id"=>"12647593500"}, {"first_name"=>"Jaime F.", "last_name"=>"Modiano", "scopus_author_id"=>"7003997675"}], "year"=>2009, "source"=>"PLoS ONE", "identifiers"=>{"pui"=>"354654309", "isbn"=>"1932-6203 (Electronic)\r1932-6203 (Linking)", "issn"=>"19326203", "doi"=>"10.1371/journal.pone.0005549", "scopus"=>"2-s2.0-66249123302", "pmid"=>"19461996", "sgr"=>"66249123302"}, "id"=>"7afcf41c-9a91-36d9-b430-a0878b3b8da0", "abstract"=>"The role an individual's genetic background plays on phenotype and biological behavior of sporadic tumors remains incompletely understood. We showed previously that lymphomas from Golden Retrievers harbor defined, recurrent chromosomal aberrations that occur less frequently in lymphomas from other dog breeds, suggesting spontaneous canine tumors provide suitable models to define how heritable traits influence cancer genotypes. Here, we report a complementary approach using gene expression profiling in a naturally occurring endothelial sarcoma of dogs (hemangiosarcoma). Naturally occurring hemangiosarcomas of Golden Retrievers clustered separately from those of non-Golden Retrievers, with contributions from transcription factors, survival factors, and from pro-inflammatory and angiogenic genes, and which were exclusively present in hemangiosarcoma and not in other tumors or normal cells (i.e., they were not due simply to variation in these genes among breeds). Vascular Endothelial Growth Factor Receptor 1 (VEGFR1) was among genes preferentially enriched within known pathways derived from gene set enrichment analysis when characterizing tumors from Golden Retrievers versus other breeds. Heightened VEGFR1 expression in these tumors also was apparent at the protein level and targeted inhibition of VEGFR1 increased proliferation of hemangiosarcoma cells derived from tumors of Golden Retrievers, but not from other breeds. Our results suggest heritable factors mold gene expression phenotypes, and consequently biological behavior in sporadic, naturally occurring tumors.", "link"=>"http://www.mendeley.com/research/gene-expression-profiles-sporadic-canine-hemangiosarcoma-uniquely-associated-breed", "reader_count"=>51, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>5, "Librarian"=>1, "Student > Doctoral Student"=>3, "Researcher"=>9, "Student > Ph. D. Student"=>7, "Student > Postgraduate"=>5, "Student > Master"=>7, "Other"=>6, "Student > Bachelor"=>2, "Lecturer"=>2, "Lecturer > Senior Lecturer"=>1, "Professor"=>3}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>5, "Librarian"=>1, "Student > Doctoral Student"=>3, "Researcher"=>9, "Student > Ph. D. Student"=>7, "Student > Postgraduate"=>5, "Student > Master"=>7, "Other"=>6, "Student > Bachelor"=>2, "Lecturer"=>2, "Lecturer > Senior Lecturer"=>1, "Professor"=>3}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Environmental Science"=>1, "Biochemistry, Genetics and Molecular Biology"=>3, "Medicine and Dentistry"=>17, "Agricultural and Biological Sciences"=>11, "Veterinary Science and Veterinary Medicine"=>14, "Social Sciences"=>1, "Computer Science"=>1, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>17}, "Social Sciences"=>{"Social Sciences"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>11}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>3}, "Unspecified"=>{"Unspecified"=>2}, "Environmental Science"=>{"Environmental Science"=>1}, "Veterinary Science and Veterinary Medicine"=>{"Veterinary Science and Veterinary Medicine"=>14}}, "reader_count_by_country"=>{"United States"=>2, "Brazil"=>1, "Mexico"=>1}, "group_count"=>2}

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  • {"files"=>["https://ndownloader.figshare.com/files/897936"], "description"=>"1<p>The filtered gene list from Golden Retrievers with hemangiosarcoma vs. non-Golden Retrievers with hemangiosarcoma were compared using the GSEA software. ES (Enrichment Score) is a value that represents how well the gene set is enriched within the selected gene list. NES (normalized enrichment score) corrects the ES for differences in gene set size and can be used to compare across gene sets. A high ES or NES indicates that gene set is highly enriched within our gene list. FDR represents the probability that the NES for a gene set gives a false positive finding. The highest FDR shown here is 0.005 indicating that there is a 0.005% chance that the gene set indicates a false positive finding. The lists shown are those gene sets with an NES higher than 2.10.</p>", "links"=>[], "tags"=>["enrichment", "pathways", "hypoxia", "retrievers"], "article_id"=>568385, "categories"=>["Genetics", "Computational Biology", "Infectious Diseases"], "users"=>["Beth A. Tamburini", "Susan Trapp", "Tzu Lip Phang", "Jill T. Schappa", "Lawrence E. Hunter", "Jaime F. Modiano"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0005549.t004", "stats"=>{"downloads"=>1, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Gene_Set_Enrichment_Analysis_Predicts_Pathways_Involved_in_Inflammation_Cancer_and_Hypoxia_Are_Important_for_Golden_Retrievers_with_Hemangiosarcoma_1_/568385", "title"=>"Gene Set Enrichment Analysis Predicts Pathways Involved in Inflammation, Cancer, and Hypoxia Are Important for Golden Retrievers with Hemangiosarcoma<sup>1</sup>.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2009-05-20 02:19:45"}
  • {"files"=>["https://ndownloader.figshare.com/files/897875"], "description"=>"<p>The effect of three VEGFR inhibitors on proliferation and viability of hemangiosarcoma cells was tested in vitro. The selectivity and half maximal inhibitory concentrations for Drugs 1, 2, and 3 are listed in the <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0005549#s4\" target=\"_blank\">Materials and Methods</a>. Cells (10,000/well) were plated in duplicate in a 96-well microtiter plates and allowed to attach for 16 hr prior to addition of inhibitors at the indicated concentration. Cells were then cultured for 72 hr, and the number of viable cells was determined using the MTS assay. Absorption at 490 nm for each well was averaged, and data normalized to % viability where the mean of wells that received no treatment (0 nm) was considered = 100%. The mean of two independent experiments is shown at drug concentrations of 100 nM. P-values were calculated using Student's T-test.</p>", "links"=>[], "tags"=>["canine", "hemangiosarcoma", "lines", "vegfr"], "article_id"=>568327, "categories"=>["Genetics", "Computational Biology", "Infectious Diseases"], "users"=>["Beth A. Tamburini", "Susan Trapp", "Tzu Lip Phang", "Jill T. Schappa", "Lawrence E. Hunter", "Jaime F. Modiano"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0005549.g004", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Differential_Sensitivity_of_Canine_Hemangiosarcoma_Cell_Lines_to_VEGFR_Inhibitors_/568327", "title"=>"Differential Sensitivity of Canine Hemangiosarcoma Cell Lines to VEGFR Inhibitors.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-05-20 02:18:47"}
  • {"files"=>["https://ndownloader.figshare.com/files/898007"], "description"=>"1<p>qPCR was performed on genes as described previously in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0005549#pone-0005549-g001\" target=\"_blank\">Figure 1C</a>. Presented is the average fold change and average fold range from at least 3 samples which were individually normalized to 18s control gene. P-values were calculated using the Welch t-test for samples with unequal variance, or Student's t-test for equal variance. Only Golden Retriever hemangiosarcoma compared to Non-Golden Retriever hemangiosarcoma showed differences that were statistically significant in each of the 3 genes analyzed.</p>", "links"=>[], "tags"=>["differences", "hemangiosarcoma", "generalized", "tissues"], "article_id"=>568456, "categories"=>["Genetics", "Computational Biology", "Infectious Diseases"], "users"=>["Beth A. Tamburini", "Susan Trapp", "Tzu Lip Phang", "Jill T. Schappa", "Lawrence E. Hunter", "Jaime F. Modiano"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0005549.t003", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Breed_Dependent_Gene_Expression_Differences_in_Hemangiosarcoma_Are_Not_Generalized_To_Normal_Tissues_or_Other_Tumors_1_/568456", "title"=>"Breed-Dependent Gene Expression Differences in Hemangiosarcoma Are Not Generalized To Normal Tissues or Other Tumors<sup>1</sup>.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2009-05-20 02:20:56"}
  • {"files"=>["https://ndownloader.figshare.com/files/897964"], "description"=>"<p>Signalment (Demographics) of Dogs in Study.</p>", "links"=>[], "tags"=>["dogs"], "article_id"=>568429, "categories"=>["Genetics", "Computational Biology", "Infectious Diseases"], "users"=>["Beth A. Tamburini", "Susan Trapp", "Tzu Lip Phang", "Jill T. Schappa", "Lawrence E. Hunter", "Jaime F. Modiano"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0005549.t001", "stats"=>{"downloads"=>0, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Signalment_Demographics_of_Dogs_in_Study_/568429", "title"=>"Signalment (Demographics) of Dogs in Study.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2009-05-20 02:20:29"}
  • {"files"=>["https://ndownloader.figshare.com/files/444470"], "description"=>"<div><p>The role an individual's genetic background plays on phenotype and biological behavior of sporadic tumors remains incompletely understood. We showed previously that lymphomas from Golden Retrievers harbor defined, recurrent chromosomal aberrations that occur less frequently in lymphomas from other dog breeds, suggesting spontaneous canine tumors provide suitable models to define how heritable traits influence cancer genotypes. Here, we report a complementary approach using gene expression profiling in a naturally occurring endothelial sarcoma of dogs (hemangiosarcoma). Naturally occurring hemangiosarcomas of Golden Retrievers clustered separately from those of non-Golden Retrievers, with contributions from transcription factors, survival factors, and from pro-inflammatory and angiogenic genes, and which were exclusively present in hemangiosarcoma and not in other tumors or normal cells (<em>i.e.</em>, they were not due simply to variation in these genes among breeds). Vascular Endothelial Growth Factor Receptor 1 (VEGFR1) was among genes preferentially enriched within known pathways derived from gene set enrichment analysis when characterizing tumors from Golden Retrievers versus other breeds. Heightened VEGFR1 expression in these tumors also was apparent at the protein level and targeted inhibition of VEGFR1 increased proliferation of hemangiosarcoma cells derived from tumors of Golden Retrievers, but not from other breeds. Our results suggest heritable factors mold gene expression phenotypes, and consequently biological behavior in sporadic, naturally occurring tumors.</p></div>", "links"=>[], "tags"=>["profiles", "sporadic", "canine", "hemangiosarcoma", "are", "uniquely", "breed"], "article_id"=>147603, "categories"=>["Genetics", "Biological Sciences", "Cancer"], "users"=>["Beth A. Tamburini", "Susan Trapp", "Tzu Lip Phang", "Jill T. Schappa", "Lawrence E. Hunter", "Jaime F. Modiano"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0005549", "stats"=>{"downloads"=>2, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Gene_Expression_Profiles_of_Sporadic_Canine_Hemangiosarcoma_Are_Uniquely_Associated_with_Breed/147603", "title"=>"Gene Expression Profiles of Sporadic Canine Hemangiosarcoma Are Uniquely Associated with Breed", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2009-05-20 02:06:43"}
  • {"files"=>["https://ndownloader.figshare.com/files/897476"], "description"=>"<p>A. Hierarchical clustering of 6 Golden Retriever (GR) hemangiosarcoma samples versus 3 non-Golden Retriever (nGR) hemangiosarcoma samples (GEO series record GSE15086). Increasing green intensity indicates increased gene expression, increasing red intensity indicates decreased gene expression, and black indicates no change. Bars represent groups that cluster together. B. Gene differences between Golden Retrievers (GR) and non-Golden Retrievers (nGR) were plotted according to their cytogenetic location along the 38 autosomes and the X chromosome. Tick marks represent individual genes that show differential regulation, with the color intensity (green to black to red) representing expression changes as described in part A. Genes plotted received a p-value<0.05 and were derived from ANOVA analysis of the global list of filtered genes. C. Quantitative expression analysis of 3 genes found in panel A, TSP-3, DLA88 (MHC), and SMARCA1 (SWI/SNF) that were differentially expressed between Golden Retrievers with hemangiosarcoma and other breeds with hemangiosarcoma. Samples were evaluated for gene expression changes by RT-PCR followed by qPCR. One sample originating from a non Golden Retriever dog (Dal-4) was normalized to 1.0 and used as a reference; gene expression is presented as fold change compared to the reference sample. The samples used for real time PCR analysis (in the order presented) include CHAD P9, Dal-4, Joey, DD1, CHAD G6, CHAD G4, and Frog. D. Schematic representation of gene expression changes between Golden Retrievers and non Golden Retrievers with hemangiosarcoma grouped by biological function using ONTO/express gene ontology program (vortex.cs.wayne.edu/Projects.html).</p>", "links"=>[], "tags"=>["retriever", "hemangiosarcoma", "cells", "segregate", "non-golden"], "article_id"=>567925, "categories"=>["Genetics", "Computational Biology", "Infectious Diseases"], "users"=>["Beth A. Tamburini", "Susan Trapp", "Tzu Lip Phang", "Jill T. Schappa", "Lawrence E. Hunter", "Jaime F. Modiano"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0005549.g001", "stats"=>{"downloads"=>2, "page_views"=>19, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Golden_Retriever_Hemangiosarcoma_Cells_Segregate_from_Non_Golden_Retriever_Hemangiosarcoma_Cells_via_Their_Expression_Profile_/567925", "title"=>"Golden Retriever Hemangiosarcoma Cells Segregate from Non-Golden Retriever Hemangiosarcoma Cells via Their Expression Profile.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-05-20 02:12:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/898054"], "description"=>"1<p>The list represents genes that were significant to p<0.001 comparing tumors from Golden Retriever to tumors from non-Golden Retriever. Each gene is grouped into functional categories as defined in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0005549#pone-0005549-g001\" target=\"_blank\">Fig. 1D</a>. Mean fold change reflects the average expression in cells from Golden Retriever tumors over the average expression in cells from tumors of non-Golden Retrievers; p-values were calculated after verifying the data were normally distributed using Student's T-test. Some genes are found within multiple functional categories.</p>", "links"=>[], "tags"=>["separates", "retriever", "hemangiosarcoma", "tumors", "non-golden"], "article_id"=>568504, "categories"=>["Genetics", "Computational Biology", "Infectious Diseases"], "users"=>["Beth A. Tamburini", "Susan Trapp", "Tzu Lip Phang", "Jill T. Schappa", "Lawrence E. Hunter", "Jaime F. Modiano"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0005549.t002", "stats"=>{"downloads"=>5, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Gene_Expression_Analysis_Separates_Golden_Retriever_Hemangiosarcoma_Tumors_from_Non_Golden_Retriever_Hemangiosarcoma_Tumors_1_/568504", "title"=>"Gene Expression Analysis Separates Golden Retriever Hemangiosarcoma Tumors from Non-Golden Retriever Hemangiosarcoma Tumors<sup>1</sup>.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2009-05-20 02:21:44"}
  • {"files"=>["https://ndownloader.figshare.com/files/897578"], "description"=>"<p>A. Bar graph representing the number of gene sets/pathways from the GSEA archived database that were enriched in hemangiosarcoma samples from Golden Retrievers versus hemangiosarcoma samples from non-Golden Retrievers. Each gene on the x-axis was present in the number of GSEA gene sets indicated on the y-axis (of 77 where FDR<0.05). B. Graphical representation of genes (x-axis) present in each GSEA pathway/gene set (y-axis), where a filled box means the gene was present and enriched in that GSEA pathway. Increasing red intensity reflects higher enrichment scores. The genes enriched in the highest number of gene sets are identified by name.</p>", "links"=>[], "tags"=>["enrichment", "validates", "retriever", "hemangiosarcoma"], "article_id"=>568031, "categories"=>["Genetics", "Computational Biology", "Infectious Diseases"], "users"=>["Beth A. Tamburini", "Susan Trapp", "Tzu Lip Phang", "Jill T. Schappa", "Lawrence E. Hunter", "Jaime F. Modiano"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0005549.g002", "stats"=>{"downloads"=>1, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Gene_Set_Enrichment_Analysis_Validates_the_Hypothesis_that_the_Golden_Retriever_Hemangiosarcoma_Gene_Set_Is_Involved_in_Hypoxia_Inflammation_and_Cancer_/568031", "title"=>"Gene Set Enrichment Analysis Validates the Hypothesis that the Golden Retriever Hemangiosarcoma Gene Set Is Involved in Hypoxia, Inflammation, and Cancer.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-05-20 02:13:51"}
  • {"files"=>["https://ndownloader.figshare.com/files/897744"], "description"=>"<p>A. Hemangiosarcoma cells from 4 Golden Retrievers (in order from top to bottom, Frog, Veronica, Tucker, Emma) and from 2 non-Golden Retrievers (Dal-4 and Joey) were cultured in chamber slides and stained with antibodies against VEGFR1 and VEGFR2 as described in the <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0005549#s4\" target=\"_blank\">methods</a>. Staining was visualized using epifluorescence. Bar = 20 µm. B. Emma, Frog, Joey, and Dal-4 cells obtained during the log growth phase were used to quantify expression of VEGFR1, VEGFR2 and ß-actin by immunoblotting. Conditions were optimized for linearity. Densitometric band quantification was done using Image J 1.37. Data are normalized to ß-actin using the sample with the highest expression for each receptor as the calibrator. C. Dal-4 cells were cultured in complete media supplemented with VEGF (+), in the absence of serum and growth supplements (−), with or without Drug 3 (100 nM) or Drug 1 (1 µM) as indicated. The activation status of VEGFR1 and VEGFR2 was examined using modification-state (phosphospecific) antibodies directed against pVEGFR1-Tyr915 and pVEGFR2-Tyr875. ß-actin was used as a loading control, and HUVEC lysates were used as a specificity control for VEGFR1.</p>", "links"=>[], "tags"=>["vegf", "receptors", "hemangiosarcoma", "cells", "retrievers", "non-golden"], "article_id"=>568191, "categories"=>["Genetics", "Computational Biology", "Infectious Diseases"], "users"=>["Beth A. Tamburini", "Susan Trapp", "Tzu Lip Phang", "Jill T. Schappa", "Lawrence E. Hunter", "Jaime F. Modiano"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0005549.g003", "stats"=>{"downloads"=>3, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Expression_of_VEGF_Receptors_in_Hemangiosarcoma_Cells_of_Golden_Retrievers_and_Non_Golden_Retrievers_/568191", "title"=>"Expression of VEGF Receptors in Hemangiosarcoma Cells of Golden Retrievers and Non-Golden Retrievers.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-05-20 02:16:31"}

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Relative Metric

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