title: Comparison against 186 canid whole-genome sequences reveals survival strategies of an ancient clonally transmissible canine tumor.
abstract: Canine transmissible venereal tumor (CTVT) is a parasitic cancer clone that has propagated for thousands of years via sexual transfer of malignant cells. Little is understood about the mechanisms that converted an ancient tumor into the world's oldest known continuously propagating somatic cell lineage. We created the largest existing catalog of canine genome-wide variation and compared it against two CTVT genome sequences, thereby separating alleles derived from the founder's genome from somatic mutations that must drive clonal transmissibility. We show that CTVT has undergone continuous adaptation to its transmissible allograft niche, with overlapping mutations at every step of immunosurveillance, particularly self-antigen presentation and apoptosis. We also identified chronologically early somatic mutations in oncogenesis- and immune-related genes that may represent key initiators of clonal transmissibility. Thus, we provide the first insights into the specific genomic aberrations that underlie CTVT's dogged perseverance in canids around the world.
authors.affiliation: Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA; Department of Public Health and Primary Care, School of Clinical Medicine, University of Cambridge, Cambridge, CB1 8RN, United Kingdom;
authors.forename: Brennan
authors.initials: B
authors.lastname: Decker
authors.affiliation: Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA;
authors.forename: Brian W
authors.initials: BW
authors.lastname: Davis
authors.affiliation: Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA;
authors.forename: Maud
authors.initials: M
authors.lastname: Rimbault
authors.affiliation: Pediatric Oncology Branch, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland 20892, USA;
authors.forename: Adrienne H
authors.initials: AH
authors.lastname: Long
authors.affiliation: Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA;
authors.forename: Eric
authors.initials: E
authors.lastname: Karlins
authors.affiliation: Institute of Genetics, University of Bern, Bern, CH-3001, Switzerland;
authors.forename: Vidhya
authors.initials: V
authors.lastname: Jagannathan
authors.affiliation: The Translational Genomics Research Institute, Phoenix, Arizona 85004, USA;
authors.forename: Rebecca
authors.initials: R
authors.lastname: Reiman
authors.affiliation: Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA;
authors.forename: Heidi G
authors.initials: HG
authors.lastname: Parker
authors.affiliation: Institute of Genetics, University of Bern, Bern, CH-3001, Switzerland;
authors.forename: Cord
authors.initials: C
authors.lastname: Drögemüller
authors.affiliation: The Translational Genomics Research Institute, Phoenix, Arizona 85004, USA;
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Corneveaux
authors.affiliation: Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA;
authors.forename: Erica S
authors.initials: ES
authors.lastname: Chapman
authors.affiliation: The Translational Genomics Research Institute, Phoenix, Arizona 85004, USA;
authors.forename: Jeffery M
authors.initials: JM
authors.lastname: Trent
authors.affiliation: Institute of Genetics, University of Bern, Bern, CH-3001, Switzerland;
authors.forename: Tosso
authors.initials: T
authors.lastname: Leeb
authors.affiliation: The Translational Genomics Research Institute, Phoenix, Arizona 85004, USA;
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Huentelman
authors.affiliation: Department of Ecology and Evolutionary Biology, University of California, Los Angeles, Los Angeles, California 90095, USA.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Wayne
authors.affiliation: Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA;
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Karyadi
authors.affiliation: Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA;
authors.forename: Elaine A
authors.initials: EA
authors.lastname: Ostrander
mesh_terms: D000818:Animals; D017209:Apoptosis; D001324:Autoantigens / Q000235:genetics; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000235:genetics; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000235:genetics; D024161:Collagen Type XI / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D004283:Dog Diseases / Q000175:diagnosis / Q000235:genetics*; D004285:Dogs / Q000235:genetics*; D056726:Genetic Association Studies; D014644:Genetic Variation; D016678:Genome; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics; D019812:Heparan Sulfate Proteoglycans / Q000235:genetics; D008840:Microfilament Proteins / Q000235:genetics; D009154:Mutation; D065636:Myotonin-Protein Kinase / Q000235:genetics; D010802:Phylogeny; D025341:Principal Component Analysis; D017422:Sequence Analysis, DNA; D014685:Venereal Tumors, Veterinary / Q000175:diagnosis / Q000235:genetics*
chemical_list: D001324:Autoantigens; D053468:CARD Signaling Adaptor Proteins; D015815:Cell Adhesion Molecules; D024161:Collagen Type XI; D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; D019812:Heparan Sulfate Proteoglycans; D008840:Microfilament Proteins; D065636:Myotonin-Protein Kinase