title: 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.
authors.affiliation: Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, 1060 William Moore Drive, Raleigh, NC, 27607, USA.
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Roode
authors.affiliation: Bioinformatics Research Center, Department of Statistics, North Carolina State University, Raleigh, NC, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rotroff
authors.affiliation: Department of Microbiology, Immunology, and Pathology, College of Veterinary Medicine and Biomedical Science, Colorado State University, Fort Collins, CO, USA.
authors.forename: Anne C
authors.initials: AC
authors.lastname: Avery
authors.affiliation: Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA.|Center for Comparative Medicine and Translational Research, North Carolina State University, Raleigh, NC, USA.|Cancer Genetics Program, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Suter
authors.affiliation: Department of Pathobiology, University of Guelph, Guelph, Ontario, Canada.
authors.forename: Dorothee
authors.initials: D
authors.lastname: Bienzle
authors.affiliation: Department of Pediatrics, University of Utah, Salt Lake City, UT, USA.|Department of Oncological Sciences, Center for Children's Cancer Research, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Schiffman
authors.affiliation: Bioinformatics Research Center, Department of Statistics, North Carolina State University, Raleigh, NC, USA.|Center for Comparative Medicine and Translational Research, North Carolina State University, Raleigh, NC, USA.
authors.forename: Alison
authors.initials: A
authors.lastname: Motsinger-Reif
authors.affiliation: Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, 1060 William Moore Drive, Raleigh, NC, 27607, USA. Matthew_Breen@ncsu.edu.|Center for Comparative Medicine and Translational Research, North Carolina State University, Raleigh, NC, USA. Matthew_Breen@ncsu.edu.|Cancer Genetics Program, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA. Matthew_Breen@ncsu.edu.
authors.forename: Matthew
authors.initials: M
authors.lastname: Breen
mesh_terms: D000465:Algorithms; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002869:Chromosome Aberrations; D002874:Chromosome Mapping; D016000:Cluster Analysis; D055028:Comparative Genomic Hybridization; D017124:Conserved Sequence; D056915:DNA Copy Number Variations; D004195:Disease Models, Animal; D004285:Dogs; D019143:Evolution, Molecular; D005260:Female; D018628:Gene Dosage; D055106:Genome-Wide Association Study; D015698:Genomic Library; D023281:Genomics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007938:Leukemia / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D008297:Male
keywords: Canine; Chromosome; Comparative genomic hybridization; Comparative genomics; Leukemia