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Distinct B-Cell and T-Cell Lymphoproliferative Disease Prevalence among Dog Breeds Indicates Heritable Risk

¹ Department of Immunology, AMC Cancer Center, and University of Colorado Cancer Center, University of Colorado Health Sciences Center, Denver, Colorado; ² Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado; ³ Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina; ⁴ Cancer Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland; ⁵ Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama; ⁶ Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts; and ⁷ Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington

Requests for reprints: Jaime F. Modiano, Department of Immunology, AMC Cancer Center, University of Colorado Health Sciences Center, 1600 Pierce Street, 2-Diamond Research Building, Denver, CO 80214. Phone: 303-239-3408; Fax: 303-239-3560; E-mail: modianoj{at}amc.org or Matthew Breen, Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC 27606. Phone: 919-513-1467; Fax: 919-513-7301; E-mail: Matthew_Breen{at}ncsu.edu.

Immunophenotypes in lymphoproliferative diseases (LPD) are prognostically significant, yet causative factors for these conditions, and specifically those associated with heritable risk, remain elusive. The full spectrum of LPD seen in humans occurs in dogs, but the incidence and lifetime risk of naturally occurring LPD differs among dog breeds. Taking advantage of the limited genetic heterogeneity that exists within dog breeds, we tested the hypothesis that the prevalence of LPD immunophenotypes would differ among different breeds. The sample population included 1,263 dogs representing 87 breeds. Immunophenotype was determined by the presence of clonal rearrangements of immunoglobulin heavy chain or T-cell receptor chain. The probability of observing the number of B-cell or T-cell tumors in a particular breed or breed group was compared with three reference populations. Significance was computed using ² test, and logistic regression was used to confirm binomial predictions. The data show that, among 87 breeds tested, 15 showed significant differences from the prevalence of LPD immunophenotypes seen across the dog population as a whole. More significantly, elevated risk for T-cell LPD seems to have arisen ancestrally and is retained in related breed groups, whereas increased risk for B-cell disease may stem from different risk factors, or combinations of risk factors, arising during the process of breed derivation and selection. The data show that domestic dogs provide a unique and valuable resource to define factors that mediate risk as well as genes involved in the initiation of B-cell and T-cell LPD.

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