Abstract
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 gamma 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 chi2 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.
Highlights
Recent advances have improved our understanding of the genetic basis of cancer and the mechanisms of oncogenesis; yet, progress in the identification of genetic factors that define risk, asNote: Supplementary data for this article are available at Cancer Research Online.well as improvements in molecular diagnosis and classification of many cancers, has been less rapid
We identified cases submitted sequentially that included a differential diagnosis of lymphoproliferative diseases (LPD) (NHL, lymphoid leukemia), which were analyzed to assess clonality and molecular phenotype [immunoglobulin heavy chain (IgH) or T-cell receptor g chain (TCRg) rearrangements; ref
We tested the hypothesis that heritable factors contribute to the risk of LPD immunophenotypes by exploring the relationship between breed and tumor immunophenotype (B or T cell) in 1,263 dogs representing 87 pure breeds and dogs of mixed breeding with a clinical or histologic diagnosis of LPD
Summary
Recent advances have improved our understanding of the genetic basis of cancer and the mechanisms of oncogenesis; yet, progress in the identification of genetic factors that define risk, asNote: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).well as improvements in molecular diagnosis and classification of many cancers, has been less rapid. Those associated with heritability, remain elusive, even for lymphoproliferative diseases (LPD) that have prognostically significant molecular signatures [1]. This is due, at least in part, to the fact that discovery of cancer-associated genes in human populations is hampered by structural features that characterize most of these populations (i.e., they are outbred) have long generation times (averaging 15-25 years) and generally have
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