Abstract
There is accumulating evidence that an individual’s inability to accurately repair DNA damage in a timely fashion may in part dictate a predisposition to cancer. Dogs spontaneously develop lymphoproliferative diseases such as lymphoma, with the golden retriever (GR) breed being at especially high risk. Mechanisms underlying such breed susceptibility are largely unknown; however, studies of heritable cancer predisposition in dogs may be much more straightforward than similar studies in humans, owing to a high degree of inbreeding and more limited genetic heterogeneity. Here, we conducted a pilot study with 21 GR with lymphoma, 20 age-matched healthy GR and 20 age-matched healthy mixed-breed dogs (MBD) to evaluate DNA repair capability following exposure to either ionizing radiation (IR) or the chemical mutagen bleomycin. Inter-individual variation in DNA repair capacity was evaluated in stimulated canine lymphoctyes exposed in vitro utilizing the G2 chromosomal radiosensitivity assay to quantify clastogen-induced chromatid-type aberrations (gaps and breaks). Golden retrievers with lymphoma demonstrated elevated sensitivity to induction of chromosome damage following either challenge compared to either healthy GR or MBD at multiple doses and time points. Using the 75th percentile of chromatid breaks per 1,000 chromosomes in the MBD population at 4 hours post 1.0 Gy IR exposure as a benchmark to compare cases and controls, GR with lymphoma were more likely than healthy GR to be classified as “sensitive” (odds ratio = 21.2, 95% confidence interval 2.3-195.8). Furthermore, our preliminary findings imply individual (rather than breed) susceptibility, and suggest that deficiencies in heritable factors related to DNA repair capabilities may be involved in the development of canine lymphoma. These studies set the stage for larger confirmatory studies, as well as candidate-based approaches to probe specific genetic susceptibility factors.
Highlights
Cancer is largely a genetic disease associated with the accumulation of mutation and rearrangement of DNA, which results in activation of oncogenes and/or deactivation of tumor suppressor genes [1]
In contrast to what is generally reported in human studies utilizing the G2 chromosomal assay, where chromatid breaks are assessed per 100 nuclei, we quantified chromatid breaks per 1,000 scoreable chromosomes
Numerous casecontrol studies have demonstrated that polymorphisms in DNA repair and related genes can be associated with human lymphoma risk [21,23,24,25,26,27]
Summary
Cancer is largely a genetic disease associated with the accumulation of mutation and rearrangement of DNA, which results in activation of oncogenes and/or deactivation of tumor suppressor genes [1]. Most lymphoma-associated heritable cancer syndromes are related to deficiencies in DNA double-strand break (DSB) repair, a critical pathway for lymphocytes as they rearrange immunoglobulin or T cell receptor genes. Exclusive of the well-defined heritable cancer syndromes mentioned above, numerous studies have demonstrated enhanced mutagen sensitivity, defined generally as unrepaired DNA damage following a genotoxic stress or challenge, as a predisposing factor for human cancer [7,8,9,10,11,12]. Family and twin studies have established that firstdegree relatives of sensitive individuals are usually sensitive, suggestive of a heritable component [13,14]
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