Abstract
Non-Hodgkin lymphomas are among the most common types of tumors in dogs, and they are currently accepted as comparative models of the disease in humans. Aberrant patterns of DNA methylation seem to play a key role in the development of hematopoietic neoplasms in humans, constitute a special mechanism of transcriptional control, and may be influenced by genetic and environmental factors. Blood leukocyte DNA global methylation has been poorly investigated in dogs. The aim of this study is to examine whether peripheral blood global DNA methylation is associated with canine multicentric lymphomas. Peripheral venous blood samples from ten healthy dogs and nine dogs bearing multicentric lymphomas were collected, and the buffy coat was separated. Global DNA methylation was analyzed by High Performance Liquid Chromatography (HPLC) and immunocytochemistry (ICC). In both analyses, leukocytes from dogs with lymphoma presented lower global DNA methylation than in healthy dogs (HPLC: p = 0.027/ 5MeCyt immunoreactivity scores: p = 0.015). Moderate correlation was observed between the results obtained by HPLC and ICC (correlation coefficient = 0.50). For the identification of differently methylated genes between both groups, the Infinium Human Methylation (HM) EPIC BeadChip (850K) was used. Of the 853,307 CpGs investigated in the microarray, there were 34,574 probes hybridized in the canine samples. From this total, significant difference was observed in the methylation level of 8433 regions, and through the homologous and orthologous similarities 525 differently methylated genes were identified between the two groups. This study is pioneer in suggesting that dogs bearing non-Hodgkin lymphoma presented DNA global hypomethylation of circulating leukocytes compared with healthy dogs. Although canine samples were used in an assay developed specifically for human DNA, it was possible to identify differently methylated genes and our results reiterate the importance of the use of peripheral blood leukocytes in cancer research and possible new biomarkers targets.
Highlights
Neoplastic processes are the leading cause of death in adult dogs in North America [1]
The aims of this study were to investigate whether a global measure of DNA methylation dispersed over a large portion of the genome could be detected in canine peripheral blood DNA, and whether such a measure was associated with development of lymphoma
Enriched annotations were related to Biological Process: developmental processes, regulation of cell development and response to external stimulus. Results of this case-control study demonstrated that global methylation is detectable in DNA extracted from canine peripheral blood samples
Summary
Neoplastic processes are the leading cause of death in adult dogs in North America [1]. Lymphomas are among the most common types of tumors in dogs, and they are responsible for 83% of all canine hematopoietic malignancies [2,3]. The disease shares many features with human lymphoma, including clinical presentation, biological behavior, tumor genetics, and treatment response [5]. Dogs with high-grade multicentric lymphoma generally show painless peripheral lymphadenopathy and infrequently present clinical signs associated with the effects of tumor infiltration [3]. Heritable risk factors causing the disease were introduced because certain dog breeds presented a prevalence of immunophenotypic subtypes of lymphoma [10,11]. Waste incinerators, polluted sites, and radioactive waste can be considered risk factors for canine lymphoma [12,13,14]. Dogs with spontaneously arising lymphoma represent a large animal model of naturally occurring lymphoma in a species that shares the human household environment and potential carcinogen exposure [12]
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