Abstract
Epigenetic deregulation is a hallmark of cancer characterized by frequent acquisition of new DNA methylation in CpG islands. To gain insight into the methylation changes of canine DLBCL, we investigated the DNA methylome in primary DLBCLs in comparison with control lymph nodes by genome-wide CpG microarray. We identified 1,194 target loci showing different methylation levels in tumors compared with controls. The hypermethylated CpG loci included promoter, 5′-UTRs, upstream and exonic regions. Interestingly, targets of polycomb repressive complex in stem cells were mostly affected suggesting that DLBCL shares a stem cell-like epigenetic pattern. Functional analysis highlighted biological processes strongly related to embryonic development, tissue morphogenesis and cellular differentiation, including HOX, BMP and WNT. In addition, the analysis of epigenetic patterns and genome-wide methylation variability identified cDLBCL subgroups. Some of these epigenetic subtypes showed a concordance with the clinical outcome supporting the hypothesis that the accumulation of aberrant epigenetic changes results in a more aggressive behavior of the tumor. Collectively, our results suggest an important role of DNA methylation in DLBCL where aberrancies in transcription factors were frequently observed, suggesting an involvement during tumorigenesis. These findings warrant further investigation to improve cDLBCL prognostic classification and provide new insights on tumor aggressiveness.
Highlights
Canine diffuse large B-cell lymphoma is the most frequent malignancy of B-lymphocytes in dog and comprises approximately 60–70% of all cases
All dogs were treated with the same dose-intense chemotherapeutic (CH) protocol, consisting of L-asparaginase, Vincristine, cyclophosphamide, doxorubicin, lomustine, and prednisone. 23 dogs received an intradermal injection of an autologous vaccine (VAX) on weeks 4, 5, 6, 7, 12, 16, 20 and 24. 20 (51.3%) dogs relapsed while being treated, whereas in 14 (35.9%) dogs lymphoma recurred after the end of treatment. 5 (12.8%) dogs never relapsed and were still in first complete remission at data analysis closure
Beyond the classification provided by the available clinical factors, we investigated whether methylation profiles were able to provide a different stratification of the Canine diffuse large B-cell lymphoma (cDLBCL) samples
Summary
Canine diffuse large B-cell lymphoma (cDLBCL) is the most frequent malignancy of B-lymphocytes in dog and comprises approximately 60–70% of all cases. Recurrent copy number variations were identified by array comparative genomic hybridization (aCGH) including gains in chr[13], syntenic to the region in human chromosome 8 containing MYC oncogene, and chr[315–7]. None of these gene signatures have been translated into clinic, suggesting the need for more robust molecular and prognostic studies. The epigenetic changes driving B-cell lymphoma have been scarcely investigated in dog and current studies on aberrant methylation patterns focused only on single genes[11,12,13,14,15]. We hypothesized that DNA methylation patterning in cDLBCLs can provide clues about gene deregulation by identifying aberrantly methylated genes and explaining the different clinical behavior of cDLBCL
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