DNA methylation profiling reveals common signatures of tumorigenesis and defines epigenetic prognostic subtypes of canine Diffuse Large B-cell Lymphoma

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.