Department of Comparative Biomedicine and Food Science, University of Padova, Legnaro (PD), Italy.
Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
Sci Rep. 2017 Sep 14;7(1):11591. doi: 10.1038/s41598-017-11724-w.
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.
表观遗传失调是癌症的一个标志特征，其表现为 CpG 岛中频繁获得新的 DNA 甲基化。为了深入了解犬类弥漫性大 B 细胞淋巴瘤（DLBCL）的甲基化变化，我们通过全基因组 CpG 微阵列比较原发性 DLBCL 与对照淋巴结，研究了 DNA 甲基组。我们发现了 1194 个靶标，这些靶标在肿瘤中的甲基化水平与对照相比存在差异。这些高度甲基化的 CpG 位点包括启动子、5'UTR、上游和外显子区域。有趣的是，多梳抑制复合物在干细胞中的靶标受到的影响最大，这表明 DLBCL 具有类似干细胞的表观遗传模式。功能分析强调了与胚胎发育、组织形态发生和细胞分化密切相关的生物学过程，包括 HOX、BMP 和 WNT。此外，对表观遗传模式和全基因组甲基化变异性的分析确定了 cDLBCL 亚组。其中一些表观遗传亚型与临床结果一致，这支持了这样一种假设，即异常的表观遗传变化的积累导致肿瘤具有更具侵袭性的行为。总之，我们的研究结果表明，DNA 甲基化在 DLBCL 中起着重要作用，在转录因子中经常观察到异常，这表明其在肿瘤发生过程中的参与。这些发现值得进一步研究，以改善 cDLBCL 的预后分类，并为肿瘤侵袭性提供新的见解。
