DNA methylation profiles aid to identify putative genome activation histories along lymphomagenesis.

DNA methylation (DNAm) is widely used to leverage biological information in the context of cancer. Active regulatory elements marked by increased chromatin accessibility and specific transcription factor (TF) binding, such as enhancers, show tumor-specific DNAm patterns reflecting the biological forces shaping tumorigenesis. However, DNAm changes also occur at regions that are inactive at histone-mark level in fully developed tumors. Beyond hypermethylation of promoters, these changes are often overlooked, leaving their functional relevance poorly understood. By analyzing DNAm and chromatin state annotations from conventional mantle cell lymphoma (cMCL), we identified a subset of ~300 CpGs with homogeneous cMCL-specific demethylation patterns located in cMCL-inactive regions. We show that these regions contain cMCL-related TF motifs and are flanked by genes with cMCL-specific expression patterns, suggesting a potential regulatory role in lymphomagenesis. We hypothesize that these regions represent DNA demethylation imprints of genome activation prior to full-blown tumor formation, either present in its cell type of origin (COO) or during early stages of tumor formation. Altogether, we put forward a new, DNAm-centered approach to gain insights into potential early tumorigenic events, allowing us to generate novel, further explorable hypotheses to better understand the features playing a role in lymphomagenesis and beyond.