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Abstract
BackgroundCancer evolution depends on epigenetic and genetic diversity. Historically, in multiple myeloma (MM), subclonal diversity and tumor evolution have been investigated mostly from a genetic perspective.MethodsHere, we performed an analysis of 42 MM samples from 21 patients by using enhanced reduced representation bisulfite sequencing (eRRBS). We combined several metrics of epigenetic heterogeneity to analyze DNA methylation heterogeneity in MM patients.ResultsWe show that MM is characterized by the continuous accumulation of stochastic methylation at the promoters of development-related genes. High combinatorial entropy change is associated with poor outcomes in our pilot study and depends predominantly on partially methylated domains (PMDs). These PMDs, which represent the major source of inter- and intrapatient DNA methylation heterogeneity in MM, are linked to other key epigenetic aberrations, such as CpG island (CGI)/transcription start site (TSS) hypermethylation and H3K27me3 redistribution as well as 3D organization alterations. In addition, transcriptome analysis revealed that intratumor methylation heterogeneity was associated with low-level expression and high variability.ConclusionsWe propose that disrupted DNA methylation in MM is responsible for high epigenetic and transcriptomic instability allowing tumor cells to adapt to environmental changes by tapping into a pool of evolutionary trajectories.
Highlights
Cancer evolution depends on epigenetic and genetic diversity
MM displayed no evidence of aberrant DNA methylation at many genes (Additional file 3: Figure S4), we observed slight methylation gain at CpG islands (CGIs) and methylation loss at adjacent shores and shelves regions compared to normal plasma cell (NPCs; Additional file 3: Figure S5a), as illustrated in the genomic region of DOC2B (Additional file 3: Figure S5b)
Given that some regions are hypomethylated in MM compared to Normal plasma cells (NPCs) while others are completely demethylated, we studied combinatorial entropy changes that occurred in these domains using the hypomethylated eloci obtained with enhanced reduced representation bisulfite sequencing (eRRBS)
Summary
Cancer evolution depends on epigenetic and genetic diversity. Historically, in multiple myeloma (MM), subclonal diversity and tumor evolution have been investigated mostly from a genetic perspective. Several mechanisms have been suggested to explain the capacity of the subpopulations of myeloma cells within an individual to survive the pressure of frontline therapy and proliferate These mechanisms include the emergence of myeloma cells that achieve bortezomib resistance by decommitment from immunoglobulin synthesis [1] or by the derepression of growth factor receptors typically not associated with the plasma cell lineage [2], somatic mutations that emerge during disease progression involving key driver genes in MM such as the mono- or biallelic loss of TP53 [3, 4] or the biallelic loss of TRAF3 [5]. Other processes generate the intratumoral functional heterogeneity of cancer cells, including global epigenetic changes [11]
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