Abstract
Background 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.
Results Here, we combined the notions of epipolymorphism and epiallele switching to analyze DNA methylation heterogeneity in MM patients. We show that MM is characterized by the continuous accumulation of stochastic methylation at the promoters of development-related genes. High entropy change is associated with poor outcomes 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.
Conclusion We propose that disordered 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.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
↵† Co-senior
Abbreviation
- MM
- Multiple myeloma
- PMDs
- Partially methylated domains
- CGI
- CpG island
- TSS
- Transcription start site
- PCs
- Plasma cells
- NPCs
- Normal plasma cells
- WGBS
- Whole genome bisulfite sequencing
- eRRBS
- Enhanced reduced representation bisulfite sequencing
- SMM
- Smoldering multiple myeloma
- PDR
- Proportion of discordant reads
- eloci
- Epigenetic loci
- EPM
- Eloci per million loci covered
- ESCs
- embryonic stem cells
- FPM
- mapped read counts per million of mapped fragments
- OR
- Odd ratio
- CLL
- Chronic lymphocytic leukemia
- TAD
- Topological associated domain
- LAD
- lamina-associated domain
- KEGG
- Kyoto encyclopedia of genes and genomes
- 3D
- Three-dimensional
- IFM
- Intergroupe francophone du myélome
- MGUS
- Gammopathy of undetermined significance
- RRBS
- Reduced representation bisulfite sequencing
- SNPs
- Single-nucleotide polymorphism
- RNA-seq
- RNA sequencing
- ICED
- Iterative correction and eigenvector decomposition
- TTS
- Transcription termination site
- FDR
- False discovery rate
- DAVID
- Database for annotation, visualization and integrated discovery
- RFS
- Relapse-free survival