The DNA methylation landscape of multiple myeloma shows extensive inter- and intrapatient heterogeneity that fuels transcriptomic variability

Autor: Jennifer Derrien, Catherine Guérin-Charbonnel, Victor Gaborit, Loïc Campion, Magali Devic, Elise Douillard, Nathalie Roi, Hervé Avet-Loiseau, Olivier Decaux, Thierry Facon, Jan-Philipp Mallm, Roland Eils, Nikhil C. Munshi, Philippe Moreau, Carl Herrmann, Florence Magrangeas, Stéphane Minvielle
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: Genome Medicine, Vol 13, Iss 1, Pp 1-21 (2021)
Druh dokumentu: article
ISSN: 1756-994X
14946831
DOI: 10.1186/s13073-021-00938-3
Popis: 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. Methods Here, 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. Results We 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. Conclusions We 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.
Databáze: Directory of Open Access Journals
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