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

• Published in: Genome medicine 2021-08, Vol.13 (1), p.127-21, Article 127
• Main Authors: Derrien, Jennifer, Guérin-Charbonnel, Catherine, Gaborit, Victor, Campion, Loïc, Devic, Magali, Douillard, Elise, Roi, Nathalie, Avet-Loiseau, Hervé, Decaux, Olivier, Facon, Thierry, Mallm, Jan-Philipp, Eils, Roland, Munshi, Nikhil C, Moreau, Philippe, Herrmann, Carl, Magrangeas, Florence, Minvielle, Stéphane
• Format: Article
• Language: English
• Subjects: Biochemistry, Molecular Biology; Bisulfite; Bone marrow; Cancer; Chromosomes; Computational Biology - methods; Consortia; CpG Islands; Deoxyribonucleic acid; Disease Susceptibility; Disordered DNA methylation; DNA; DNA Methylation; DNA sequencing; Entropy; Environmental changes; Epiallele switching; Epigenesis, Genetic; Epigenetics; Epigenomics - methods; Epipolymorphism; Evolution; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genetic diversity; Genetic Heterogeneity; Genomes; Genomics; Hematology; Histones - metabolism; Human health and pathology; Humans; Inter- and intrapatient heterogeneity; Life Sciences; Molecular Sequence Annotation; Multiple myeloma; Multiple Myeloma - diagnosis; Multiple Myeloma - genetics; Multiple Myeloma - metabolism; Multiple Myeloma - mortality; Patients; Plasma; Prognosis; Promoter Regions, Genetic; Software; Stem cells; Stochasticity; Transcription; Transcriptome; Transcriptomes; Transcriptomic variability; Tumor cells
• ISSN: 1756-994X; 1756-994X
• DOI: 10.1186/s13073-021-00938-3

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. 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. 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. 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.