The DNA methylation landscape of multiple myeloma shows extensive inter- and intrapatient heterogeneity that fuels transcriptomic variability.
Computational Biology
/ methods
CpG Islands
DNA Methylation
Disease Susceptibility
Epigenesis, Genetic
Epigenomics
/ methods
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Genetic Heterogeneity
Histones
/ metabolism
Humans
Molecular Sequence Annotation
Multiple Myeloma
/ diagnosis
Prognosis
Promoter Regions, Genetic
Transcriptome
Disordered DNA methylation
Epiallele switching
Epipolymorphism
Inter- and intrapatient heterogeneity
Multiple myeloma
Transcriptomic variability
Journal
Genome medicine
ISSN: 1756-994X
Titre abrégé: Genome Med
Pays: England
ID NLM: 101475844
Informations de publication
Date de publication:
09 08 2021
09 08 2021
Historique:
received:
17
08
2020
accepted:
09
07
2021
entrez:
10
8
2021
pubmed:
11
8
2021
medline:
17
2
2022
Statut:
epublish
Résumé
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.
Sections du résumé
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.
Identifiants
pubmed: 34372935
doi: 10.1186/s13073-021-00938-3
pii: 10.1186/s13073-021-00938-3
pmc: PMC8351364
doi:
Substances chimiques
Histones
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
127Informations de copyright
© 2021. The Author(s).
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