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The pharmacoepigenomic landscape of cancer cell lines reveals the epigenetic component of drug sensitivity.
Comm. Biol. 6:825 (2023)
Aberrant DNA methylation accompanies genetic alterations during oncogenesis and tumour homeostasis and contributes to the transcriptional deregulation of key signalling pathways in cancer. Despite increasing efforts in DNA methylation profiling of cancer patients, there is still a lack of epigenetic biomarkers to predict treatment efficacy. To address this, we analyse 721 cancer cell lines across 22 cancer types treated with 453 anti-cancer compounds. We systematically detect the predictive component of DNA methylation in the context of transcriptional and mutational patterns, i.e., in total 19 DNA methylation biomarkers across 17 drugs and five cancer types. DNA methylation constitutes drug sensitivity biomarkers by mediating the expression of proximal genes, thereby enhancing biological signals across multi-omics data modalities. Our method reproduces anticipated associations, and in addition, we find that the NEK9 promoter hypermethylation may confer sensitivity to the NEDD8-activating enzyme (NAE) inhibitor pevonedistat in melanoma through downregulation of NEK9. In summary, we envision that epigenomics will refine existing patient stratification, thus empowering the next generation of precision oncology.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Island Methylator Phenotype; Dna Methylation; Gene-expression; Hypermethylation; Connectivity; Dacomitinib; Mechanisms; Target
Language
english
Publication Year
2023
HGF-reported in Year
2023
ISSN (print) / ISBN
2399-3642
e-ISSN
2399-3642
Journal
Communications Biology
Quellenangaben
Volume: 6,
Issue: 1,
Article Number: 825
Publisher
Springer
Publishing Place
London
Reviewing status
Peer reviewed
Institute(s)
Institute of Computational Biology (ICB)
POF-Topic(s)
30205 - Bioengineering and Digital Health
Research field(s)
Enabling and Novel Technologies
PSP Element(s)
G-554700-001
Grants
European Union's Horizon 2020 research and innovation programme
WOS ID
001045489100003
Scopus ID
85167532221
PubMed ID
37558831
Erfassungsdatum
2023-10-06