Abstract
The malignant transformation of normal cells is driven by both genetic and epigenetic changes. With the advent of next-generation sequencing and large-scale international consortia, it is now possible to profile the genomes and epigenomes of thousands of primary tumors from nearly every cancer type. These studies clearly demonstrate that the dynamic regulation of DNA methylation is a critical epigenetic mechanism of cancer initiation, maintenance, and progression. Proper control of DNA methylation is not only crucial for regulating gene transcription and tissue-specific cellular functions, but its broader consequences include maintaining the integrity of the genome and modulating the immune response. Here, we describe the aberrant DNA methylation changes in human cancers and how they contribute to the disease phenotypes. Aside from CpG island promoter DNA hypermethylation-based gene silencing, human cancers also display gene body DNA hypomethylation that is also associated with downregulated gene expression. In addition, the implementation of whole genome bisulfite sequencing (WGBS) has unveiled DNA hypomethylation of large blocks of the genome, known as partially methylated domains (PMDs), as well as cancer-specific DNA methylation aberrancies at enhancers and super-enhancers. Integrating WGBS and DNA methylation array data with mutation, copy number, and gene expression data has allowed for the identification of novel tumor suppressor genes and candidate driver genes of the disease state. Finally, we highlight potential clinical implications of these changes in the context of prognostic and diagnostic biomarkers, as well as therapeutic targets. Mounting evidence shows that DNA methylation data are effective and highly-sensitive disease classifiers, not only from analyses of the primary tumor but also from tumor-derived, cell free DNA (cfDNA) in blood of cancer patients. These findings highlight the power of DNA methylation aberrancies in providing efficacious biomarkers for clinical utility in improving patient diagnostics and their reversal using DNA methylation inhibitors in cancer treatment may be key in surveillance, treatment, and quality of life for cancer patients.
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Abbreviations
- 5-Aza-CR:
-
5-azacytidine
- 5-Aza-CdR :
-
5-Aza-2′deoxycytidine
- 5caC:
-
5-carboxylcytosine
- 5fC :
-
5-formylcytosine
- 5hmC :
-
5-hydroxymethylcytosine
- 5mC:
-
The carbon-5 atom of cytosine
- AML:
-
Acute myeloid leukemia
- ccRCC:
-
Clear cell renal cell carcinoma
- cfDNA:
-
Cell free DNA
- CGIs:
-
CpG islands
- CIMP:
-
CpG island methylator phenotype
- CMS:
-
Consensus molecular subgroups
- CpG:
-
Cytosine-guanine dinucleotide
- DNMT:
-
DNA methyltransferases
- DNMTi:
-
DNA methyltransferase inhibitor
- dsRNA:
-
Double-stranded RNA
- ENCODE:
-
Encyclopedia of DNA Elements
- EOC:
-
Epithelial ovarian carcinoma
- ERV:
-
Endogenous retrovirus
- FFPE:
-
Paraffin embedded
- GBM:
-
Glioblastoma multiforme
- H3K27M:
-
Histone H3 lysine 27 to methionine
- H3K27me3:
-
Histone H3 lysine 27 trimethylation
- Hypermutation:
-
High global somatic mutation rates
- ICR:
-
Imprinting control region
- IGF2:
-
Insulin-like growth factor 2
- LADs:
-
Laminin-associated domains
- LUAD:
-
Lung adenocarcinomas
- MAVS:
-
Mitochondrial antiviral signaling
- MDS:
-
Myelodysplastic syndrome
- MGMT:
-
O-6-Methylguanine-DNA methyltransferase
- MSI-H:
-
High microsatellite instability
- MSS:
-
Microsatellite stable
- NSCLC:
-
Non-small cell lung cancer
- pHGGs:
-
Pediatric high-grade gliomas
- TCGA:
-
The Cancer Genome Atlas
- TDG:
-
Thymine DNA glycosylase
- TET:
-
Ten-eleven translocation
- TMZ:
-
Temozolomide
- TSGs:
-
Tumor suppressor genes
- TSS:
-
Transcription Start Site
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The work in the Liang laboratory has been supported in part by the generous contribution of George and Vicky Joseph.
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Weisenberger, D.J., Lakshminarasimhan, R., Liang, G. (2022). The Role of DNA Methylation and DNA Methyltransferases in Cancer. In: Jeltsch, A., Jurkowska, R.Z. (eds) DNA Methyltransferases - Role and Function. Advances in Experimental Medicine and Biology, vol 1389. Springer, Cham. https://doi.org/10.1007/978-3-031-11454-0_13
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