Epigenomics in cancer management

Figures & data

Table 1 Drugs developed using epigenetics and epigenomics tools

Drug	Mode of action	Types of cancer	References
Belinostat1	Histone deacetylase inhibitor	Hematological malignancies and solid tumors	^Citation71,Citation72
Dacogen^®1 or Vidaza^®2 and decitabine2	DNA methyltransferase inhibitors (5-azacytidine and 5-aza-2′-deoxycytidine)	Myelodysplastic syndrome and hematological malignancies. Tests have already started in solid tumors	^Citation38,Citation73,Citation74
DZNep1 (Deazaneplanocin A)	Histone methyltransferase inhibitor	Acute myeloid leukemia	^Citation75
Entinostat1 (MS-275)	Benzamide histone acetylase inhibitor	Blood and lung tumors	^Citation72,Citation76
Panobinostat1 (LBH589)	Inhibitor of the enzyme histone deacetylase in a mechanism leading to apoptosis of malignant cells via multiple pathways	Cutaneous T-cell lymphoma, chronic myelogenous leukemia, myelodysplastic syndromes, breast cancer, pancreatic cancer, and prostate cancer	^Citation77^–^Citation79
RG1083	Small molecule specifically designed to bind and inhibit the active domain of the DNA methyltransferase 1 enzyme	Different types of cancer	^Citation80
CP-42003	Molecule conjugated to a lipid chain linked to azacytidine that accelerates cellular uptake	Different types of cancer	^Citation81
S1103	Modified and less toxic version of 5-aza-2′-deoxycytidine; DNA methyltransferase inhibitor	Different types of cancer	^Citation82
Romidepsin1	Natural product that inhibits histone deacetylases and causes cancer cell apoptosis	Under clinical trials to cutaneous T-cell lymphoma, peripheral T-cell lymphoma, and a variety of other cancers	^Citation83
Valproic Acid2 (Depakote^®)	Histone deacetylase inhibitor	Multiple myeloma, gliomas, and melanoma	^Citation84
Vorinostat2 (Solinza^®)	Histone deacetylase inhibitor	Lymphomas, glioblastoma multiforme, and other solid tumors	^Citation72,Citation85
Pyroxamide2 (SAHA)	Histone deacetylase inhibitor	Hematological malignancies, prostate cancer, bladder cancer, and neuroblastoma	^Citation86
Sirtinol and Salermide3	SIRT1 protein inhibitors	Different types of cancer	^Citation43,Citation87

Notes: There might be other examples of epigenetic-based drugs under development and/or in clinical trials that were not described here.

1 In clinical trials;

2 Approved by the FDA;

3 Under development.

Figure 1 Epigenomics and cancer therapy. Schematic representation of the three main epigenomic/epigenetic components that are implicated in gene expression control in human cells (blue). Some drugs that are in current use, under development, and in clinical trials for each epigenetic mechanism of gene regulation are shown in green. The drugs presented here are just a representative list for each mechanism, and some drugs under development and in clinical trials at the moment are not shown.

Table 2 Different types of technologies to uncover epigenomic changes in cancer

Method(s)	Description	Examples	References
Gene-by-gene analyses	Different methods that are used to evaluate methylation status of gene promoters. The most utilized technology is based in sodium bisulfite treatment that converts unmethylated citosines to uracil by deamination. Methylation changes are easily detected using this method after DNA sequencing. Other methods include digestion with MSRE and antibodies against methyl-binding proteins that can be used to detect specific methylation changes.	MSRE digestion, bisulfite sequencing, MSP, MethyLight, and others	^Citation45,Citation46,Citation88,Citation89
ChiP-ChiP arrays	Specific antibodies are used for proteins (ie, histones) that are binding to the DNA followed by array hybridization. Mainly used to identify regions that are active and/or inactive based on epigenetic modifications.	Chromatin immunoprecipitation combined with microarray hybridization	^Citation90
ChiP–Seq technology	Specific antibodies are used for proteins (ie, histones) that are binding to the DNA followed by DNA sequencing to map the locations of the histone proteins in the genome and their specific modifications. Second-generation DNA sequencing has been used to uncover these changes.	Chromatin immunoprecipitation combined with DNA sequencing	^Citation91
DNA methylation arrays	Different types of DNA methylation arrays have been used such as arrays containing CG-rich regions of the DNA. Whole genome arrays are also generated after bisulfite conversion of the DNA.	CpG island specific arrays, whole genome bisulfite arrays	^Citation92,Citation93
Second-generation DNA sequencing	Methodologies based on pyrosequencing and other technologies are allowing the generation of huge amounts of genomic and trascriptomic data. They have been also used to detect epigenomic modifications in human genomes.	Pyrosequencing, sequencing by oligo ligation and detection, sequencing by synthesis, and others	^Citation94,Citation95
Third-generation DNA sequencing	This new generation comprises methodologies that will be available soon mainly based in nanotechnology (ie, nanopores and nanodetectors). These new methods have the potential to decrease the costs of sequencing a genome in a faster way than the current technologies. Applications for epigenomic analyses have been recently reported.	SMRT, nanosequencing, and others	^Citation47,Citation48,Citation96^–^Citation99

Abbreviations: ChiP, chromatin immunoprecipitation; MSP, methylation-specific PCR; MSRE, methylation-sensitive restriction enzymes; SMRT, single molecule real time PCR.

Table 3 Some examples of epigenetic and epigenomic changes in single genes or group of genes and their potential impact in cancer management

Gene(s)	Epigenetic/epigenomic changes	Impact for cancer management	References
GSTP1	Hypermethylated in 80%–90% of prostate cancers and unmethylated in benign hyperplasic tissue.	Detection of hypermethylated GSTP1 could help to distinguish normal prostate cells from cancer cells. It could also be used as a biomarker in body fluids and biopsy specimens.	^Citation51
P16ink4A	One of the most common tumor suppressors inactivated by DNA methylation in tumors. Hypermethylation has been linked to poor outcome in different types of cancer.	p16ink4A could be used as prognostic marker in cancer.	^Citation100
Apoptosis and cell cycle genes (ie, DAPK, p73, and others)	Hypermethylation has been linked to poor outcome in different types of cancer.	Genes associated to apoptosis that are hypermethylated in cancers could be used as prognostic markers.	^Citation101^–^Citation103
Adhesion molecules (ie, cadherins, ADAM23, ADAM33, and others)	Hypermethylated in different types of cancer and associated with cancer metastasis.	Genes associated to cell adhesion could be used as markers for disease progression.	^Citation52^–^Citation55,Citation104
DNA repair genes (ie, MGMT, hMLH1, BRCA1, and others)	Hypermethylation of genes implicated in DNA repair could help in identifying tumors that are more susceptible to therapies such as radiotherapy helping in personalized treatment.	The use of individualized therapies could aid in patient outcome.	^Citation56,Citation57,Citation105
Histones	Differential histone modifications such as acetylation and methylation are associated to cancer recurrence and a worse prognosis.	The identification of patients that are at more risk of recurrence of the disease could help in decisions related to treatment and a better follow-up into the clinic.	^Citation58
miRNAs	DNA methylation and histone modifications of miRNA genes has been reported by different groups.	miRNAs are noncoding genes that can regulate several proteins in a cellular network and/or pathway. Reexpression of miRNAs in tumors may have an impact for the regulation of key genes in the cells.	^Citation60,Citation70,Citation106

Abbreviations: ADAM23, a desintegrin and metalloprotease domain 23; ADAM33, a desintegrin and metalloprotease domain 33; BRCA1, breast cancer gene 1; DAPK, Death-associated protein kinase; GSTP1, glutathione S-transferase P1; hMLH1, human mutL homolog 1; MGMT, O6-methylguanine-DNA methyltransferase; miRNAs, microRNAs.

Table 4 Examples of companies offering predictive epigenetic-based tests for cancer diagnosis and monitoring

Company	Epigenetic test(s)	Impact for clinical decisions	Website
Oncomethylome sciences	MGMT methylation analysis	This test indicates if patients with unmethylated (functioning) MGMT will benefit from the addition of temozolomide to the standard treatment of radiation therapy. Patients with methylated (silenced) MGMT have longer progression-free and overall survivals with the combination of radiation therapy and temozolomide. This company also tests other genes for different tumor types in body fluids.	www.oncomethylome.com
Epigenomics AG	OncoSign and Epi proColon	Biomarker candidates are used to identify drug response in cancer patients based in the DNA methylation analyses of a set of genes. Other epigenetic tests are also offered for colon cancer management facilitating clinical decisions.	www.epigenomics.com
Sequenom	Cancer EpiPanels	The Cancer EpiPanel contains targets of more than 400 cancer-related genes. It includes prevalidated assays covering over 12,000 CpG sites in promoter regions of genes known to be involved in neoplastic transformation. The Cancer EpiPanel can be used to produce quantitative DNA methylation profiles helping in tumor classification.	www.sequenom.com
Exact sciences	Stool-based DNA methylation analyses	The company offers noninvasive, molecular screening technologies for the early detection of colorectal cancer using a combination of DNA methylation markers. Stool-based DNA technology is used for disease management.	www.exactsciences.com

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