Lattanzio L, Lo Nigro C. Epigenetics and DNA methylation in cancer. World J Transl Med 2015; 4(1): 11-24 [DOI: 10.5528/wjtm.v4.i1.11]
Corresponding Author of This Article
Cristiana Lo Nigro, PhD, Laboratory Cancer Genetics and Translational Oncology, Medical Oncology, S. Croce University Hospital, Via Carle 25, 12100 Cuneo, Italy. lonigro.c@ospedale.cuneo.it
Research Domain of This Article
Oncology
Article-Type of This Article
Review
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Runx3, Twist, Er α, Er β, PR, RAR, vitamin D receptor
Drug responsiveness
Glutatione S-transferase, thymidylate synthase
Table 4 Comparison of methylation arrays vs ultra-deep sequencing for DNA methylation analysis
Methylation arrays
Ultra-deep sequencing
CpG coverage
+
+++
Sensitivity
+++
++/+ (antibody-based)
Time consuming
++
++
Data analysis
+++
+
High-throughput
+++
+
Price
++
+/++ (price decreasing)
Table 5 Epigenetic drug discovery challenges
Category
Issues
Target selection
Few activating mutations, translocations or syntethic lethal relationships known limited high-quality antibodies to epigenetic proteins and histone marks (e.g., confirm target expression linkage of target to mark) Biology driving cancer phenotype unknown or poorly understood Post-translation modification of histone vs non-histone substrates by "epigenetic" targets unclear
Chemistry
Existing chemical librairies may not have adeguate diversity to provide goog strating points Few crystal structures solved; are structrues relevant if not reflecting complete complex?
Assay development
Few reference compunds to establish assy signal window, sensitivity, reproducibility Are binding or enzyme configured to properly reflect physiological context? Production of actibe enzymes is difficult, may require multimeric complex and specific sunstrate (nucleosome, histone, non-histone) Limited high-quality antibodies to epigenetic proteins and histone marks (quantify mark or target gene product)
In vivo biology
Histone marks and target genes slow to change, require longer-duration studies to assess engagement (PD biomarker) May necessitate higer compund requirement to conduct studies, earlier optimation of PK properties than traditional paradigm May require novel models for tumors with mutation or traslocations
Toxicology
Acute and/or chronic liabilities of specific isofrom targed epigenetic therapies currently unknown Knockout animal data limited; inducibile knockouts, dominant negatives preferred but more scarce and technically challening
Clinical
Identify and implement appropriate patient selection markers, more challenging if not activating mutation (overexpression, gene profile?) Identify and implement suitable PD marker (posttranslational modification or mark, target gene, surrogate tissue or tumor?) Epigenetic changes at metastatic sites can differ from primary tumor, which should be targed clinically?
Citation: Lattanzio L, Lo Nigro C. Epigenetics and DNA methylation in cancer. World J Transl Med 2015; 4(1): 11-24