Review Article | Published:

Clinical epigenetics: seizing opportunities for translation

Nature Reviews Geneticsvolume 20pages109127 (2019) | Download Citation


Biomarker discovery and validation are necessary for improving the prediction of clinical outcomes and patient monitoring. Despite considerable interest in biomarker discovery and development, improvements in the range and quality of biomarkers are still needed. The main challenge is how to integrate preclinical data to obtain a reliable biomarker that can be measured with acceptable costs in routine clinical practice. Epigenetic alterations are already being incorporated as valuable candidates in the biomarker field. Furthermore, their reversible nature offers a promising opportunity to ameliorate disease symptoms by using epigenetic-based therapy. Thus, beyond helping to understand disease biology, clinical epigenetics is being incorporated into patient management in oncology, as well as being explored for clinical applicability for other human pathologies such as neurological and infectious diseases and immune system disorders.

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The authors are supported by the Health Department PERIS, project SLT/002/16/00374 and AGAUR projects 2017SGR1080, 2014SGR633 and 2009SGR1315 of the Catalan Government (Generalitat de Catalunya); the Spanish Institute of Health Carlos III (ISCIII) projects DTS16/00153, PI15/00638 and PI18/00910; the Integrated Project of Excellence PIE13/00022 (ONCOPROFILE); the Ministerio de Economía y Competitividad (MINECO) under grant SAF2014-55000-R co-financed by the European Development Regional Fund ‘A way to achieve Europe’ (ERDF); CIBER 2016 CB16/12/00312 (CIBERONC); the Cellex Foundation; ‘la Caixa’ Banking Foundation (LCF/PR/PR15/11100003); COST Action CM1406; and the Scientific Foundation of the Spanish Association Against Cancer (AECC).

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Nature Reviews Genetics thanks A. Lorincz and the other, anonymous reviewer(s) for their contribution to the peer review of this work.

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  1. Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain

    • María Berdasco
    •  & Manel Esteller
  2. Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Madrid, Spain

    • Manel Esteller
  3. Josep Carreras Leukaemia Research Institute, Badalona, Barcelona, Catalonia, Spain

    • Manel Esteller
  4. Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona, Barcelona, Catalonia, Spain

    • Manel Esteller
  5. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain

    • Manel Esteller


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Both authors contributed to all aspects of the manuscript.

Competing interests

M.E. reports grants from Ferrer International SA and Quimatryx.

Corresponding authors

Correspondence to María Berdasco or Manel Esteller.


Personalized medicine

(Also known as precision medicine). A form of medicine that uses specific information about a person (for example, genes, proteins or environment) to tailor preventive care, disease prognosis or drug therapy.


The study of heritable changes in gene function that do not involve changes in the DNA sequence. Epigenetic mechanisms include the covalent modifications of DNA and histones.


The complete set of epigenetic modifications across an individual’s entire genome.


Small-molecule inhibitors that target either the epigenome or an enzyme with epigenetic activity. They are classified according to their respective target enzymes and include the following: DNA methyltransferase inhibitors (DNMTi), histone acetyltransferase inhibitors (HATi), histone methyltransferase inhibitors (HMTi), histone demethylase inhibitors (HDMi), histone deacetylase inhibitors (HDACi) and bromodomain inhibitors.

CpG methylation

Methylation of a cytosine that is 5′ to a guanine. CpG methylation is essential for normal development and is associated with multiple biological processes, including gene regulation, genomic imprinting, X chromosome inactivation or repression of transposable elements.

Histone modifications

Covalent post-translational modifications in the tails of histone proteins that can affect chromatin structure. Modifications include methylation, phosphorylation, acetylation, ubiquitylation and sumoylation, among others.

Epigenetic biomarkers

Any epigenetic mark or altered epigenetic mechanism that is stable and reproducible during sample processing and can be measured in the body fluids or primary types of tissue preparations that may predict risk of future disease development, detection of the disease (diagnosis), outcome of disease (prognosis) and response to therapy (pharmacoepigenetics) or allow simultaneous determination of diagnosis and suitable targeted therapy (theragnosis).

Circulating cell-free DNA

(cfDNA). Degraded DNA fragments released to the blood plasma. These fragments can include circulating tumour DNA or cell-free fetal DNA. Release of circulating tumour DNA may be a consequence of apoptosis and necrosis from dying cells but also as a result of active release from viable tumour cells.

Chromatin immunoprecipitation

(ChIP). A common and powerful technique for analysing histone modifications and other DNA-binding proteins at specific loci.

Liquid biopsy samples

Any samples taken from a non-solid biological tissue, such as blood, saliva or urine, among others. Because of their non-invasive nature, liquid biopsies are mainly used as a diagnosis and prognosis biomarker of diseases.

Faecal occult blood tests

(FOBTs). Non-invasive screening tests for detecting colorectal cancer on the basis of the presence of hidden blood in the stool, which is a sign of early colorectal cancer but also of other gastrointestinal disorders. Chemical faecal occult blood testing is based on the ability of haemoglobin to transfer an oxygen atom from peroxide to a specific chromogen (for example, guaiac). Oxidation of the chromogen can be visualized by the production of a colorimetric reaction.

Faecal immunochemical tests

(FITs). Faecal occult blood tests based on an immunological method that uses a specific antibody for the recognition of human haemoglobin.

Circulating cell-free nucleosomes

(cfnucleosomes). Nucleosomes released from dying cells into the blood.

Methylation quantitative trait locus

(mQTL). A locus where genotype is associated with the DNA methylation level. Individual genotype variation at a given locus may result in different patterns of DNA methylation owing to allele-specific methylation. The methylation effect of a mQTL can be extended across large genomic regions and can vary during development and show cell-type specificity.

Epigenome editing

A set of genome engineering technologies that are able to alter the epigenetic composition of the genome at a specific genomic location.

Whole-genome bisulfite sequencing

(WGBS). Next-generation sequencing technology used to determine the DNA methylation status of single cytosines by sequencing the entire genome after sodium bisulfite treatment. Cytosine methylation protects from bisulfite-mediated deamination of cytosine to uracil, which would be read as thymine during sequencing.

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