DNA methylation and personalized medicine

Abstract

SUMMARYWhat is known and objective: Variation in the expression of drug-response-related genes contributes significantly to interindividual differences in drug response. DNA methylation is one of the most common epigenetic modifications that control gene expression. DNA methylation may occur in genes encoding drug metabolizing enzymes (DMEs), drug transporters and drug targets, and can thereby alter the pharmacokinetics and pharmacodynamics of drugs. In this review, we discuss recent advances in pharmacoepigenetics with a focus on DNA methylation. Methods: The literature search focusing on DNA methylation of drug-response-related genes and DNA methylation-related SNPs in pharmacogenomics was carried out using the PUBMED database and a combination of keywords including DNA methylation, drug response, DMEs, drug transporters, drug target and SNPs. Results and discussion: An extensive range of research has contributed to our understanding of how DNA methylation of drug-response-related genes alters their function. This is particularly well studied in cancer chemotherapy and drug resistance. The impact of polymorphisms of miRNAs in these processes requires further study. What is new and conclusion: DNA methylation-related genetic variation is an increasingly recognized mechanism for altered drug-response and disease susceptibility. These new discoveries require assimilation into the practice of personalized medicine. WHAT IS KNOWN AND OBJECTIVEInterest in the epigenetic modification of genomes has grown exponentially in recent years. Epigenetics plays an important role in regulating gene expression. DNA methylation, the biological methylation of specific nucleotides by DNA methyltransferases (DNMTs), is the epigenetic modification that has attracted most interest. DNA methylation can result in suppression of gene expression, a process that can be reactivated by demethylation.DNA methylation occurs mainly as 5-methylcytosine (5-mC), with a small fraction of N6-methylpurine (N6-mA) and 7-methylguanine (7-mG). Clusters of cytosine-phosphate-guanine dinucleotides in a chromosomal region are referred to as CpG islands. In mammalian genomes, there are about 40 000 CpG islands, which are typically located in the promoters or in the first exon of the genes.1,2 CpG island methylation is a dynamic epigenetic process during mammalian development and is critical in regulating gene expression, 3 maintaining the stability of the genome and its chromosomal structure, 4 and inactivating genomic imprinting and X-chromosome dosage. 5Aberrant methylation of the CpG island may also result in human diseases such as cancer, amentia, autoimmunity and diabetes. Therefore, DNA methylation has become an important focus of recent epigenomics research.Understanding of the role of DNA methylation in pathogenesis has led to the development of several drugs targeting DNA methylation. Two DNMT inhibitors, 5-azacitidine 6,7 and decitabine, 8,9 are approved by the U.S. FDA for the treatment of myelodysplastic syndromes (MDS) and haematological malig...

Impact of ZBTB7A hypomethylation and expression patterns on treatment response to hydroxyurea

“…Epigenetic modifications, such as DNA methylation and histone methylation/acetylation, constitute an additional layer of gene expression regulation and affect phenotypic heterogeneity of human diseases and drug responses [ 12 , 13 ]. DNA methylation mainly occurs in the context of CG dinucleotides (CpGs) and has traditionally been associated with gene repression [ 14 ].…”

Precision medicine: from pharmacogenomics to pharmacoproteomics

“…Epigenetic modifications have largely been implicated in cancer, among other diseases, and represent an important class of drug targets [ 26 , 27 ]. Indeed, DNA methylation has been shown to play a significant role in regulating the expression of members of the cytochrome P450 superfamily of enzymes, which is responsible for the metabolism of over 75 percent of commonly-prescribed pharmaceuticals [ 28 – 30 ]. While significant evidence exists in the literature for the epigenetic regulation of genes involved in the absorption, distribution, metabolism, and excretion (ADME) of drugs [ 31 ], the clinical relevance of this regulation remains to be seen.…”

Measuring pharmacogenetics in special groups: geriatrics

“…Polymorphisms in the CYP2A6 --CYP2A7 gene cluster are associated with nicotine level in plasma [58]. Evidence has also shown that polymorphism at the CYP2C gene cluster can cause allele-specific DNA methylation for the genes of this cluster [69].…”