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DNA Methylation Analysis: a Promising Diagnostic Tool DNA-Methylierungs-Analyse: Ein Vielversprechendes Diagnostisches Werkzeug

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DNA Methylation Analysis: a Promising Diagnostic Tool DNA-Methylierungs-Analyse: Ein Vielversprechendes Diagnostisches Werkzeug J Lab Med 2004;28(3):233–238 ᮊ 2004 by Walter de Gruyter • Berlin • New York 2004/04017 Molekulargenetische Diagnostik Redaktion: H.G. Klein DNA methylation analysis: a promising diagnostic tool DNA-Methylierungs-Analyse: ein vielversprechendes diagnostisches Werkzeug Matthias Schuster* sionsmarkern gewidmet ist, etabliert sich die DNA-Me- thylierung mit großer Geschwindigkeit als eine alternative Epigenomics AG, Berlin, Germany zellula¨ re Informationsebene. Die DNA-Methylierung ist an der Regulation der Genaktivita¨ t beteiligt. A¨ nderungen des Abstract Methylierungsmusters werden mit verschiedensten Erkrankungen in Verbindung gebracht. DNA-Methylie- Since the investigation of molecular biological mechan- rungsmarker gelten daher heute zu Recht als vielver- isms was extended to the genomic level and after the sprechende diagnostische Werkzeuge, z. B. fu¨ r die sequence of the human genome was established, inter- Fru¨ herkennung von Krebserkrankungen. Mehrere Me- est in DNA-based diagnostics has increased tremen- thoden stehen fu¨ r die genomweite Entdeckung von Me- dously. While most research is currently being devoted thylierungsmarkern zur Verfu¨ gung, die die Unter- to the discovery and clinical application of genetic, pro- scheidung verschiedener Pha¨ notypen zuverla¨ ssig teomic and RNA expression markers, DNA methylation ermo¨ glichen. Im Gegensatz zu RNA-Expressionsmarkern is rapidly emerging as a new level of cellular information ko¨ nnen DNA-Methylierungsmarker auch in historischen, with biomarker potential. DNA methylation is involved in in Paraffin eingebetteten Geweben gut analysiert werden. the regulation of gene activity. Aberrant DNA methylation Etablierte Methoden erlauben den Nachweis weniger has been associated with a variety of human diseases. DNA-Kopien, die ein spezifisches Methylierungsmuster As such, DNA methylation markers hold a great promise aufweisen, vor dem Hintergrund eines Vielfachen an nor- as a diagnostic tool, e.g. in early cancer screening w1x. mal methylierter DNA. Damit sind alle Voraussetzungen Methods are available for the genome-wide discovery of fu¨ r den Nachweis von DNA-Methylierungsmarkern in methylation markers that differentiate between different Ko¨ rperflu¨ ssigkeiten als gut zuga¨ nglichem klinisch rele- types of tissue samples. In contrast to expression mark- vantem Probenmaterial gegeben. ers, DNA methylation markers are accessible at the DNA level, which enables their analysis even in archived par- affin-embedded tissue samples. Methods are available to Schlu¨ sselwo¨ rter: DNA-Methylierung; Biomarker; mole- detect a few copies of aberrantly methylated DNA in a kulare Diagnostik; Krebs-Screening; Pharmakogenomics. background of a vast excess of normally methylated DNA, which is the prerequisite for assaying methylation DNA methylation markers also in body fluids that are readily accessible in clinical practice. General Keywords: DNA methylation; biomarker; molecular diag- The genetic information, as it is passed from generation nostics; cancer screening; pharmacogenomics. to generation, is defined by the sequential order of the four nucleobases thymine, adenine, guanine, and cyto- Zusammenfassung sine within a polymeric high molecular desoxynucleic acid. In humans, however, the C-5 methylation of cyto- Seit der Ausweitung der Erforschung molekularbiolo- sine in the sequence context CpG gives rise to 5-meth- gischer Mechanismen auf das genomische Niveau und ylcytosine, which represents a ‘‘fifth’’ base with a unique der erfolgreichen Sequenzierung des Humangenoms ist covalent structure w2x. Cytosine methylation is catalysed das Interesse an DNA-basierten diagnostischen Verfah- by methyltransferases using S-adenosylmethionine as ren enorm gestiegen. Wa¨ hrend die gegenwa¨ rtige For- the methyl donor. The distribution of 5-methylcytosine schung hauptsa¨ chlich der Identifizierung und klinischen throughout the genome is closely related to the transcrip- Anwendung von genetischen, Protein- und RNA-Expres- tional activity of genes. Since 5-methylcytosine exhibits nearly the same base pairing behaviour as cytosine itself, *Correspondence: Matthias Schuster, Epigenomics AG, Kastanienallee 24, 10435 Berlin, Germany proven methods in molecular biology can typically not be E-mail: [email protected] used to understand this interdependence. Indeed, only 234 M. Schuster: DNA methylation analysis more recent research has highlighted that DNA methyl- affin-embedded tissue, which is extremely beneficial ation is central to a complex framework of ‘‘epigenetic’’ when e.g. considering retrospective clinical studies. The factors that regulate and fine-tune the transcriptional mRNA expression level of genes in one cell differs by activity in most parts of the human genome w3x. These several orders of magnitude. Since the methylation of are factors that bring about alterations in the action of each gene on one allele comprises a binary signal, DNA genes without changing the DNA sequence. It has been methylation signals in mixtures of cells vary between 0% known for some time that the promoters of most human and 100%, i.e. over a linear range. Therefore, the analysis genes contain ‘‘CpG islands’’ that are characterized by of DNA methylation marker panels is technically more an increased density of guanines, cytosines and CpG feasible. In comparison to the above mentioned genomic dinucleotides, and significantly exceed the average classes of biomarkers, changes in the proteome of a cell occurrence within the genome w4x. It is now generally are the closest reflection of its phenotype. Accordingly, accepted that the degree of the CpG methylation of intensive research is devoted to the discovery and eval- these CpG islands can be closely correlated to the chro- uation of proteomic markers w10x, e.g. for cancer screen- matin structure, especially the density of the chromatin ing. However, although significant progress has been w5x. As a rule of thumb, promoters of transcriptionally made in the development of technologies for finding pro- active genes show low methylation levels, whereas tein markers, no method is available for amplifying the promotor hypermethylation leads to a dense chromatin proteome comparable to efficient nucleic acid amplifi- structure that is transcriptionally inactive w6x. According cation methods, such as the polymerase chain reaction to current models, methylated DNA attracts methyl bind- (PCR w11x), enabling systematic approaches for discov- ing proteins that themselves recruit histone deacetylases. ering genomic and epigenomic markers (see below). Histone acetylation is generally associated with active Methylation positions have been identified that corre- chromatin. On the other hand, histone deacetylation, as late with diabetes type II, cancer, atherosclerosis, rheu- associated with DNA methylation, makes the histones matoid arthritis, and disease of the CNS w12x. Methylation accessible to histone methyltransferases. Histone meth- at other positions has been shown to correlate with age, ylation represents inactive chromatin. It is currently not gender, nutrition, drug use, and probably a whole range entirely clear how genes are reactivated, since no of other environmental influences w13x. Due to their enzymes catalyzing the demethylation of histones or potential for molecular diagnostics, our knowledge about DNA have yet been described in sufficient detail. During DNA methylation changes associated with cancer has DNA recombination, the methylation profile of the parent been growing exponentially over the last years and new strand is enzymatically copied onto the complementary markers are reported weekly, if not daily. The emerging strand w7x. This process, which is catalyzed by mainte- pattern of DNA methylation found in cancer cells sup- nance methyltransferases, is the basis for the relative ports two general notions. CpG islands in the promoter stability of the DNA methylation information content and exon 1 regions of tumor suppressor genes have throughout cell divisions and even generations. The inhi- been described to be hypermethylated in a range of dif- bition of this process can lead to gene reactivation. ferent cancers. However, most CpG sites within the human genome are part of repetitive elements that are DNA methylation markers methylated in benign cells. Hypomethylation of these ele- ments in some cancers has been associated with When compared to single nucleotide polymorphisms genomic instability w14x. Although at a lower scale than (SNPs w8x), which are under intensive investigation as hypermethylation, the hypomethylation of gene promot- genetic predisposition markers either alone or in combi- ers in cancer cells has also been described w15x. In com- nation (haplotypes), alterations in DNA methylation can parison to promoter hypermethylation, hypomethylation occur much more frequently. A SNP occurs every 100 to of individual genes currently needs to be considered 300 bases along the 3-billion-base human genome, underexplored, mainly as a result of the limitations of the whereas the number of CpG positions within a CpG analysis methods used today. island is significantly higher. SNPs represent inherited genetic alterations that can potentially be used to describe the likelihood for developing certain diseases. DNA methylation technology They do not normally change over time in an individual. In contrast, DNA methylation is a much more dynamic Marker discovery process. Like its transcriptional profile, the methylation pattern of the DNA of a
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