Oncology
From Wikibooks, the open-content textbooks collection
Contents |
[edit] DNA methylation dissorders and cancer
DNA methylation system controls genes exprexssion. This system depends on ONE CARBON UNITS (OCU) metabolism - Folate system, Methionine cycle... Any disturb of OCU metabolism sytem disregulates normal DNA methylation and could couse abnormal DNA methylation pattern. DNA methylation closely depends aproximately on 170 substrates, metabolites, enzymes, the other SAM acceptors...
http://www.protocol-online.org/forums/index.php?showtopic=5897&st=45
[edit] About DNA Methylation
Methylation is a natural epigenetic process that occurs when a methyl group binds to one of DNA’s four bases, cytosine. Methylation exerts control over the activity of genes by turning them off when not needed. Measuring the differences in the methylation patterns between healthy and diseased tissue can be used to detect a change in gene activity that could trigger diseases such as cancer. Similarly, DNA methylation patterns can be used to predict a patient’s response to a drug. Epigenomics has developed an industrial process that is able to read and interpret these methylation patterns and uses them as biomarkers for developing molecular diagnostic and pharmacodiagnostic tests.
S-Adenosylmethionine (SAM) is the universal methyl donor for a broad range of methyltransferase reactions. Among the most important of these is the methyltransferase reaction in which cytosines at CpG sites on DNA become methylated. DNA methylation is a critical factor in the control of gene expression and both hyper- and hypo-methylation have been implicated in the inappropriate regulation of proto-oncogenes and tumor-suppressor genes, and have been associated with the development of various cancers.1,2 Therefore, understanding the regulatory mechanisms that control DNA methylation is important for understanding normal cell function, gene expression, and neoplastic transformation. DNA methylation depends on the availability of methyl groups provided by the folate and methionine cycles, the control of the DNA methyltransferase (DNMT) reaction, and the availability of cytosine substrates that is controlled by histones and other DNA-binding proteins. In the present paper we are solely concerned with the first two mechanisms, and so assume that the availability of methylation sites is constant. The level of SAM and the velocity of the DNA methyltransferase reaction depend on the properties of both the methionine and folate cycles. These metabolic cycles in turn depend on the dietary intake of certain nutrients (methionine, choline, betaine) and vitamins (B12, folate, B6) and are affected by polymorphisms in the genes for enzymes of the methionine and folate cycles.3-6 Because defects in folate and methionine metabolism are associated with a large number of serious disorders (several types of cancer,7-10 cardiovascular disease,11-13 neural tube defects14 and neurodegenerative diseases15,16), the genes and enzymes of these cycles have been well studied.
from Long-Range Allosteric Interactions between the Folate and Methionine Cycles Stabilize DNA Methylation Reaction Rate H. Frederik Nijhout, Michael C. Reed, David F. Anderson, Jonathan C. Mattingly, S. Jill James and Cornelia M. Ulrich
volume 1 | issue 2 april/may/june 2006 Pages: 81 - 87
[edit] About DMH
Differential Methylation Hybridization (DMH) is the most recent addition to Epigenomics’ proprietary DNA methylation technology portfolio. With Epigenomics’ DMH microarrays more than 50,000 human genomic fragments can be profiled for their methylation status in a single experiment. DMH is robust and delivers highly reproducible results. This makes DMH a fast and cost-effective tool to discover novel DNA methylation biomarkers for diagnostic and pharmacodiagnostic applications.
Epigenomics AG (Frankfurt, Prime Standard: ECX), a cancer molecular diagnostics company developing products based on DNA methylation, has entered into an R&D collaboration with Myriad Genetics, Inc. (NASDAQ: MYGN) to identify and analyze DNA methylation biomarkers that may predict patients’ response to an undisclosed marketed oncology drug.
Under the agreement, Epigenomics will use its proprietary Differential Methylation Hybridization (DMH) microarray platform to perform genome-wide DNA methylation profiling on samples provided by Myriad and compare these profiles to identify DNA methylation biomarkers associated with sensitivity and resistance to the drug.
Date: Wednesday, 09.05.2007
[edit] Genome Wide DNA Methylation in Cancer
Christoph Plass, Ph.D., Associate Professor, Department of Medical Microbiology and Immunology, Division of Human Cancer Genetics, James Cancer Hospital and Solove Research Institute, Ohio State University
Numerous genetic defects have been reported that contribute to human malignancies. Equally effective are interconnected epigenetic modifications including DNA methylation, histone tail modifications and microRNA expression changes, that interfere with the expression profiles of hundreds of genes. DNA methylation of promoter sequences or loss of DNA methylation at repetitive sequences results in gene silencing or affects the integrity of chromosomes and consequently impacts on the stability of the genome. DNA methylation is tightly linked to histone tail modifications that alter the chromatin condensation status. More recently, the alterations of microRNAs expression patterns emerged as an additional epigenetic modifications of the malignant cell targeting and modifying the expression of multiple cancer genes. Epigenetic modifications of the DNA do not change the DNA sequence and are therefore potentially reversible by either removing methyl groups or by interference with the enzymes that mediate histone tail modifications, both of these interferences can potentially reactivate silenced genes. The presentation will review current concepts and strategies to study genome wide alterations in epigenetic modifications in human malignancies.
Date: 01.03.2007
[edit] Regulation of RASSFS1A gene by methylation
http://sundoc.bibliothek.uni-halle.de/diss-online/05/05H171/t5.pdf
[edit] Clinical Research
DNA Methylation of Tumor Suppressor Genes in Clinical Remission Predicts the Relapse Risk in Acute Myeloid Leukemia
Shuchi Agrawal1, Matthias Unterberg1, Steffen Koschmieder1, Udo zur Stadt2, Uta Brunnberg1, Walter Verbeek3, Thomas Büchner1, Wolfgang E. Berdel1, Hubert Serve1 and Carsten Müller-Tidow1 1 Department of Medicine, Hematology and Oncology, University of Münster, Münster, Germany; 2 Department of Pediatric Hematology and Oncology, University Medical Center Hamburg Eppendorf, Hamburg, Germany; and 3 Department of Medicine, Maria-Hilf Kliniken, Mönchengladbach, Germany
Requests for reprints: Carsten Müller-Tidow and Hubert Serve, Department of Medicine A, Hematology and Oncology, University of Münster, Domagkstr. 3, 48129 Münster, Germany. Phone: 49-251-835-2995; Fax: 49-251-835-2673; E-mail: muellerc@uni-muenster.de.
Epigenetic changes play an important role in leukemia pathogenesis. DNA methylation is among the most common alterations in leukemia. The potential role of DNA methylation as a biomarker in leukemia is unknown. In addition, the lack of molecular markers precludes minimal residual disease (MRD) estimation for most patients with hematologic malignancies. We analyzed the potential of aberrant DNA promoter methylation as a biomarker for MRD in acute leukemias. Quantitative real-time PCR methods with bisulfite-modified DNA were established to quantify MRD based on estrogen receptor (ER) and/or p15INK4B methylation. Methylation analyses were done in >370 DNA specimens from 180 acute leukemia patients and controls. Methylation of ER and/or p15INK4B occurred frequently and specifically in acute leukemia but not in healthy controls or in nonmalignant hematologic diseases. Aberrant DNA methylation was detectable in >20% of leukemia patients during clinical remission. In pediatric acute lymphoblastic leukemia, methylation levels during clinical remission correlated closely with T-cell receptor/immunoglobulin MRD levels (r = +0.7, P < 0.01) and were associated with subsequent relapse. In acute myelogenous leukemia patients in clinical remission, increased methylation levels were associated with a high relapse risk and significantly reduced relapse-free survival (P = 0.003). Many patients with acute leukemia in clinical remission harbor increased levels of aberrant DNA methylation. Analysis of methylation MRD might be used as a novel biomarker for leukemia patients' relapse risk.
Data: Cancer Research 67, 1370-1377, February 1, 2007. doi: 10.1158/0008-5472.CAN-06-1681
[edit] The other mechanism of genes expression regulation
http://nobelprize.org/nobel_prizes/medicine/laureates/2006/press.html
Several other important findings were reported by plant researchers in the 1990s. Towards the end of the decade Fire and Mello shed light on the mechanism underlying this mysterious gene shut-down. The pair injected single-stranded sense RNA from a muscle gene into worms. Nothing happened, nor did anything happen when they instead injected antisense RNA from the same gene. But both sense and antisense RNA, administered together, made the worms begin to twitch. Antisense and sense RNA were forming double-stranded RNA (dsRNA) that intercepted translation of the muscle gene into protein.
Both in plants and animals, RNAi is a natural defence against invading genetic material, whether artificially introduced, as in the above experiments, or by nature in the form of viruses. In addition, this process is one of three key ways of silencing genes throughout development. Beyond the natural role of RNAi the technology has huge implications for medicine. Being able to target and silence faulty genes holds great promise for treating diseases with a genetic component. And without the worms and the petunia, we’d be none the wiser.
from http://epigenome.eu/en/1,38,0
[edit] General remarks on Epigenetics
http://www.sciencemag.org/feature/plus/sfg/resources/res_epigenetics.dtl
