A Genome-wide screen identifies frequently methylated genes in haematological and epithelial cancers

Department of Medical and Molecular Genetics, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham B152TT, UK.
Molecular Cancer (Impact Factor: 5.4). 02/2010; 9:44. DOI: 10.1186/1476-4598-9-44
Source: PubMed

ABSTRACT Genetic as well as epigenetic alterations are a hallmark of both epithelial and haematological malignancies. High throughput screens are required to identify epigenetic markers that can be useful for diagnostic and prognostic purposes across malignancies.
Here we report for the first time the use of the MIRA assay (methylated CpG island recovery assay) in combination with genome-wide CpG island arrays to identify epigenetic molecular markers in childhood acute lymphoblastic leukemia (ALL) on a genome-wide scale. We identified 30 genes demonstrating methylation frequencies of > or =25% in childhood ALL, nine genes showed significantly different methylation frequencies in B vs T-ALL. For majority of the genes expression could be restored in methylated leukemia lines after treatment with 5-azaDC. Forty-four percent of the genes represent targets of the polycomb complex. In chronic myeloid leukemia (CML) two of the genes, (TFAP2A and EBF2), demonstrated increased methylation in blast crisis compared to chronic phase (P < 0.05). Furthermore hypermethylation of an autophagy related gene ATG16L2 was associated with poorer prognosis in terms of molecular response to Imatinib treatment. Lastly we demonstrated that ten of these genes were also frequently methylated in common epithelial cancers.
In summary we have identified a large number of genes showing frequent methylation in childhood ALL, methylation status of two of these genes is associated with advanced disease in CML and methylation status of another gene is associated with prognosis. In addition a subset of these genes may act as epigenetic markers across hematological malignancies as well as common epithelial cancers.

Download full-text


Available from: Daniel Catchpoole, Jul 03, 2015
1 Follower
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Epigenetic modifications have been considered as hallmarks of cancer and play an important role in tumor initiation and development. Epigenetic mechanisms, including DNA methylation, histone modifications, and microRNAs, may regulate cell cycle and apoptosis, as well as macroautophagy (hereafter referred to as autophagy). Autophagy, as a crucial cellular homeostatic mechanism, performs a dual role, having pro-survival or pro-death properties. A variety of signaling pathways including epigenetic control have been implicated in the upregulation or downregulation of autophagy. However, the role of epigenetic regulation in autophagy is still less well acknowledged. Recent studies have linked epigenetic control to the autophagic process. Some epigenetic modifiers are also involved in the regulation of autophagy and potentiate the efficacy of traditional therapeutics. Thus, understanding the novel functions of epigenetic control in autophagy may allow us to develop potential therapeutic approaches for cancer treatment. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Cancer Letters 02/2015; 360(2). DOI:10.1016/j.canlet.2015.02.009 · 5.02 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Autophagy is a physiological process in which cellular components are degraded by the lysosomal machinery. Thereby, organelles are recycled and monomers are produced in order to maintain energy production. Current studies indicate autophagy might suppress or augment survival of cancer cells. Therefore, by elucidating the role of autophagy in cancer pathogenesis, novel therapeutic intervention points may be revealed. Leukemia therapy has advanced in recent years; but a definitive cure is still lacking. Since autophagy often is deregulated in this particular type of cancer, it is clear that future findings will have clinical implications. This review will discuss the current knowledge of autophagy in blood cancers.
    Critical reviews in oncology/hematology 05/2011; 81(3):275-85. DOI:10.1016/j.critrevonc.2011.03.009 · 4.05 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Considerable scientific activity has been recently generated in the field of experiments on implosion of liners, plasma focus, plasma-erosion opening switches and the like. In the simplest case, experimental installation comprises a low-inductance capacitor bank charged up to a voltage, a switching device, a transmitting line and a load. Typical current for the middle-rate installations amounts to several hundreds of kiloamperes, at voltage Vo of several tens of kilovolts, and current pulse duration from 1 to 2 μs. Most of the above installations operate in a single-pulse mode. However, some technological applications require the facilities in a pulse repetition mode with a pulse repetition rate of 1 Hz and more. In this connection, the problem of switching device for such facilities emerges. The high-pressure spark gaps are of limited utility for this problem since they fail to operate in the pulse repetition mode and have a low lifetime. Currently, a new type of low-pressure switching device with a cold cathode, a so called pseudospark switch, is under intensive investigation. This switch offers a possibility to commutate current of about 100 kA for the devices in ceramic-metal sealed-off design. This report presents some data on parallel operation of the sealed-off switches onto a common low resistance load. Virtually, the experimental conditions are chosen to model the switch operating modes for the above described applications
    Discharges and Electrical Insulation in Vacuum, 1996. Proceedings. ISDEIV., XVIIth International Symposium on; 08/1996