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: 4.26). 02/2010; 9(1):44. DOI: 10.1186/1476-4598-9-44
Source: PubMed


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.

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Available from: Daniel Catchpoole, Sep 29, 2015
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    • "Please cite this article in press as: Xinbing Sui, et al., Epigenetic modifications as regulatory elements of autophagy in cancer, Cancer Letters (2015), doi: 10.1016/ j.canlet.2015.02.009 methylation status of ATG5 and MAP1LC3B/LC3 can be used as a diagnostic marker for distinguishing malignant from benign melanoma [28]. ATG16L2, an autophagy related gene, is frequently silenced in hematological malignancies via DNA methylation and its inactivation is associated with poorer treatment outcome to Imatinib [22]. Beclin 1 is often inactivated in human cancers and high score of BPCE (cytoplasmic expression of Beclin 1 protein) is an additional favorable prognosis factor among glioma patients showing a MGMT (O6-methylguanine-DNA methyltransferase) methylated gene [93]. "
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    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 · 5.62 Impact Factor
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    • "Tcfap2a (transcription factor AP-2, alpha) is induced during RA-mediated differentiation of primary astrocytes (49). Abnormal expression of the human homolog was reported in breast cancer, acute lymphoblastic leukemia, and head and neck squamous cell carcinomas (50–52). HMGcs1 (3-hydroxy-3-methylglutaryl-CoA synthase 1) is involved in cholesterol biosynthesis (53). "
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    ABSTRACT: Retinoic acid receptors (RARs) α, β and γ are key regulators of embryonic development. Hematopoietic differentiation is regulated by RARα, and several types of leukemia show aberrant RARα activity. Through microarray expression analysis, we identified transcripts differentially expressed between F9 wild-type (Wt) and RARα knockout cells cultured in the absence or presence of the RAR-specific ligand all trans retinoic acid (RA). We validated the decreased Mest, Tex13, Gab1, Bcl11a, Tcfap2a and HMGcs1 transcript levels, and increased Slc38a4, Stmn2, RpL39l, Ref2L, Mobp and Rlf1 transcript levels in the RARa knockout cells. The decreased Mest and Tex13 transcript levels were associated with increased promoter CpG-island methylation and increased repressive histone modifications (H3K9me3) in RARα knockout cells. Increased Slc38a4 and Stmn2 transcript levels were associated with decreased promoter CpG-island methylation and increased permissive histone modifications (H3K9/K14ac, H3K4me3) in RARα knockout cells. We demonstrated specific association of RARα and RXRα with the Mest promoter. Importantly, stable expression of a dominant negative, oncogenic PML-RARα fusion protein in F9 Wt cells recapitulated the decreased Mest transcript levels observed in RARα knockout cells. We propose that RARα plays an important role in cellular memory and imprinting by regulating the CpG methylation status of specific promoter regions.
    Nucleic Acids Research 09/2011; 40(1):102-15. DOI:10.1093/nar/gkr637 · 9.11 Impact Factor
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    • "This suggests that autophagy might be an important pathway for cell death in different chemotherapeutic modalities. Indeed, in a recent study, genome-wide analysis of DNA methylation patterns revealed that hypermethylation of autophagy-related genes correlated with poor prognosis in CML cells indicating that blocking autophagy reduces the leukemic cell clearance [98]. Refractory ALL was sensitized to glucocorticoids and other cytotoxic drugs by Bcl-2 antagonists in a process involving rapid activation of autophagy-dependent necroptosis which overcame the block in mitochondria-dependent apoptosis. "
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    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 · 4.03 Impact Factor
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