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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    • "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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    • "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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    • "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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