title: A genome-wide screen identifies frequently methylated genes in haematological and epithelial cancers.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medical and Molecular Genetics, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham B152TT, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Dunwell
authors.forename: Luke
authors.initials: L
authors.lastname: Hesson
authors.forename: Tibor A
authors.initials: TA
authors.lastname: Rauch
authors.forename: Lihui
authors.initials: L
authors.lastname: Wang
authors.forename: Richard E
authors.initials: RE
authors.lastname: Clark
authors.forename: Ashraf
authors.initials: A
authors.lastname: Dallol
authors.forename: Dean
authors.initials: D
authors.lastname: Gentle
authors.forename: Daniel
authors.initials: D
authors.lastname: Catchpoole
authors.forename: Eamonn R
authors.initials: ER
authors.lastname: Maher
authors.forename: Gerd P
authors.initials: GP
authors.lastname: Pfeifer
authors.forename: Farida
authors.initials: F
authors.lastname: Latif
mesh_terms: D001752:Blast Crisis / Q000235:genetics; D045744:Cell Line, Tumor; D002648:Child; D003001:Cloning, Molecular; D019175:DNA Methylation / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics; D004848:Epithelium / Q000378:metabolism / Q000473:pathology*; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D052138:Genes, Neoplasm / Q000235:genetics*; D005820:Genetic Testing; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics; D009369:Neoplasms / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D015203:Reproducibility of Results; D017422:Sequence Analysis, DNA; D013447:Sulfites / Q000378:metabolism
chemical_list: D004273:DNA, Neoplasm; D013447:Sulfites; C042345:hydrogen sulfite