title: Epigenetic differences in cytogenetically normal versus abnormal acute myeloid leukemia.
abstract: BACKGROUND
  Methylation of tumor suppression genes (TSGs) is common in myeloid malignancies. However, application of this as a molecular marker for risk stratification in patients with AML is limited.
  
  
  METHODS
  To elucidate the impact of patterns of TSG methylation on outcome in cytogenetically normal patients, 106 samples from patients with having normal cytogenetic AML were evaluated for methylation of 12 genes by MSP. For sake of comparison, samples from patients with AML and abnormal cytogenetics (n = 63) were also evaluated.
  
  
  RESULTS
  Methylation frequencies in the whole group (n = 169) were similar to previous reports for CDH1 (31%), ER (31%), FHIT (9%), p15 (INK4b) (44%), p73 (25%), and SOCS1 (75%). Methylation of CTNNA1 was observed in 10%, CEBP-α in16%, CEBP-δ in 2%, MLH1 in 24%, MGMT in 11% and DAPK in 2% of AML samples. We find that DNA methylation was more prevalent in patients with normal compared to karyotypically abnormal AML for most genes; CEBPα (20% vs 9%), CTNNA1 (14% vs 4%), and ER (41% vs 19%) (p < 0.05 for all comparisons). In contrast, p73 was more frequently methylated in patients with karyotypic abnormalities (17% vs 38%; p < 0.05), perhaps due to specific silencing of the pro-apoptotic promoter shifting p73 gene expression to the anti-apoptotic transcript. In AML patients with normal cytogenetics, TSG methylation was not associated with event free or overall survival in a multivariate analysis.
  
  
  CONCLUSIONS
  In patients with AML, TSG methylation is more frequent in patients with normal karyotype than those with karyotypic abnormalities but does not confer independent prognostic information for patients with normal cytogenetics.
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Griffiths
authors.forename: Steven D
authors.initials: SD
authors.lastname: Gore
authors.forename: Craig M
authors.initials: CM
authors.lastname: Hooker
authors.forename: Helai P
authors.initials: HP
authors.lastname: Mohammad
authors.forename: Michael A
authors.initials: MA
authors.lastname: McDevitt
authors.forename: B Douglas
authors.initials: BD
authors.lastname: Smith
authors.forename: Judith E
authors.initials: JE
authors.lastname: Karp
authors.forename: James G
authors.initials: JG
authors.lastname: Herman
authors.forename: Hetty E
authors.initials: HE
authors.lastname: Carraway
mesh_terms: D000368:Aged; D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics; D016022:Case-Control Studies; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D044127:Epigenesis, Genetic; D016147:Genes, Tumor Suppressor; D018922:HL-60 Cells; D006801:Humans; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics; D011960:Receptors, Estrogen / Q000235:genetics; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000235:genetics; D020298:U937 Cells; D051178:alpha Catenin / Q000235:genetics; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; C495273:CTNNA1 protein, human; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011960:Receptors, Estrogen; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D051178:alpha Catenin; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3