Dataset Information

Frequency and prognostic impact of CEBPA proximal, distal and core promoter methylation in normal karyotype AML: a study on 623 cases.

ABSTRACT: The clinical impact of aberrant CEBPA promoter methylation (PM) in AML is controversially discussed. The aim of this study was to clarify the significance of aberrant CEBPA PM with regard to clinical features in a cohort of 623 cytogenetically normal (CN) de novo AML. 555 cases had wild-type CEBPA, 68 cases harbored CEBPA mutations. The distal promoter was methylated in 238/623 cases (38.2%), the core promoter in 8 of 326 cases (2.5%), whereas proximal PM was never detected. CEBPA PM and CEBPA mutations were mutually exclusive. CEBPA distal PM positive cases were characterized by reduced CEBPA mRNA expression levels and elevated white blood cell counts. CEBPA distal PM was less frequent in patients with mutations in FLT3, NPM1 and TET2 and more frequent in cases with RUNX1 and IDH2R140 mutations. Overall, no association of methylation to prognosis was seen. However CEBPA distal PM was associated with inferior outcome in cases with low FLT3-ITD ratio or TET2 mutations. A distinct gene expression profile of CEBPA distal PM positive cases compared to CEBPA mutated and CEBPA distal PM negative cases was observed. In conclusion, the presence of aberrant CEBPA PM is associated with distinct biological features but impact on outcome is weak.

SUBMITTER: Fasan A

PROVIDER: S-EPMC3562230 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Frequency and prognostic impact of CEBPA proximal, distal and core promoter methylation in normal karyotype AML: a study on 623 cases.

Fasan Annette A Alpermann Tamara T Haferlach Claudia C Grossmann Vera V Roller Andreas A Kohlmann Alexander A Eder Christiane C Kern Wolfgang W Haferlach Torsten T Schnittger Susanne S

PloS one 20130201 2

The clinical impact of aberrant CEBPA promoter methylation (PM) in AML is controversially discussed. The aim of this study was to clarify the significance of aberrant CEBPA PM with regard to clinical features in a cohort of 623 cytogenetically normal (CN) de novo AML. 555 cases had wild-type CEBPA, 68 cases harbored CEBPA mutations. The distal promoter was methylated in 238/623 cases (38.2%), the core promoter in 8 of 326 cases (2.5%), whereas proximal PM was never detected. CEBPA PM and CEBPA m ...[more]

PMID: 23383300

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Project description:The clinical impact of aberrant CEBPA promoter methylation (PM) in AML is controversial discussed. The aim of this study was to clarify the significance of aberrant CEBPA PM with regard to clinical features in a cohort of 572 de novo AML with wildtype CEBPA and normal karyotype. The distal promoter was methylated in 54/572 cases (9.41%) whereas proximal PM was never detected. Methylation of the core promoter was detected in only 8 of 326 cases (2.45%) and thus seems to be a rare event in AML. There was no correlation between CEBPA distal PM, age, sex, white blood cell (WBC) count or Hb levels at diagnosis. We also were not able to detect a significant correlation between the presence of CEBPA distal PM and molecular mutations such as FLT3-ITD, NPM1, AML1, MLL-PTD and IDH1. Solely the frequency of IDH2R140 mutations was significantly reduced in CEBPA distal PM positive compared to CEBPA distal PM negative cases (p=0.01). Furthermore, analysis of CEBPA mRNA expression level revealed no difference between CEBPA distal PM positive and CEBPA distal PM negative cases, suggesting that CEBPA distal PM has no influence on CEBPA expression. CEBPA distal PM did not show impact on overall survival (OS), event free survival (EFS) or incidence of relapse. Also when other mutations were taken into regard no prognostic impact of CEBPA distal PM could be shown. In contrast, a distinct expression profile of CEBPA distal PM positive cases compared to CEBPA mutated and CEBPA distal PM negative cases was observed. In addition, a significantly higher frequency of CEBPA distal PM was detected in RUNX1-RUNX1T1 positive AML compared to the CEBPA witdtype cases. We conclude that the presence of aberrant CEBPA PM has no clinical relevance and is therefore a negligible prognostic marker in de novo AML with normal karyotype. To detect underlying common differences in their gene expression profiles, we investigated 9 CEBPA methylated (unmutated), 8 CEBPA single-mutated, 10 CEBPA double-mutated, and 10 non-methylated/non-mutated cases (Affymetrix HG-U133 Plus 2.0 microarrays; Santa Clara, CA). The microarray sample preparation assay was performed as previously reported. Gene expression raw data were processed according to the manufacturer’s recommendations.

Dataset Information

Frequency and prognostic impact of CEBPA proximal, distal and core promoter methylation in normal karyotype AML: a study on 623 cases.

Publications

Frequency and prognostic impact of CEBPA proximal, distal and core promoter methylation in normal karyotype AML: a study on 623 cases.

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