Concurrent methylation of promoters from tumor associated genes predicts outcome in acute myeloid leukemia

By assessment of the methylation status of 25 candidate tumor suppressor genes (TSGs) in 119 acute myeloid leukemia (AML) patients and 5 controls, we aimed to determine whether simultaneous methylation of multiple TSGs exerts prognostic impact. Methylation-specific multiplex ligation probe amplifica...

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Bibliographic Details
Published in:Leukemia & lymphoma 2008-01, Vol.49 (6), p.1132-1141
Main Authors: Hess, Corine J., Errami, Abdellatif, Berkhof, Johannes, Denkers, Fedor, Ossenkoppele, Gert J., Nygren, Anders O. H., Schuurhuis, Gerrit J., Waisfisz, Quinten
Format: Article
Language:English
Subjects:
acute myeloid leukemia
Adolescent
Adult
Aged
Case-Control Studies
DNA - genetics
DNA Methylation
DNA methylation/epigenetics
Estrogen Receptor alpha - genetics
Female
Gene Expression Regulation, Leukemic
Humans
Leukemia, Myeloid, Acute - classification
Leukemia, Myeloid, Acute - genetics
Leukemia, Myeloid, Acute - pathology
Male
Middle Aged
Polymerase Chain Reaction
Prognosis
Promoter Regions, Genetic - genetics
Risk assessment
Survival Rate
tumor suppressor genes
Tumor Suppressor Proteins - genetics
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Summary:By assessment of the methylation status of 25 candidate tumor suppressor genes (TSGs) in 119 acute myeloid leukemia (AML) patients and 5 controls, we aimed to determine whether simultaneous methylation of multiple TSGs exerts prognostic impact. Methylation-specific multiplex ligation probe amplification (MS-MLPA) revealed methylation of at least one TSG in 59 119 patients, while no methylation was found in controls. Methylation of different TSGs within patients was substantially correlated (intra-class correlation; 0.38). ESR1 methylation (34 119) strongly predicted concurrent methylation of other genes, OR 7.33 (95%CI 4.13-12.99). A Cox regression model that included the three most frequently methylated TSGs ESR1, CDKN2B p15 and IGSF4, showed ESR1 to have opposite effects on overall survival (OS) compared with the other two, HR 0.22 (95% CI 0.09-0.53) and HR 1.66 (95% CI 0.73-3.79), HR 1.61 (95%CI 0.66-3.93). By assessment of CDKN2B p15 and IGSF4 methylation, patients with methylation at multiple loci can be identified. Accumulation of methylation aberrancies is much more pronounced in ESR1 methylated patients. When combined, the methylation status of ESR1, CDKN2B p15 and IGSF4 enable identification of patient subgroups with large differences in OS (p
ISSN:1042-8194
1029-2403
DOI:10.1080/10428190802035990