Gene-specific and global methylation patterns predict outcome in patients with acute myeloid leukemia.
This study was designed to analyze the effect of global and gene-specific DNA methylation patterns on the outcome of patients with acute myeloid leukemia (AML). Methylation of CDKN2B (p15), E-cadherin (CDH) and hypermethylated in cancer 1 (HIC1) promoters and global DNA methylation by luminometric methylation assay (LUMA) was analyzed in 107 AML patients and cytogenetic and molecular mutational analysis was performed. In addition, genome-wide promoter-associated methylation was assessed using the Illumina HumanMethylation27 array in a proportion of the patients. Promoter methylation was discovered in 66, 66 and 51% of the patients for p15, CDH and HIC1, respectively. In multivariate analysis, low global DNA methylation was associated with higher complete remission rate (hazard ratio (HR) 5.9, P=0.005) and p15 methylation was associated with better overall (HR 0.4, P=0.001) and disease-free survival (HR 0.4, P=0.016). CDH and HIC1 methylation were not associated with clinical outcome. Mutational status and karyotype were not significantly associated with gene-specific methylation or global methylation. Increased genome-wide promoter-associated methylation was associated with better overall and disease-free survival as well as with LUMA hypomethylation. We conclude that global and gene-specific methylation patterns are independently associated with the clinical outcome in AML patients.
Division of Hematology, Department of Medicine, Karolinska Institutet, Huddinge, Stockholm, Sweden. stefan.deneberg@ki.se
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S
Deneberg
M
M
Grövdal
M
M
Karimi
M
M
Jansson
H
H
Nahi
A
A
Corbacioglu
V
V
Gaidzik
K
K
Döhner
C
C
Paul
T J
TJ
Ekström
E
E
Hellström-Lindberg
S
S
Lehmann
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D015820:Cadherins / Q000235:genetics; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics; D019175:DNA Methylation; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000145:classification / Q000235:genetics* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D012074:Remission Induction; D015996:Survival Rate; D016896:Treatment Outcome; D055815:Young Adult
D014408:Biomarkers, Tumor; D015820:Cadherins; D050762:Cyclin-Dependent Kinase Inhibitor p15