Abstract
Multiple genes have been shown to be independently hypermethylated in lymphoid malignancies. We report here on the extent of concurrent methylation of E-cadherin, Dap-kinase, O(6)MGMT, p73, p16, p15 and p14 in 129 pediatric ALL cases. While most of these genes demonstrated methylation in a proportion of cases, O(6)MGMT, p16 and p14 were infrequently methylated (11, 7 and 3%, respectively). Methylation of at least one gene was found in the vast majority (83%) of cases. To determine the extent and concordance of methylation we calculated a methylation index (MI=number of methylated genes/number of studied genes) for each sample. The average MI was 0.28, corresponding to 2/7 methylated genes. MI was correlated with standard prognostic factors, including immunophenotype, age, sex, WBC and presence of specific translocations (TEL-AML1, BCR-ABL, E2A-PBX1 or MLL-AF4). We determined that children >/=10 years old and children presenting with high WBC (>/=50 x 10(9)/l) both associated with a higher MI (P<0.01 and <0.05, respectively). T-ALLs demonstrated a lower MI (median=0.17) than precursor B ALLs (median=0.28). Among the different molecular subgroups, MLL-ALLs had the highest MI (mean=0.35), while ALLs carrying the t(1;19) had the lowest MI (mean=0.07). The most common epigenetic lesion in childhood ALL was methylation of E-cadherin (72%) independent of the molecular subtype or other clinicopathological factors.
MeSH terms
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Adolescent
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Apoptosis Regulatory Proteins
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Cadherins / genetics
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Calcium-Calmodulin-Dependent Protein Kinases / genetics
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Cell Cycle Proteins*
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Child
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Child, Preschool
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Core Binding Factor Alpha 2 Subunit
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CpG Islands
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Cyclin-Dependent Kinase Inhibitor p15
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Cyclin-Dependent Kinase Inhibitor p16 / genetics
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DNA Methylation*
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DNA Primers / chemistry
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DNA Repair
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DNA, Neoplasm / genetics*
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DNA-Binding Proteins / genetics
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Death-Associated Protein Kinases
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Female
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Genes, Tumor Suppressor
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Genes, p53 / genetics
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Humans
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Infant
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Infant, Newborn
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Male
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Nuclear Proteins / genetics*
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O(6)-Methylguanine-DNA Methyltransferase / genetics
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / metabolism
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Phenotype
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Polymerase Chain Reaction
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
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RNA, Neoplasm / genetics
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Transcription Factors / genetics
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Translocation, Genetic
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Tumor Protein p73
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Tumor Suppressor Protein p14ARF / genetics
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Tumor Suppressor Proteins*
Substances
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Apoptosis Regulatory Proteins
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CDKN2B protein, human
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Cadherins
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Cell Cycle Proteins
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Core Binding Factor Alpha 2 Subunit
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Cyclin-Dependent Kinase Inhibitor p15
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Cyclin-Dependent Kinase Inhibitor p16
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DNA Primers
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DNA, Neoplasm
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DNA-Binding Proteins
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Homeodomain Proteins
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Nuclear Proteins
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Oncogene Proteins, Fusion
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RNA, Neoplasm
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TEL-AML1 fusion protein
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TP73 protein, human
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Transcription Factors
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Tumor Protein p73
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Tumor Suppressor Protein p14ARF
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Tumor Suppressor Proteins
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E2A-Pbx1 fusion protein
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O(6)-Methylguanine-DNA Methyltransferase
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Death-Associated Protein Kinases
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Calcium-Calmodulin-Dependent Protein Kinases