title: Concurrent methylation of multiple genes in childhood ALL: Correlation with phenotype and molecular subgroup.
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.
authors.affiliation: King Fahad National Centre for Children's Cancer and Research, Riyadh, Saudi Arabia.
authors.forename: M I
authors.initials: MI
authors.lastname: Gutierrez
authors.forename: A K
authors.initials: AK
authors.lastname: Siraj
authors.forename: M
authors.initials: M
authors.lastname: Bhargava
authors.forename: U
authors.initials: U
authors.lastname: Ozbek
authors.forename: S
authors.initials: S
authors.lastname: Banavali
authors.forename: M A
authors.initials: MA
authors.lastname: Chaudhary
authors.forename: H
authors.initials: H
authors.lastname: El Solh
authors.forename: K
authors.initials: K
authors.lastname: Bhatia
mesh_terms: D000293:Adolescent; D051017:Apoptosis Regulatory Proteins; D015820:Cadherins / Q000235:genetics; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics; D018797:Cell Cycle Proteins; D002648:Child; D002675:Child, Preschool; D050676:Core Binding Factor Alpha 2 Subunit; D018899:CpG Islands; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D019175:DNA Methylation; D017931:DNA Primers / Q000737:chemistry; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D064550:Death-Associated Protein Kinases; D005260:Female; D016147:Genes, Tumor Suppressor; D016158:Genes, p53 / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics*; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D016133:Polymerase Chain Reaction; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D012334:RNA, Neoplasm / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D014178:Translocation, Genetic; D000072160:Tumor Protein p73; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics; D025521:Tumor Suppressor Proteins; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D051017:Apoptosis Regulatory Proteins; D015820:Cadherins; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D018797:Cell Cycle Proteins; D050676:Core Binding Factor Alpha 2 Subunit; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D017931:DNA Primers; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D064550:Death-Associated Protein Kinases; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D019853:O(6)-Methylguanine-DNA Methyltransferase; D015514:Oncogene Proteins, Fusion; D012334:RNA, Neoplasm; D014157:Transcription Factors; D000072160:Tumor Protein p73; D025803:Tumor Suppressor Protein p14ARF; D025521:Tumor Suppressor Proteins; C493966:CDKN2B protein, human; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein; C000606460:TP73 protein, human; C089847:E2A-Pbx1 fusion protein