TY - JOUR
T1 - Concurrent methylation of multiple genes in childhood ALL
T2 - Correlation with phenotype and molecular subgroup
AU - Gutierrez, M. I.
AU - Siraj, A. K.
AU - Bhargava, M.
AU - Ozbek, U.
AU - Banavali, S.
AU - Chaudhary, M. A.
AU - El Sohl, H.
AU - Bhatia, K.
PY - 2003/9/1
Y1 - 2003/9/1
N2 - 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, O6MGMT, p73, p16, p15 and p14 in 129 pediatric ALL cases. While most of these genes demonstrated methylation in a proportion of cases, O6MGMT, 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 × 109/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.
AB - 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, O6MGMT, p73, p16, p15 and p14 in 129 pediatric ALL cases. While most of these genes demonstrated methylation in a proportion of cases, O6MGMT, 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 × 109/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.
KW - Chrosomal translocations
KW - Epigenetics
KW - Hematological neoplasia
KW - Immunophenotype
KW - Tumor-suppressor genes
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U2 - 10.1038/sj.leu.2403060
DO - 10.1038/sj.leu.2403060
M3 - Article
C2 - 12970785
AN - SCOPUS:0141725586
SN - 0887-6924
VL - 17
SP - 1845
EP - 1850
JO - Leukemia
JF - Leukemia
IS - 9
ER -