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CpG Island Methylator Phenotype Redefines the Prognostic Effect of t(12;21) in Childhood Acute Lymphoblastic Leukemia

Authors' Affiliations: ¹ Hematology Department, Reina Sofia Hospital, Cordoba; ² Hematology Department, Carlos Haya Hospital, Malaga; and ³ Hematology Department, Cellular Therapy Area, Clinica Universitaria/School of Medicine, Foundation for Applied Medical Research, University of Navarra, Pamplona, Spain

Requests for reprints: Jose Roman-Gomez, Hematology Department, Reina Sofia Hospital, Avda. Menendez Pidal s/n, 14004 Cordoba, Spain. Phone: 34-957-010250; Fax: 34-957-010429; E-mail: peperosa{at}teleline.es.

Purpose: To examine cancer genes undergoing epigenetic inactivation in a set of ETV6/RUNX1-positive acute lymphoblastic leukemias in order to define the CpG island methylator phenotype (CIMP) in the disease and evaluate its relationship with clinical features and outcome.

Experimental Design: Methylation-specific PCR was used to analyze the methylation status of 38 genes involved in cell immortalization and transformation in 54 ETV6/RUNX1-positive samples in comparison with 190 ETV6/RUNX1-negative samples.

Results: ETV6/RUNX1-positive samples had at least one gene methylated in 89% of the cases. According to the number of methylated genes observed in each individual sample, 20 patients (37%) were included in the CIMP– group (0-2 methylated genes) and 34 (67%) in the CIMP+ group (>2 methylated genes). Remission rate did not differ significantly among either group of patients. Estimated disease-free survival and overall survival at 9 years were 92% and 100% for the CIMP– group and 33% and 73% for the CIMP+ group (P = 0.002 and P = 0.04, respectively). Multivariate analysis showed that methylation profile was an independent prognostic factor in predicting disease-free survival (P = 0.01) and overall survival (P = 0.05). A group of four genes (DKK3, sFRP2, PTEN, and P73) showed specificity for ETV6/RUNX1-positive subset of samples.

Conclusion: Our results suggest that methylation profile may be a potential new biomarker of risk prediction in ETV6/RUNX1-positive acute lymphoblastic leukemias.

Commentary

CpG Island Methylator Phenotype and Childhood Leukemia

Norman J. Lacayo, Jorge F. DiMartino, Michael C. Wei, and Gary V. Dahl
Clin. Cancer Res. 2006 12: 4787-4789. [Full Text] [PDF]

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