CpG Island Methylator Phenotype Redefines the Prognostic Effect of t(12;21) in Childhood Acute Lymphoblastic Leukemia
- Jose Roman-Gomez1,
- Antonio Jimenez-Velasco2,
- Xabier Agirre3,
- Juan A. Castillejo1,
- German Navarro2,
- Maria J. Calasanz3,
- Leire Garate3,
- Edurne San Jose-Eneriz3,
- Lucia Cordeu3,
- Felipe Prosper3,
- Anabel Heiniger2 and
- Antonio Torres1
- Authors' Affiliations:1Hematology Department, Reina Sofia Hospital, Cordoba; 2Hematology Department, Carlos Haya Hospital, Malaga; and 3Hematology 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.
Abstract
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.
Footnotes
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Grant support: Fondo de Investigacion Sanitaria (Spain) 03/0141, 01/0013-01, 01/F018, 02/1299; Navarra Goverment (31/2002); RETIC C03/10, Junta de Andalucia 03/143; 03/144 and funds from IMABIS (Malaga, Spain), “UTE project CIMA,” Fundación de Investigación Médica Mutua Madrileña Automovilista, and Asociacion Medicina e Investigacion.
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- Accepted February 7, 2006.
- Received November 24, 2005.
- Revision received January 10, 2006.
