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Blood, 15 October 2004, Vol. 104, No. 8, pp. 2492-2498.
Prepublished online as a Blood First Edition Paper on June 15, 2004; DOI 10.1182/blood-2004-03-0954.
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NEOPLASIA
Promoter hypermethylation of cancer-related genes: a strong independent prognostic factor in acute lymphoblastic leukemia
Jose Roman-Gomez,
Antonio Jimenez-Velasco,
Juan A. Castillejo,
Xabier Agirre,
Manuel Barrios,
German Navarro,
Francisco J. Molina,
Maria J. Calasanz,
Felipe Prosper,
Anabel Heiniger, and
Antonio Torres
From the Hematology Department, Reina Sofia Hospital, Cordoba, Spain; Hematology Department, Carlos Haya Hospital, Malaga, Spain; Hematology Department, Cellular Therapy Area, Clinica Universitaria/School of Medicine, Foundation for Applied Medical Research, University of Navarra, Pamplona, Spain.
Promoter hypermethylation plays an important role in the inactivation of cancer-related genes. This abnormality occurs early in leukemogenesis and seems to be associated with poor prognosis in acute lymphoblastic leukemia (ALL). To determine the extent of hypermethylation in ALL, we analyzed the methylation status of the CDH1, p73, p16, p15, p57, NES-1, DKK-3, CDH13, p14, TMS-1, APAF-1, DAPK, PARKIN, LATS-1, and PTEN genes in 251 consecutive ALL patients. A total of 77.3% of samples had at least 1 gene methylated, whereas 35.9% of cases had 4 or more genes methylated. Clinical features and complete remission rate did not differ among patients without methylated genes, patients with 1 to 3 methylated genes (methylated group A), or patients with more than 3 methylated genes (methylated group B). Estimated disease-free survival (DFS) and overall survival (OS) at 11 years were 75.5% and 66.1%, respectively, for the nonmethylated group; 37.2% and 45.5% for methylated group A; and 9.4% and 7.8% for methylated group B (P < .0001 and P = .0004, respectively). Multivariate analysis demonstrated that the methylation profile was an independent prognostic factor in predicting DFS (P < .0001) and OS (P = .003). Our results suggest that the methylation profile may be a potential new biomarker of risk prediction in ALL.
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