title: Promoter hypermethylation of cancer-related genes: a strong independent prognostic factor in acute lymphoblastic leukemia.
abstract: 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.
authors.affiliation: Hematology Department, Reina Sofia Hospital, Avda. Menendez Pidal s/n, 14004 Cordoba, Spain. peperosa@teleline.es
authors.forename: Jose
authors.initials: J
authors.lastname: Roman-Gomez
authors.forename: Antonio
authors.initials: A
authors.lastname: Jimenez-Velasco
authors.forename: Juan A
authors.initials: JA
authors.lastname: Castillejo
authors.forename: Xabier
authors.initials: X
authors.lastname: Agirre
authors.forename: Manuel
authors.initials: M
authors.lastname: Barrios
authors.forename: German
authors.initials: G
authors.lastname: Navarro
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Molina
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Calasanz
authors.forename: Felipe
authors.initials: F
authors.lastname: Prosper
authors.forename: Anabel
authors.initials: A
authors.lastname: Heiniger
authors.forename: Antonio
authors.initials: A
authors.lastname: Torres
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis* / Q000235:genetics*; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D016016:Proportional Hazards Models; D015996:Survival Rate; D016896:Treatment Outcome