Detection of hypermethylation in tumor suppressor genes APAF1, ASSP1, p73 and FHIT in childhood acute lymphoblastic leukemia

DOI : http://dx.doi.org/10.4067/S0717-95022013000300033
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Angélica Melo A.; Carmen Gloria Artigas A.; Sergio Muñoz N.; Priscilla Brebi M.; Rene Hoffstetter G. & Juan Carlos Roa S.

Summary

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. It is manifested by a loss of differentiation of lymphoid progenitors, producing an increase of immature cells. Hypermethylation in promoter region of tumor suppressor genes (GST) may produce a gene silencing that provides a leukemic cell a proliferative advantage or prevent apoptosis. We studied the hypermethylation status of 4 GST involved in apoptosis: APAF1, ASPP1, p73 and FHIT and its association with survival of patients <15 years diagnosed with ALL. We analyzed 38 samples of bone marrow by DNA bisulfite modification and chain reaction methylation- specific polymerase (MSP). The mean age at diagnosis was 10 months to 13.8 years. Overall survival was 69% at 5 years. 81.5% of patients had at least one hypermethylated gene. The frequency observed was: APAF1 68.4%, 56.4% FHIT, p73 ASPP1 42% and 18.4%. The association between hypermethylation and group <5 years and ≥5 years was: Global p = 0.20, APAF1 p = 0.03, FHIT p = 0.51, p73 p = 0.51, ASPP1 p = 0.67. Survival curves were calculated by frequency of hypermethylation of each gene: APAF1 p = 0.05, p = 0.31 FHIT, p73 p = 0.98 and ASPP1 p = 0.82. The high frequency of hypermethylation obtained confirms enrollment of methylation in the promoter region of GST in the pathogenesis of ALL. APAF1 gene hypermethylation was very frequent and was significantly associated with survival in the study group, showing this gene as a predictor of poor prognosis in patients with ALL.

KEY WORDS: Hypermethylation; Childhood acute lymphoblastic leukemia; Tumor suppressor genes; p53 target genes; Apoptosis; Survival.

How to cite this article

MELO, A. A.; ARTIGAS, A. C. G.; MUÑOZ, N. S.; BREBI, M. P.; HOFFSTETTER, G. R. & ROA, S. J. C. Detection of hypermethylation in tumor suppressor genes APAF1, ASSP1, p73 and FHIT in childhood acute lymphoblastic leukemia. Int. J. Morphol., 31(3):973-979, 2013.