Epigenetic alterations ofp15^INK4Bandp16^INK4Agenes in pediatric primary myelodysplastic syndrome

Abstract

We studied the methylation status of the p15(INK4B) and p16(INK4A) genes in 47 pediatric patients with primary MDS, its correlation with subtype, and the role of p15(INK4B) and p16(INK4A) in the evolution of MDS toward AML. Aberrant methylation of the p15(INK4B) gene was detected in 15 of 47 patients (32%), whereas only four patients demonstrated methylation of the p16(INK4A) gene (8%). The frequency of p15(INK4B) methylation was significantly higher in RAEB and RAEB-t subtypes (p<0.003). Aberrant methylation of the p16(INK4A) gene was also more frequent in the subtypes that characterize advanced stages of the disease (p<0.05). Evolution of disease was verified in 17 (36%) of the 47 patients. The association of p15(INK4B) and p16(INK4A) methylation status with evolution of disease was clearly significant (p<0.008 and p<0.05, respectively). These results suggest that methylation of the p15(INK4B) and p16(INK4A) genes is an epigenetic biomarker of pediatric disease evolution.

p15INK4b, a Tumor Suppressor in Acute Myeloid Leukemia

“…However, more recently, it was found that even in patients with the RARS subtype, which falls within the lower risk of MDS, p15INK4b was found to be the most frequently methylated gene (>20% of cases) of 25 known tumor suppressors that were evaluated in the study (Valencia et al, 2011). Although most studies have been conducted in MDS in adults, comparable levels of aberrant methylation patterns have been observed in pediatric MDS patients as well (Hasegawa et al, 2005), and a similar correlation with the disease subtypes has been established (Rodrigues et al, 2010). In chronic myelomonocytic leukemia (CMML), aberrant methylation of p15INK4b is found in about 60% of cases and is associated with a high proportion of blastic transformation (Tessema et al, 2003).…”

Epigenetics in Cancer: The Myelodysplastic Syndrome as a Model to Study Epigenetic Alterations as Diagnostic and Prognostic Biomarkers

“…It has been observed the importance of epigenetic alterations in the pathogenesis of MDS, but the majority of these studies is focused in adult patients. Few studies showed the epigenetic alterations in children (Hasegawa et al, 2005;Rodrigues et al, 2010;Vidal et al, 2007). Rodrigues and colleagues, 2010, suggested that methylation of p15 INK4B and p16 INK4A genes are epigenetic alterations in pediatric MDS patients and, as in adult patients, are later events associated with the leukemogenesis process in MDS.…”

“…In fact, it is a correction factor, which is necessary w h e n w e h a v e a s m a l l n u m b e r o f d a t a . T h i s is known as chi-square with continuity Quantitative analysis to evaluate whether there was a correlation between percentage of p15 INK4B methylation and MDS subtypes was performed in (Rodrigues et al, 2010). The percentage of p15 INK4B methylation was higher in RAEB and RAEB-t compared to RC.…”

“…Figure 6 shows comparative survival curves for pediatric and adult patients diagnosed with MDS treated with allogeneic hematopoietic stem cell transplantation (HSCT). In the Rodrigues et al (2010) study, the authors studied the methylation status of the p15 INK4B and p16 INK4A genes in 47 pediatric patients with MDS, its correlation with subtype, and the role of p15 INK4B and p16 INK4A in the evolution of MDS toward AML. The results obtained suggest that methylation of these genes is an epigenetic biomarker of pediatric disease evolution.…”

“…Therefore, the silencing of these genes via aberrant methylation is a critical event in leukaemogenesis. In MDS, aberrant methylation of p15 INK4B gene has been related to more aggressive subtypes of disease and it is a possible biomarker of disease evolution (Quesnel et al, 1998;Rodrigues et al, 2010).…”