Methylation of the p15(INK4B) gene in myelodysplastic syndrome: it can be detected early at diagnosis or during disease progression and is highly associated with leukaemic transformation

To investigate the time sequence of occurrence of p15(INK4B) gene methylati on in myelodysplastic syndrome (MDS) and its correlation with leukaemic tra nsformation and survival of patients, the methylation status of the p15(INK 4B) promoter region was analysed in 50 patients and was serially studied in 22 of them. Of the 50 patients, 17 (34%) showed p15(INK4B) gene methylatio n, first demonstrated at diagnosis or during follow-up. When FAB subtypes a t the time of study were used in the analysis, the incidence of p15(INK4B) methylation in each risk group of MDS remained stable throughout the course : 0% for low-risk MDS [refractory anaemia (RA) and RA with ring sideroblast s] and from 23% at diagnosis to 30% for high-risk MDS [RA with excess of bl asts (RAEB), RAEB in transformation and chronic myelomonocytic leukaemia] r espectively. The incidence of p15(INK4B) methylation rose to 60% at initial study and, finally, to 75% in cases of acute myeloid leukaemia (AML) evolv ed from MDS. Most patients (69%) with p15(INK4B) methylation showed disease progression to AML; it could be detected before, at the time or after the diagnosis of leukaemic transformation. p15(INK4B) methylation in MDS patien ts implicated a shorter survival time in univariate analyses, but its progn ostic significance disappeared in multivariate analyses. In conclusion, p15 (INK4B) methylation can be detected early at the diagnosis of MDS or acquir ed during disease progression. It may play an important role in the pathoge nesis of some high-risk MDS and is related to leukaemic transformation of M DS.