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 methylation in myelodysplastic syndrome (MDS) and its correlation with leukaemic transformation and survival of patients, the methylation status of the p15(INK4B) 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 methylation, first demonstrated at diagnosis or during follow-up. When FAB subtypes at the time of study were used in the analysis, the incidence of (p15INK4B) methylation in each risk group of MDS remained stable throughout the course: 0% for low-risk MDS [refractory anaemia (RA) and RA with ring sideroblasts] and from 23% at diagnosis to 30% for high-risk MDS [RA with excess of blasts (RAEB), RAEB in transformation and chronic myelomonocytic leukaemia] respectively. The incidence of p15(INK4B) methylation rose to 60% at initial study and, finally, to 75% in cases of acute myeloid leukaemia (AML) evolved 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 patients implicated a shorter survival time in univariate analyses, but its prognostic significance disappeared in multivariate analyses. In conclusion, p15(INK4B) methylation can be detected early at the diagnosis of MDS or acquired during disease progression. It may play an important role in the pathogenesis of some high-risk MDS and is related to leukaemic transformation of MDS.
Tien
H F
HF
Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. hftd@ha.mc.ntu.edu.tw
Tang
J H
JH
Tsay
W
W
Liu
M C
MC
Lee
F Y
FY
Wang
C H
CH
Chen
Y C
YC
Shen
M C
MC
D000208:Acute Disease; D000753:Anemia, Refractory / Q000235:genetics; D000754:Anemia, Refractory, with Excess of Blasts / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics*; D018797:Cell Cycle Proteins; D016009:Chi-Square Distribution; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D020732:Cytogenetic Analysis; D019175:DNA Methylation; D018450:Disease Progression; D004791:Enzyme Inhibitors; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics; D015477:Leukemia, Myelomonocytic, Chronic / Q000235:genetics; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000401:mortality; D011379:Prognosis; D047428:Protein Kinase Inhibitors; D015996:Survival Rate; D025521:Tumor Suppressor Proteins
C493966:CDKN2B protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D025521:Tumor Suppressor Proteins