title: Methylation of p15INK4B is common, is associated with deletion of genes on chromosome arm 7q and predicts a poor prognosis in therapy-related myelodysplasia and acute myeloid leukemia.
abstract: The p14(ARF), p15(INK4B), and p16(INK4A) genes are important negative cell-cycle regulators often inactivated by deletions, mutations, or hypermethylation in malignancy. Hypermethylation of the three genes was studied in 81 patients with therapy-related myelodysplasia (t-MDS) or acute myeloid leukemia (t-AML) by methylation-specific PCR, and p15 methylation additionally by bisulfite genomic sequencing. In all, 55 patients disclosed p15 methylation, five patients showed p16 methylation, whereas p14 methylation was not observed. Methylation of p15 was closely associated with deletion or loss of chromosome arm 7q (P=0.0006). In t-MDS, the p15 methylation frequency and the p15 methylation density both increased significantly by stage (P=0.004 and 0.0002), and p15 methylation frequency increased with an increasing percentage of myeloblasts in the bone marrow (P=0.006). In a two-variable Cox model including the percentage of myeloblasts, p15 methylation was an independent prognostic factor (P=0.005). Methylation of p15 was less common in t-AML of subtype M5 than in other FAB subtypes (P=0.03). Methylation of p15 was unrelated to type of previous therapy, to latent period from start of therapy, to platelet count, and to p53 mutations. Inactivation of p15 and deletion of genes on chromosome arm 7q possibly cooperate in leukemogenesis.
authors.affiliation: Section of Hematology/Oncology, Cytogenetic Laboratory, Department of Clinical Genetics, Juliane Marie Center, Rigshospitalet, Blegdamsvej, Copenhagen Ø, Denmark.
authors.forename: D H
authors.initials: DH
authors.lastname: Christiansen
authors.forename: M K
authors.initials: MK
authors.lastname: Andersen
authors.forename: J
authors.initials: J
authors.lastname: Pedersen-Bjergaard
mesh_terms: D000208:Acute Disease; D018797:Cell Cycle Proteins / Q000235:genetics*; D002869:Chromosome Aberrations; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics*; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D004791:Enzyme Inhibitors; D005260:Female; D017353:Gene Deletion; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006689:Hodgkin Disease / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D016609:Neoplasms, Second Primary / Q000235:genetics; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D012074:Remission Induction; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics; D025521:Tumor Suppressor Proteins
chemical_list: C493966:CDKN2B protein, human; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D025803:Tumor Suppressor Protein p14ARF; D025521:Tumor Suppressor Proteins