Aberrant p15, p16, p53, and DAPK Gene Methylation in Myelomagenesis: Clinical and Prognostic Implications.
Aberrant DNA methylation is considered a crucial mechanism in the pathogenesis of monoclonal gammopathies. We aimed to investigate the contribution of hypermethylation of 4 tumor suppressor genes to the multistep process of myelomagenesis.



The methylation status of p15, p16, p53, and DAPK genes was evaluated in bone marrow samples from 94 patients at diagnosis: monoclonal gammopathy of uncertain significance (MGUS) (n = 48), smoldering multiple myeloma (SMM) (n = 8) and symptomatic multiple myeloma (MM) (n = 38), and from 8 healthy controls by methylation-specific polymerase chain reaction analysis.



Overall, 63% of patients with MM and 39% of patients with MGUS presented at least 1 hypermethylated gene (P < .05). No aberrant methylation was detected in normal bone marrow. The frequency of methylation for individual genes in patients with MGUS, SMM, and MM was p15, 15%, 50%, 21%; p16, 15%, 13%, 32%; p53, 2%, 12,5%, 5%, and DAPK, 19%, 25%, 39%, respectively (P < .05). No correlation was found between aberrant methylation and immunophenotypic markers, cytogenetic features, progression-free survival, and overall survival in patients with MM.



The current study supports a relevant role for p15, p16, and DAPK hypermethylation in the genesis of the plasma cell neoplasm. DAPK hypermethylation also might be an important step in the progression from MGUS to MM.
Clinical Hematology Department, Centro Hospitalar Universitário de Coimbra (CHUC), Coimbra, Portugal; University Clinic of Hematology, Faculty of Medicine, University of Coimbra (FMUC), Coimbra, Portugal; Center of Investigation on Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra (FMUC), Coimbra, Portugal. Electronic address: csantps@fmed.uc.pt.
Catarina
C
Geraldes
Center of Investigation on Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra (FMUC), Coimbra, Portugal; Applied Molecular Biology and University Clinic of Hematology, Faculty of Medicine, University of Coimbra (FMUC), Coimbra, Portugal; Center for Neuroscience and Cell Biology.IBILI (CNC.IBILI), University of Coimbra, Coimbra, Portugal.
Ana Cristina
AC
Gonçalves
Clinical Hematology Department, Centro Hospitalar Universitário de Coimbra (CHUC), Coimbra, Portugal; University Clinic of Hematology, Faculty of Medicine, University of Coimbra (FMUC), Coimbra, Portugal; Center of Investigation on Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra (FMUC), Coimbra, Portugal.
Emília
E
Cortesão
Clinical Hematology Department, Centro Hospitalar Universitário de Coimbra (CHUC), Coimbra, Portugal; University Clinic of Hematology, Faculty of Medicine, University of Coimbra (FMUC), Coimbra, Portugal.
Marta Isabel
MI
Pereira
Clinical Hematology Department, Centro Hospitalar Universitário de Coimbra (CHUC), Coimbra, Portugal.
Adriana
A
Roque
Flow Cytometry Unit, Clinical Pathology Department, Centro Hospitalar Universitário de Coimbra (CHUC), Coimbra, Portugal.
Artur
A
Paiva
Clinical Hematology Department, Centro Hospitalar Universitário de Coimbra (CHUC), Coimbra, Portugal.
Letícia
L
Ribeiro
Center of Investigation on Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra (FMUC), Coimbra, Portugal; University Clinic of Oncology, Faculty of Medicine, University of Coimbra (FMUC), Coimbra, Portugal; Oncology Department, Centro Hospitalar Universitário de Coimbra (CHUC), Coimbra, Portugal.
José Manuel
JM
Nascimento-Costa
Clinical Hematology Department, Centro Hospitalar Universitário de Coimbra (CHUC), Coimbra, Portugal; University Clinic of Hematology, Faculty of Medicine, University of Coimbra (FMUC), Coimbra, Portugal; Center of Investigation on Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra (FMUC), Coimbra, Portugal; Applied Molecular Biology and University Clinic of Hematology, Faculty of Medicine, University of Coimbra (FMUC), Coimbra, Portugal; Center for Neuroscience and Cell Biology.IBILI (CNC.IBILI), University of Coimbra, Coimbra, Portugal.
Ana Bela
AB
Sarmento-Ribeiro
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers; D016022:Case-Control Studies; D002869:Chromosome Aberrations; D018899:CpG Islands; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D019175:DNA Methylation; D064550:Death-Associated Protein Kinases / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000175:diagnosis / Q000235:genetics / Q000401:mortality; D009367:Neoplasm Staging; D010265:Paraproteinemias / Q000097:blood / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D011379:Prognosis; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D015415:Biomarkers; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016159:Tumor Suppressor Protein p53; D064550:Death-Associated Protein Kinases
Epigenetic modifications; Gene expression; Monoclonal gammopathies; Pathogenesis; Tumor suppressor genes