title: Methylation status of nine tumor suppressor genes in multiple myeloma.
abstract: Aberrant methylation in promoter-associated CpG islands has been recognized as a major mechanism for tumor suppressor gene silencing in several malignancies. We determined the methylation status of nine tumor suppressor genes in 68 newly diagnosed MM patients by methylation-specific PCR. The frequency of promoter hypermethylation for individual genes was: CDH1, 50%; p16 INK4a, 42.8%; p15 INK4b, 16.2%; SHP1, 14.7%; ER and BNIP3, 13.2%; RAR beta, 11.8%; DAPK 5.9%; and MGMT 0%. Overall, 79% of patients presented at least one hypermethylated gene. By univariate analysis, hypermethylation of DAPK (P < 0.001) and RAR beta (P = 0.01) genes were identified as adverse prognostic features. Median OS of patients with hypermethylation in DAPK (4 months) and RAR beta (34 months) was significantly lower than in patients without hypermethylation (median survival not reached), with values of P < 0.001 and P = 0.01, respectively. Our data suggest that DAPK and RAR beta hypermethylation are adverse prognostic factors in MM. The relevance of these findings as poor prognosis indicators requires confirmation in a larger sample with longer follow-ups.
authors.affiliation: Laboratory of Molecular Biology, Bone Marrow Transplantation Center, Instituto Nacional de Câncer, Rio de Janeiro, Brazil. ebraggio@hotmail.com
authors.forename: Esteban
authors.initials: E
authors.lastname: Braggio
authors.forename: Angelo
authors.initials: A
authors.lastname: Maiolino
authors.forename: Maria E
authors.initials: ME
authors.lastname: Gouveia
authors.forename: Roberto
authors.initials: R
authors.lastname: Magalhães
authors.forename: João T
authors.initials: JT
authors.lastname: Souto Filho
authors.forename: Márcia
authors.initials: M
authors.lastname: Garnica
authors.forename: Marcio
authors.initials: M
authors.lastname: Nucci
authors.forename: Ilana Zalcberg
authors.initials: IZ
authors.lastname: Renault
mesh_terms: D000328:Adult; D000368:Aged; D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D015820:Cadherins / Q000235:genetics; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D019175:DNA Methylation / Q000502:physiology*; D015254:DNA Modification Methylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D064550:Death-Associated Protein Kinases; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009101:Multiple Myeloma / Q000235:genetics* / Q000401:mortality*; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000502:physiology; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D011960:Receptors, Estrogen / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; C090121:BNIP3 protein, human; C513384:CDH1 protein, human; D015820:Cadherins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D011960:Receptors, Estrogen; D018168:Receptors, Retinoic Acid; D025521:Tumor Suppressor Proteins; C082925:retinoic acid receptor beta; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D045643:DNA Repair Enzymes