title: DNA methylation analysis of tumor suppressor genes in monoclonal gammopathy of undetermined significance.
abstract: Aberrant DNA methylation is considered an important epigenetic mechanism for gene inactivation. Monoclonal gammopathy of undetermined significance (MGUS) is believed to be a precursor of multiple myeloma (MM). We have analyzed methylation status of p15 INK4B , p16 INK4A , ARF, SOCS-1, p27 KIP1 , RASSF1A, and TP73 genes in bone marrow DNA samples from 21 MGUS and 44 MM patients, in order to determine the role of aberrant promoter methylation as one of the steps involved in the progression of MGUS to MM. Methylation specific polymerase chain reaction assay followed by DNA sequencing of the resulting product was performed. SOCS-1 gene methylation was significantly more frequent in MM (52%) than in MGUS (14%; p=0,006). Methylation frequencies of TP73, ARF, p15 INK4B , p16 INK4A , and RASSF1A were comparable in MGUS: 33%, 29%, 29%, 5%, and 0%, to that observed in MM: 45%, 29%, 32%, 7%, and 2%. All patients lacked methylation at p27 KIP1 gene. In both entities, a concurrent methylation of p15 INK4B and TP73 was observed. The mean methylation index of MGUS was lower (0.16) than that of MM (0.24; p<0.05). Correlations with clinicopathologic characteristics showed a higher mean age in MGUS patients with SOCS-1 methylated (p<0.001); meanwhile in MM, methylation of p15 INK4B was more frequent in males (p=0.009) and IgG isotype (p=0.038). Our findings suggest methylation of TP73, ARF, p15 INK4B , and p16 INK4A as early events in the pathogenesis and development of plasma cell disorders; meanwhile, SOCS-1 methylation would be an important step in the clonal evolution from MGUS to MM.
authors.affiliation: Departamento de Genética, Instituto de Investigaciones, Hematológicas Mariano R. Castex, Academia Nacional de Medicina, J.A. Pacheco de Melo 3081, C1425AUM Buenos Aires, Argentina.
authors.forename: Carmen
authors.initials: C
authors.lastname: Stanganelli
authors.forename: Jorge
authors.initials: J
authors.lastname: Arbelbide
authors.forename: Dorotea Beatriz
authors.initials: DB
authors.lastname: Fantl
authors.forename: Claudia
authors.initials: C
authors.lastname: Corrado
authors.forename: Irma
authors.initials: I
authors.lastname: Slavutsky
mesh_terms: D020727:ADP-Ribosylation Factors / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008998:Monoclonal Gammopathy of Undetermined Significance / Q000235:genetics*; D009101:Multiple Myeloma / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C411762:RASSF1 protein, human; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D020727:ADP-Ribosylation Factors