title: Identification of highly methylated genes across various types of B-cell non-hodgkin lymphoma.
abstract: Epigenetic alterations of gene expression are important in the development of cancer. In this study, we identified genes which are epigenetically altered in major lymphoma types. We used DNA microarray technology to assess changes in gene expression after treatment of 11 lymphoma cell lines with epigenetic drugs. We identified 233 genes with upregulated expression in treated cell lines and with downregulated expression in B-cell lymphoma patient samples (n = 480) when compared to normal B cells (n = 5). The top 30 genes were further analyzed by methylation specific PCR (MSP) in 18 lymphoma cell lines. Seven of the genes were methylated in more than 70% of the cell lines and were further subjected to quantitative MSP in 37 B-cell lymphoma patient samples (diffuse large B-cell lymphoma (activated B-cell like and germinal center B-cell like subtypes), follicular lymphoma and Burkitt`s lymphoma) and normal B lymphocytes from 10 healthy donors. The promoters of DSP, FZD8, KCNH2, and PPP1R14A were methylated in 28%, 67%, 22%, and 78% of the 36 tumor samples, respectively, but not in control samples. Validation using a second series of healthy donor controls (n = 42; normal B cells, peripheral blood mononuclear cells, bone marrow, tonsils and follicular hyperplasia) and fresh-frozen lymphoma biopsies (n = 25), confirmed the results. The DNA methylation biomarker panel consisting of DSP, FZD8, KCNH2, and PPP1R14A was positive in 89% (54/61) of all lymphomas. Receiver operating characteristic analysis to determine the discriminative power between lymphoma and healthy control samples showed a c-statistic of 0.96, indicating a possible role for the biomarker panel in monitoring of lymphoma patients.
authors.affiliation: Department of Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway ; Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway.
authors.forename: Nicole
authors.initials: N
authors.lastname: Bethge
authors.forename: Hilde
authors.initials: H
authors.lastname: Honne
authors.forename: Vera
authors.initials: V
authors.lastname: Hilden
authors.forename: Gunhild
authors.initials: G
authors.lastname: Trøen
authors.forename: Mette
authors.initials: M
authors.lastname: Eknæs
authors.forename: Knut
authors.initials: K
authors.lastname: Liestøl
authors.forename: Harald
authors.initials: H
authors.lastname: Holte
authors.forename: Jan
authors.initials: J
authors.lastname: Delabie
authors.forename: Erlend B
authors.initials: EB
authors.lastname: Smeland
authors.forename: Guro E
authors.initials: GE
authors.lastname: Lind
mesh_terms: D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000235:genetics; D051180:Desmoplakins / Q000235:genetics; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D016393:Lymphoma, B-Cell / Q000235:genetics*; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics*; D009124:Muscle Proteins; D010749:Phosphoprotein Phosphatases / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics
chemical_list: C495294:DSP protein, human; D051180:Desmoplakins; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C529739:Fzd8 protein, human; D047908:Intracellular Signaling Peptides and Proteins; C000606913:KCNH2 protein, human; D009124:Muscle Proteins; C107507:PPP1R14A protein, human; D011956:Receptors, Cell Surface; D010749:Phosphoprotein Phosphatases